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SOUTHAMPTON ENGLAND BRITISH- AMERICAN TOBACCO COMPANY LIMITED m roll i lib II _J • This r.ont~t~! repot", ~ the Ixol~W of British-Amerca,'ToL~c¢o Compirt, f Lwni|ed. a~¢l must not be co~ed ar shown to unaulhorised persons, ,.J ~.# t.j U~.' BAT Co LTD - MINNESOTA TOBACCO LITIGATION

~IO~ OF Sl40~ ~ ~ F~ 3: 'tHE EFFECT OF C'1~ SHOE]H(; R3~OR~ mO. mD. 3._16~-R J~'~.: JL]r.. cc,~r LZ. Tbot-ncou 12 ~, I2 ._1974 ZSS~D is~z C.I. ,Lyres ]PIKIJXCT JOB 1~0. 19Z Dr. S.J. Groam Dr. Z.V. liuShes Dr. I.&. 8mdc:d KoM. G:Ubb p Ssq. Z.S. Wade, Ksq. I.G. BLcholls, bq. Herr K. Fmct:oz'~ Dr. Y. 8eeho£er &,J. i[."u:zTu.sk£, Esq. Dr. CoJo1Do de S:Lquei=8 D:. D.G. relearn 1~braz? 1rile !1o. ~r COpTNO. 1, 2, 3, 4, 5 m ee (5 *" " 7, II R n 9 " " 10, 11, 12 I* u 13, 1: n w ]..5 u w i.'6 w u 17 *, n 18 w w ~9 u u 2Oi 21 a w 22 qmmmmmm 'mlmeo ~tmmedn -.,..j BAT Co LTD - MINNESOTA TOBACCO LITIGATION

~,aCC l ~r. l~146 a Group Research & Development Centre, Britlsh-American Tobacco Co. Ltd., SOUTHAMPTON. 12th December, 1974 PA~T= 3: THE EFFECT OF CICAR£TT£ ~fOF.TNG (Report No. 2D, i164-K) .... H The effects of c~Karette 8mokLnK on electrical activity in the brain, measured by electroencephalography (EEG), are. being investigated as part of • study of the interactions between the smoker and the c£8aret~e. One index of brain acttTlty vhich hu been measured is the con~nKenc neaative variation (C~q). or expeccan~ wave. The GqV is a slow potential shift ~n the baseline EEG which occurs ~n the interval between two stimuli (such as noises or l~ght fIashes), £f the second one requites a decision or ~Clon by the subject. The meEnltude of the CNV was determined a number of times before and after each subject smoked a cigarette. Some smokers showed m~ increase and others • decrease after they had smoked. This divergence of ~esponse can be interpreted in two different ways. Nicotine (~lich has been assumed to be the main phsrmacolo$ieally active component in s~ke) way act in • bi-phu~c mr, either ~s a st£mulant (CNV ~ncrease) or • depressant (CMV dec=me). Rm~ver, nicot[ne could act only as • st~nulan~ and the direction of chanse in O~V ma81~tuda would depend en~rely on the level of activity in the brain before smoking, 0 ,mumt~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-2- Although the method of analysis of our results is more ~gorous than ~hat used by other workers in this fleld It can be L1proved on by the usa o£ • large computer. This ere complex analysls £$ now bein@ carried out and it is hoped that it rill yleld further si~j~ficant results, which will be reported later. The final results of this and future experLmente may help to elucidate the mode of action of nicotine durlns emoklnl. One ¢uz~rent hypoChes£s is that smokLnS may wss£st some people to Opt/~.se the level of ect£v~cy ~n the brain. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o -.-,.I

-3- L~I~HO DUCT ZON __ e • _ e As part o~ 8 study of the interactions between 8~kers and cigarettes a research progr~nme covering the following areu hu been £o~laCed:- How people smoke. 2. Why smokers smoke. The ef£ecCs of smokin~ end m~ introductory report, descr~b~nK t~e scope of t~ase etudles, has been ~r~£tten (I). The ma~n ~eature of thls work L8 the use of elcctcoeucephaloKraphy ~EG) to determine the level of actlvity in the brain end this report describes a prelin~nary analysis of the ef£ects of smokir~ on a particular aspect of activit7 in rJ3e brain, the continsent neSative variation (CNV), Or expectancy wave. The c~ntlngent negative variation was first demonstrated by Walter et a~1. (2) who eho~ed it Co be a 81ow change in electrical potential over the fronto-~erCical re,Lone of the head, occurz~ng in the period between the cerebral evoked responses to p&Lr8 of 8~mul~, when the second stimulus requires de~s£ou or action by the subject. Evoked ceapouse8 are the chanKe8 in e~eccr~l potential whlch ocau~ in the bra~n when the subject /~ presented w~th eti~ull, such a8 audio or vLeual s£KnaLSo ~n an experiment in vhlch CNV~s are to be recorded the first s~mulus (S1) need noc be of the same type as the second atLnmlu8 ($2). Often the subject i8 required to make a simple motor ceJponse ~ to S2. CMV'8 are shown by abou~ 90Z of adults z they art Lees we~l de£~nad ~n children (3). BAT Co LTD - MINNESOTA TOBACCO LITIGATION O O",, Cr~ O ¢,.a,4

