Psychopharmacology (2000) 152:87–92 DOI 10.1007/s002130000528

O R I G I N A L I N V E S T I G AT I O N

C. Heather Ashton · Brian Lunn · V. Richard Marsh Allan H. Young

Subchronic hydrocortisone treatment alters auditory evoked potentials in normal subjects Received: 6 March 2000 / Accepted: 19 June 2000 / Published online: 28 July 2000 © Springer-Verlag 2000

Abstract Rationale: Abnormalities of cortical evoked potentials and background electroencephalographic (EEG) frequencies occur in several psychiatric disorders, some of which, especially depression, are associated with hypercortisolaemia. However, there have been few investigations of the effects of exogenously administered cortisol on waking EEG measures. Objectives: To examine the effects of subchronic hydrocortisone administration on auditory evoked potentials and background EEG activity. Methods: Hydrocortisone, 20 mg twice daily, or placebo was administered to 30 normal male volunteers for 7 days in a between-subjects, double-blind trial. Auditory evoked potentials and EEG frequencies were measured on the last day. Results: Hydrocortisone significantly increased the amplitudes of the N1P2 and P300 components of the auditory evoked response, but there was no change in background EEG. Conclusion: The results indicate that subchronic hydrocortisone treatment in normal subjects increases the amplitude of auditory evoked potentials, possibly reflecting a central alerting effect. Key words Hydrocortisone · Normal volunteers · Electroencephalogram (EEG) · Auditory evoked potential · P300 · Background EEG frequencies

also been reported to be present in these disorders, especially in depression (Murphy 1991), but there have been few investigations of the effects of corticosteroids on the waking EEG, despite observations that they alter sleep EEG measures (Young et al. 1994). The aim of the present study was to examine the effects of subchronic administration of hydrocortisone on the waking EEG. We hypothesised that this procedure would reproduce some of the abnormalities found in patients with depression.

Materials and methods Subjects The study employed a between-subjects, placebo-controlled, double-blind design. This design was chosen to avoid long-lasting carry-over effects of hydrocortisone treatment. The subjects were 30 healthy male volunteers aged 19–36 years recruited by local advertisement. Exclusion criteria were present or past history of medical or psychiatric disorder and psychiatric disorder in firstdegree relatives. Subjects were screened for depression with the Beck depression inventory (BDI; Beck et al. 1961) and the profile of mood states (POMS; McNair et al. 1992), and IQ was measured by the national adult reading test (NART; Nelson 1982). Participants were randomly allocated to take hydrocortisone or placebo. All participants gave written informed consent and the study was approved by the Joint Ethics Committee, Newcastle and North Tyneside Health Authority.

Introduction

Procedure

Abnormalities in evoked potentials and background electroencephalographic (EEG) activity have been described in many psychiatric conditions including depression, bipolar affective disorder, schizophrenia and Alzheimer’s disease (Shagass et al. 1978; Roth et al. 1981; Pfefferbaum et al. 1984, 1985). Hypercortisolaemia has

The active drug group (n=16) received 20 mg hydrocortisone orally twice daily (8 a.m. and 10 p.m.) for 7 days. This regimen has been shown to elevate urinary cortisol in normal subjects to levels similar to those found in depressive illness [urinary cortisol levels mean (SE): after hydrocortisone 524 nmol/24 h (56.3); after placebo 171 nmol/24 h (23); Young et al. 1994, 1999]. The placebo group (n=14) took placebo twice daily for 7 days. EEG recording took place on the last day of treatment.

