1. Effect Of Cortisol On Event Related Potential Correlates Of Recollection In Healthy Men R.H. McAllister-Williams 1 and M.D. Rugg 2 1 - Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK 2 - Institute of Cognitive Neuroscience, University College London, London, UK 751.8 4.66uV 1.34uV 3.84uV -0.15uV 1.97uV -2.16uV 0.59uV 5.17uV3.28uV -1.46uV 1.17uV -3.39uV Placebo Cortisol 500-800800-11001100-1400 Introduction l Depression is associated with high cortisol and impaired neuropsychological function 1 l Healthy subjects administered glucocorticoids have impaired memory 2,3,4 l Hypotheses F Cortisol administration will reversibly impair source memory (recollection) F This impairment will be associated with attenuated recollection-related ERP activity, especially in right frontal cortex. FZF5 F6 FP2 FP1 T8 C3 C5 TP7 O1 PZ O2 TP8 CZT7 C6 C4 l Study phase F 40 low frequency words (1-7/million) – 20 in male voice, 20 in female voice F Repeat word, then state “pleasant”/“unpleasant”, “active”/“passive” decision based on sex of voice l Test phase (after delay of 5 minutes) F 80 words presented visually F Initial old/new judgement F If old then male/female judgement l Study-test-study-test design l Significant effect of visit on source judgement accuracy(F(1,12) = 9.74, p < 0.01) l Cortisol significantly reduced recognition accuracy on visit 2 (t(6) = 2.62, p < 0.025) l Cortisol significantly speeded response times(F(1,12) = 9.58, p < 0.01) l Words presented on screen for 500 ms l First response ASAP when see word l Second response ASAP when see “?” presented 1000 ms after 1st response l Next trial 1400 ms after 2nd response l EEG recorded from 100ms prior to word presentation to 1400ms post word Methods l 2 way cross over, double blind, random and balanced order experiment in 14 healthy male volunteers l 20mg hydrocortisone/placebo for 7 days F commencing evening of day 1 F finishing morning of day 8 F ERP recordings in afternoon of day 8 l 24 hour urinary free cortisol from a.m. day 7 to a.m. day 8 Behavioural Analysis l Responses categorised as: F ‘Correct rejections’ (CR) - correctly identified new items F ‘False alarms’ (FA) - new items identified as old F ‘Hits’ (H) - correctly identified old items F ‘Misses’ (M) - old items identified as new F ‘Hit/Hits’ (HH) - old items with correct sex judgement F ‘Hit/Misses’ (HM) - old items with incorrect sex judgement l Main focus of interest F recognition probability (pH - pFA) F source judgement probability (pHH/H) ERP Analysis l Words presented on screen for 500 ms l First response ASAP when see word l Second response ASAP when see “?” presented 1000 ms after 1st response l Next trial 1400 ms after 2nd response l EEG recorded from 100ms prior to word presentation to 1400ms post word l The effect of cortisol began around 400 ms after stimuli presentation and was long lasting l The effect of cortisol on correct rejection ERPs was widespread across the scalp (Fig. 4A and D) l There was a relative lack of effect of cortisol on ERPs to hit/hits at frontal sites (Fig 4B and D) l This differential effect of cortisol depending on the nature of the stimuli led to an apparent reduction in the frontal ‘old/new’ effect (Fig 4C and 5) l Sphericalsplinemaps illustrating the scalp topography of the differences between ERPs to hit/hits and correct rejections following placebo and cortisol l Topographic analysis revealed significant drug by site interactions between 500 and 800 ms (F(5.2,67.4) = 2.90, p < 0.025) and 1100 and 1400 ms (F(5.2,68.2) = 2.38, p < 0.05) F Analysis conducted on all sites on HH-CR amplitude difference re- scaled to remove global differences in amplitude l No effect of cortisol on left parietal or right frontal ‘old/new’ effects F subsidiary analysis on lateral parietal sites 500-800ms and lateral frontal sites 1100-1400ms F significant hemisphere by site interactions unmodified by an interaction with drug. Conclusions l Chronic administration of cortisol to healthy subjects causes an impairment in verbal recognition memory and a speeding of response times l The ERP correlates of episodic memory are markedly affected by cortisol F cortisol increased the ERPpositivitywith a differential effect on ERPs elicited by correct rejections and hit/hits F These effects were additive with the ‘left parietal’ and ‘right frontal’ old/new effects l The hypothesis of attenuated old/new component(s) is not supported F Cortisol modulates neural generators distinct from those responsible for the old/new ERP effect References 1.McAllister-Williams R.H., Ferrier I.N., and Young A.H. (1998) Mood and neuropsychological function in depression: the role of corticosteroids and serotonin. Psychol. Med. 28, 573-584. 2.Young A.H., Sahakian B.J., Robbins T.W., and Cowen P.J. (1999) The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharm. 145, 260-266. 3.Newcomer J.W., Selke G., Melson A.K., Hershey T., Craft S., Richards K., and Alderson A.L. (1999) Decreased memory performance in healthy humans induced by stress-level cortisol treatment.Arch. Gen. Psychiatry 56, 527-533. 4.de Quervain D.J.F., Roozendaal B., Nitsch R.M., McGaugh J.L., and Hock C. (2000) Acute cortisone administration impairs retrieval of long-term declarative memory in humans.Nature Neurosci. 3, 313-314. 5. Wilding E.L. and Rugg M.D. (1996) An event-related potential study of recognition memory with and without retrieval of source.Brain 119, 889-905. Acknowledgements Work supported by the Medical Research Council (UK) via aClinican Scientist Fellowship to RHMcAW. MDR is supported by the Wellcome Trust 1 2 3 4 5 AB CD l EEG sampling time-locked to onset of each word at test F 29 scalp electrodes (red + blue) F referenced to left mastoid, re- referenced off-line to linked mastoids F band width 0.03 - 35 Hz F blink corrected using VEOG F Post-hoc analysis used 6 red sites to examine ant/post and left/right differences l ERPs following placebo demonstrate the same ‘old/new’ effects as previously reported 5 F Significant response (CRvsHH) by ant./post. by hemisphere interaction 500-800 ms post stimuli (F(1,13) = 13.13, p < 0.005) due to left parietal positivityof ERPs for hit/hits relative to correct rejections F Significant response(CRvsHH) by ant./post. by hemisphere interaction 11-1400 ms post stimuli (F(1,13) = 15.70, p < 0.005) due to right frontal positivity of ERPs for hit/hits relative to correct rejections l Cortisol significantly modulated memory-related ERP effects F Significant drug by response (CRvsHH) by ant./post. interaction 500- 800 ms post stimuli (F(1,13 = 7.42, p < 0.025) F Significant drug by response (CRvsHH) by ant./post. interaction 800- 1100 ms post stimuli (F(1,13 = 5.02, p < 0.05) F Significant drug by response (CRvsHH) interaction 1100-1400 ms post stimuli (F(1,13 = 6.12, p < 0.05)