-4- The ~europhys£olog£cal or£K£n of scalp recorded CNV is thought to involve both cortical sad sub-cortical mechanisms. Xc ham been concluded by WalCer (2) ChaC CNV reflects slow elecCrlcal acCLv~Cy Lu the upper layers of the frontal cortex of the bra£n. Rowever, ic has also been found (4) thaC slov negative poCent£als on Ohm cortex result from electrical scimulac£on of the m~d-bra~n recicula: £ormac£on of animals. Attempts co relate the G4V Co psycholoK£cal processes ~ man have ~nd£caCed that ~C is celaCed not only Co expeccsacy bu¢ also to conac£on, moc£vacion, aCcencion and arousal (S) and is no c necessarily conclnsenc q on a motor response (6). NormaLly the evoked response co a stimulus d~cinLshes trLch C£me: this tendency being known as hab£cuaclon. Hc~rever CNVVs are resLsCanc Co hab£cuacion suEsesClu~ thac they represent a special class o£ response (7). The GqV £s noC read£1y seen in ~he EEC o£ most (8el) normal adults (5) and the tachs/qua o£ "averalr, ing", vh:Lch :Ls roucinely emplc~ed :i.u the study c~ evoked brain pot:ent:Lals in man :[.a used tee enhance CHV mnpl~Cude relaClve to background EEG. TC iS normal practice to average beL~een 10 amd 20 CNV's, CgV rosEn/rude can be defLuecl in m number o£ rays | c~e technique is to measure the maximum nesaClve voltage o£ C~7 occuzrln8 between the t~,ro sc£muli. The "C~ max" ave=aSas about 20 ~V (8), ranges £rom 10 ~V Co 50 MV and ham a sl~sadard deviation o£ 8 IJV. Another vey ~ ~'L:J.ch C~V maK'uLtude may be esC:f.met:ed 4s to measure the area uncle: the GfV t:race (9). A. th£rd approach Lnvolves upect:a o£ che~e t:byo met:hods, and the negative ~'o].caSa occurrJ.nK at: vac£ous rime tncervals during the CNV Ls measured. BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0 0

-5- In vie~ of the factors Co which the CNV has been related (e.K. arousal and attenclon) ic would be expected chac mo~e pharmacologically- active aKencs u~KhC have an effect on the magulCude of the C~V. This has been confirmed by a number of experiments (10, 11). AlthouKh the resulr~ are not unequivocal, the Keneral eonclus£on is that ar~mJlants e.g. caffeine, cause an increase in CNV masnitude while depressants e.K. nltrazep~m cause a decrease. It has area been ~eported that carbon monoxLde (at concentrations of 50-150 ppm) can causes decrease in OgV m&n~tude (12). Ashcan ec a_.~l. (11) are the oaly 8~oup known Co have scud]Led the 4 ef£ects of r_LgarecCe smok£nS oa the mazn£cude of the (2~V. They clued that s0ne smokers showed consistent increases, and ochers consLscenc decreases, in C~V mgn£tude inmed£acely after emkinK. These changes were Lnterpreced as re£1ect£nK at£mulant and depressant effects respectively. Coz~alat£ons of she pereentase chm~Ke in CNV maKn£tude with race of u£cot£ne intake, personal£t7 (13) and ~tivac£on (14) were c&le~laCed. The race of n£cotlne in~dce for extraverted smokers was found Co bm slower and assoc£aCed w£th a 8~mulant effect whi1e for £ntroverCed smokers the race was faster md associated wLth a depressant effect. ~eurocic£sm and motivation were not siKnificancly related to ra~e of x~Lcoti~e intake or d£rection of chanKe in C~V mKnicude after emokinK. We have recently completed an experlmmnC in which a group of smokers were subjected to an experimnnCml protocol duz~n8 which GqV's warm obtained before m~d after 8mokinK, mad the prtli~tnau ulye/~s of the ~sult8 i~ descrlbed ~n th£e report. & u~re deta£1ed, computer assured, mnmlys£s of the results will be reported in due course. emmdb ~m cr~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