C.H. Ashton · B. Lunn · V.R. Marsh · A.H. Young (✉) Department of Psychiatry, School of Neuroscience and Psychiatry, University of Newcastle, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK e-mail: [email protected] Tel.: +44-191-2227582, Fax: +44-191-2275108

EEG recording EEG recordings were carried out in the morning with each session lasting about 1 h. The EEG was recorded from silver/silver chloride gel-filled electrodes from 11 sites: F5, Fz, F6, T3, Cz, T4, T5, Pz,

88 Fig. 1a,b Grand means of auditory evoked potentials recorded from vertex (Cz ) electrode in hydrocortisone and placebo groups. a Response to frequent unattended tones. b Response to infrequent target tones. A significant increase was found in N1P2 and P300 amplitude in hydrocortisone group compared with placebo group (see Table 1 for statistics)

T6, 01 and 02, all referred to linked mastoids. Electrode impedances were <0.2KΩ. EEG signals were amplified by a Synamps amplifier system connected to a NeuroScan operating system. Eye movement compensation was derived from nasion-linked mastoid electrodes. Any sections of the EEG still contaminated with eye movements, muscle activity or other artefacts were excluded from analysis. Evoked potentials and power frequency spectra were recorded. The evoked potentials included contingent negative variation (CNV) with associated reaction time and postimperative negative variation (PINV) and a standard two stimulus “oddball” auditory P300 measure using procedures described previously (Dahabra et al. 1998; see Fig. 1). The power frequency spectrum of the resting EEG was calculated by fast Fourier transform (NeuroScan 4 Workstation) of the average of 25.2 s continuous epochs of EEG activity, eyes open and eyes closed, over the frequency range 0.5–22 Hz in 0.45-Hz steps. Total power was expressed in µV2/Hz in the delta (0.5–3.9 Hz), theta (4–7.9 Hz), alpha (8–14 Hz) and beta (14.1–22 Hz) frequency bands.

Data analysis Evoked potential and spectral power measurements from each of the 11 electrode sites in the two groups were compared using the Minitab program (PC version 10.2). The Anderson-Darling test was used to confirm a normal distribution and the differences between groups were computed using one-way ANOVA. For topographical brain mapping of power spectra, mean EEG power (obtained from grand means of the active drug and placebo groups) at each frequency interval of 0.45 Hz across the frequency spectrum of 0.5–22 Hz and at each electrode were compared between the two treatments. Using the NeuroScan program “Window”, which is based on a linear algorithm linking an individual electrode with its four nearest neighbours, t values at each electrode site in each frequency band (delta, theta, alpha, beta) were mapped over the surface of the skull.

89 Table 1 Auditory evoked potentials Auditory evoked responses

Hydrocortisone (n=16)

Placebo (n=14)

Mean

(SD)

Mean

(SD)

F

P

N1P2 amplitude (µV) (frequent tones: unattended) 10.12 Fz Cz 13.17 Pz 10.63 T3 7.54 T4 7.71

(3.48) (4.27) (3.72) (2.47) (2.92)

7.62 9.39 7.92 5.91 5.78

(2.07) (2.47) (2.69) (1.64) (2.38)

5.56 8.47 5.82 4.36 3.88

0.026 0.007 0.023 0.046 0.059

N1P2 amplitude (µV) (rare tones: attended) 11.84 Fz Cz 15.40 Pz 13.54 T3 9.13 T4 8.81

(4.09) (5.13) (3.97) (3.11) (3.29)

10.30 12.87 10.95 6.99 7.82

(3.18) (3.03) (3.29) (2.16) (3.02)

1.29 2.39 3.74 4.69 0.72

0.265 0.133 0.063 0.039 0.402

P300 amplitude (µV) Fz Cz Pz T3 T4 T5 T6

(4.40) (5.48) (5.28) (4.14) (6.20) (4.39) (3.87)

8.00 9.04 8.99 8.26 7.34 8.15 6.99

(3.07) (4.81) (4.75) (3.78) (3.03) (3.50) (3.48)

5.44 6.92 5.47 3.20 4.14 4.40 8.58

0.027 0.014 0.027 0.085 0.051 0.045 0.007

11.28 14.03 13.30 10.87 11.06 11.22 10.95

Results The placebo and active treatment groups were well matched with no significant difference [mean (SD): hydrocortisone (n=16); placebo (n=14)] for age [24.38 (3.83); 21.64 (2.87)], IQ [110.53 (8.44); 108.14 (5.29)], BDI [3.56 (2.61); 3.71 (2.73)] and POMS [1.62 (4.78); 1.64 (3.35)]. No difference was found on any subscale of the POMS (data not shown). The main results are shown in Table 1. There were no differences between groups for reaction time, or for CNV or PINV at any electrode site. However, significant differences between groups were evident in the auditory evoked potentials (AEPs). Subjects taking hydrocortisone had significantly greater amplitudes of the N1P2 response to frequent tones and larger P300 amplitudes in response to rare tones than subjects taking placebo. The differences were evident centrally (Fz, Cz, Pz) and at temporal (T3, T4, T5, T6) sites (Table 1). The differences shown at Cz are displayed graphically in Fig. 1. There were no significant differences in the latencies of N1, P2 or P300 components. Analysis of spectral power showed no significant differences between groups at any wave band (delta, theta, alpha, beta) at any electrode site. This was confirmed by the absence of significant differences between groups in the quantitative power spectral brain maps.

Discussion This is the first study to investigate the effect of subchronically administered hydrocortisone on the waking

Difference (ANOVA)

EEG in normal subjects. The results show that 7 days treatment with hydrocortisone increased the amplitude of the late components, N1P2 and P300 of the AEP, indicating an enhanced response to auditory stimuli, an alerting effect. Born et al. (1987) investigated the effects of acute administration of hydrocortisone on the AEP in normal subjects. Intravenous infusion of 16 mg hydrocortisone over 2 h resulted in a slightly decreased amplitude of the N1 and mismatch negativity components of the AEP compared to placebo infusion. It was concluded that hydrocortisone had an inhibitory action on sensory stimulus processing. However, in a later investigation (Born et al. 1989), in which higher doses of hydrocortisone (20 and 40 mg) were infused, it was found that enhanced plasma cortisol levels were related to increased amplitude of the N1 and P2 components. Furthermore, higher levels of cortisol augmented self-reports of concentration and reduced subjective tiredness in an auditory vigilance task. These results suggest that cortisol may exert biphasic effects, with higher doses having an excitatory influence on cortical arousal. The acute effects of corticotrophin releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH) fragments on AEPs have been studied. For example, Hartmann et al. (1996) found that both CRH (100 µg), which raises plasma cortisol concentrations, and ACTH 4–9 (300 µg), which does not, infused intravenously on separate days in normal subjects decreased N1 latency and increased P2 amplitude. However, the results of other studies with CRH and ACTH fragments have been mixed, with various authors finding either increases

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or decreases or no effect on N1 and P2 latencies or amplitudes (Rockstroh et al. 1981, 1983; Born et al. 1984, 1990, 1991; Fehm and Born 1987). There are few studies of the effect of cortisol or other hormones on the P300 component. Born et al. (1987) found no significant change after an infusion of 16 mg hydrocortisone and a recent review of the neurochemical substrates of the P300 (Frodl-Bauch et al. 1999) does not mention hypothalamic-pituitary-adrenal (HPA) axis hormones. Nevertheless most investigators are in agreement that HPA hormones modulate sensory and cognitive processing and may contribute to the neurophysiological changes found in psychiatric disorders. Some studies have examined correlations between endogenous cortisol concentrations and background EEG activity. Chapotot et al. (1998) measured the relation between EEG beta activity (absolute power density in the 13–35 Hz range), taken as an index of alertness, and cortisol secretion rate in healthy male subjects during a day of bed rest following an 8-h night-time sleep. Analysis revealed a significant positive correlation between fluctuating cortisol secretory rate and EEG beta activity. However, there was a temporal dissociation in that increases in beta activity were followed after a delay of 10 min with increases in cortisol secretory activity. The results were interpreted as indicating that daytime cortisol secretion is related, though not directly, to brain activation processes. Evoked potentials and other EEG rhythms (delta, theta, alpha) were not measured in this study, although the same group (Gronfier et al. 1998) showed that delta activity during sleep was independent of cortisol secretion rates. The lack of difference in beta activity between hydrocortisone and placebo treatments in the present study could have been due to the different experimental procedures. Nevertheless, the present finding of increased AEP amplitudes are consistent with an alerting effect of hydrocortisone. Sannita et al. (1999) measured alpha (6.5–14.0 Hz) power in the waking EEG, taken in resting conditions, of normal subjects selected for prominent alpha activity. Recordings were made over a 6-h period during which blood concentrations of cortisol, glucose and ACTH were monitored. They found no correlations between alpha power and cortisol or glucose concentrations, but an inverted U-shaped correlation with ACTH concentration. Power in other EEG frequencies, delta and theta (0.5–6.0 Hz) and beta (14–5-32 Hz) was also measured and showed no correlations with ACTH or cortisol concentrations. The apparent lack of effect of cortisol concentration with beta activity as observed by Chapotot et al. (1998) may have been due to different experimental conditions, but is consistent with the present study. Several studies have shown that raised corticosteroid levels, whether stress-induced (Kirschbaum et al. 1996), age-related (Lupien et al. 1994), associated with Cushing’s disease or depression (Wolkowitz et al. 1990) or following cortisol or dexamethasone administration (Wolkowitz et al. 1990; Newcomer et al. 1994; Kirschbaum et al. 1996; Young et al. 1999), are associated with

cognitive impairments, especially deficits in explicit memory. Young et al. (1999), using the same regimen of subchronic hydrocortisone administration as the present study, found that the treatment caused impaired performance in visuospatial memory tests in normal volunteers. In view of these findings, it might be expected that hydrocortisone would prolong the latency of the P300 (a cognitive potential associated with information processing) and perhaps decrease the amplitude of the AEPs. However, Young et al. (1999) also noted that hydrocortisone speeded response latencies in certain cognitive tests (pattern and spatial recognition), and the present finding of increased auditory potential amplitudes may reflect this aspect of the cognitive response. De Kloet et al. (1999) have pointed out that corticosteroids, which play a role in various stages of information processing, do not necessarily disrupt memory, but are normally involved in adapting behaviours towards those most relevant to the situation. The observed increase in evoked potential amplitudes may be part of such an adaptive response. It is possible that chronically raised cortisol levels could contribute to the EEG abnormalities found in depression and other psychiatric disorders. Studies of evoked potentials in depression have yielded inconsistent results. In depressed patients decreased amplitudes of N1P2 components of auditory and visual responses, which increased on clinical recovery, were reported by several authors (Shagass et al. 1978, 1985; Giedke et al. 1980; Roth et al. 1981; Ashton et al. 1988, 1994). Others found no reliable differences from controls (Buchsbaum et al. 1971, 1973, 1981; Satterfield 1972). In contrast, Vandoolaeghe et al. (1998) found increased P2 amplitudes in depressed patients, especially in non-responders to treatment, compared to controls. Friedman and Meares (1979) and Friedman et al. (1980) also found that N1P2 AEP components were greater during depression and decreased after clinical recovery following treatment with either placebo or tricyclic antidepressants. The literature concerning the P300 components of evoked potentials in depression is also conflicting. Some authors report a decrease in P300 amplitude which increases on clinical recovery, but no change in P300 latency, compared with controls (Pfefferbaum et al. 1984, 1985; Blackwood et al. 1987; Muir et al. 1991; Gangadhar et al. 1993; Hansenne et al. 1994; Yanai et al. 1997). However, Hendrikson et al. (1979), Kalayam (1997) and Vandoolaeghe et al. (1998) reported an increase in P300 latency in non-demented depressed patients. Dahabra et al. (1998) found prolonged auditory P300 latencies but no change in amplitude in elderly patients who were clinically recovered from depression compared with age-matched controls. Previously reported EEG changes in psychiatric disorders have not been related to plasma cortisol levels. It is likely that cortisol is only one of many factors contributing to abnormalities in EEG measures, as well as mood and neurocognitive performance, and that its effects are biphasic depending on concentration. The present findings that subchronic treatment with hydrocortisone in-

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creased AEP amplitudes in normal subjects suggest that electrophysiological abnormalities found in depression are not directly related to alterations in cortisol levels. However, further studies relating EEG measures to chronically raised cortisol concentrations in depressed patients are needed. Acknowledgements We thank Margaret Cheek and Anne Stals for assistance with preparation of the manuscript.

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