mm6~ SUBJECTS 30 c£gszette smokers (15 male, 15 £eaale) veze stud£ed in£t£ally. ~hey were a11 members of the Group Research and Development Centre and represented a cross-sectlon of the scarf of the Centre v[ch regard to occupation, age and personality (ms assessed by the Eysenck ~erso~aIity Lnventory (13)). Six further smokers (3 male, 3 £mmale) took part in additional experiments. acc£v£cy was recorded betveen vertex m,d le~C maaCo~d s£tas, usir~ chlorided s£lver sC£ck-on dlm¢ electrodes mad sodium chZor£de gel. The EEC s£gnals vere recorded us£ng an Elema-Schonander PLLngo~caph. The GgV activlcy yes evoked by pa~red audio sisnele vhich were 60 d~ above threshold £or ~se subject. The EEG was recorded on analogue magnatlc Cape £e: subsequent analysis, and on-Line evers~iu8 o£ the CNVes was performed with • laboratory computer (BZONAC 1000). During the £irst part o£ the e~per£uent (last£ng approx/~ateZy &5 m~nutes), the restir~ EFt. audio and visual evoked responses, mud routine C~TVJs wre measured. The second pert o£ the e~perLmJnc 4nvoZved the record/ms of CNV's be/~ore and a~cer 8mokLmS. Zn the routine CLqV 50 pa~z~ o~ sCJJnuX& were delivered at izresula: r.Lme iutecval~. Zn the subsequent (2TV series 20 pa£zs 0£ st~auZ~ vere used. The ~nCezva]Ls between successive S1-82 pa~rs were varied aC random from 3, Co 8 seconds, so Zhac the sc4~ll could not be anclcSpeced by the subject: the interval betveen SI end S2 remained constant at 1.2 seconds. s~mh 0 0 O% BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-7- Before amok/=8, each subject completed three series of C24V'E, scarring ac five n~nuce /nCervals. The subject then 8moked one cigarette, and smok£ng parameters were recozded using the smoki~K analFser (15). When the subject had f~n~had his c~garecte, five series of CNV's were then recorded, asain aC five-mlnuce intervals. Eye movement dur£us the recording o£ (2;V's was mLn£mised by ask£ug subjects ~ flxaCe on the p~pil of one of Chair eyes in a mirror. The average of each series was written out using one channel of the EEG machine. The area of the averaged Q~V was determined by planimetry. The contribution of the eye movement: co the CNV was deceTucLned by a method similar co Chat of Hillyar~ and Calambos (16), and corrected CNVrs were derived. All subjects completed this 8xperlment and smoked a Benson and HedKes K.S.F.T. (TPM delivery 27 ,~, Nicoclne deliver7 1.68 rag). The procedure was repeated d, ree more r~mes for each of four subjects, and the. effects of smoking Capstan ¥uli Strength (Nicotine dellvery 3.2 mE), Boneyrose SpecLal (a herbal cigarette containing no nicotine) and of puffing on an unl£c cigarette were investigated. ~THOD OF ANALYSIS In Chair analysis Aahcon et a.__~l. (II) cla4mmd Chat smoking s4~ificancly changed the masniCude of the G~V, which was decreased in soml subjects and ~creasad in others. They expressed their z~mults as the pIrcantaKe chanle (increase or decrease) between the first pre-smoklng CNV sarles and each CNV series after smokLnK. For our work IC was decided that, in the first instance, smokers would be divided into two groups, chose showinE an increase in the magnitude of the CNV after smoking and those showing a decrease. The s[Eulficance tJ~ O~ C~ C~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-8- of chanles Ln uslnS a modLf£ed 'tv test (WeLch) in which no .assumptions are made about the variance in the senile• (in Students 't' test it is assL~ed t~at the variances in the smnples are equal). Our results were also analysed by a second marA~od: 1~he ::esult~ ware considered on an individual basis and the significance of m~y chart@as in the magnitude of ~hs a~V after smoking was determined. s£Knificance o£ chanKe8 in the mean ~ maj~£tude before and after smok~K was calculated for these two Stoups. RESULTS Fifteen subjects showed an increase in CNV iKnltude after smoking a Benson and Hedges K~S.F.T. cigarette. The mean increase was 38Z~ significant at the 95Z confidence level.T Another fifteen subjects showed a decrease in C~Y magnitude after smoking. However, the mean decrease was only lOZ,and this was not considered to be significant. There was a large mnounc of both inter- and incra-gubjecc variatLon. When the individual results were considered, 13 sets were obtained which showed significant changes in the magnitude of the CgV (confidence level • 86Z). Of these ~3 sets of ~esults. I0 wets for aub~ecCs smoking the s~tndard delivery r.igarecteo For Slx of these there was an increase in nhe magnitude of the ~V, and for three, • decrease. One subject produced signlficant changes on ~o different oct•simms. She shoved an increase in (2tV magnitude after smoking a cigarette wlth about t~ice the aclmdard u£cor.ine delivery (Capstan Full Strength). and in | • e _ T.As complete records were not available .for all subjects, this analysis was res~icted to ~he three CNV'e before smoking and the three CHV's after smokinK. U C7% C~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION