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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

-9- a decrease after simulated smok£nK. One ocher Subject showed • signi££canc change after simulated smok£ne. The ind£vidmsl results for some of ~he subjects u~ho smoked Benson and Hedges K.S.F.T. are shown in Table 1. 411 thee• results show chanKes in C~V mag~n£tude agter smoking, which are s£~a£flcant at the 90Z cong£dence level or above. Chanee (X) S£gni£icanee Leve I tAm . , r UDES AND k" R_moKn c q °Kout~.ne 1 2 3 1 2 3 4 5 Ch'V's (arbitrary m~ta of area) A B D E 61..5 72.6 71.9 67.6 .52.8 50.5 59.8 4.2 25.5 -44 95Z 66.5 78.8 86.3 8.5.6 69.5 62.0 74.1 10.4 4.0 C 110.4 103.2 107.6 128.6 132.0 114.6 'JL~,O. 6 123.8 127.8 +12 93[ 77.7 54.2 38.2 64.2 74.3 74.9 81.3 76.6 90.9 +36 90% 116.1 82.9 87.0 96.8 94.4 125.5 110.8 11.5.9 129.7 +20 91% F = . -20.8 -).5.8 -40.1 +24.5 1.9.5 2..5. A 37.6 A6..5 -8.1 1 93% t" The ganges for this subject cannot: be cmleulmCed in the same way as the others since some of the CNV's are reeKer:ire. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O O% O%

-I0- For the rema£n~nK subjects, the chanKes in aqV vere not statistically siKn~f~cant, as defined by the method of analysis used. However, vhen the CNV results are ~malysed by computer-asslsted methods, it ks possible Chac add£t£onal sets o£ statistically sisnificant changes will be established. since it should be possLble to completely elim4naCe the Kross effects of eye mew~nt. Dzscussz(~ It has been known for some c£me chmc eye mov~ncs durins the time in vhich the CNV is beins produced can severely contm~nate the record£nss obtained (16)o. This is caused by an electrical potential across the back of the retina, which is detected by the electrodes used to record the ~V. It has been d4monstrmcsd that involtmCary eye movements durLng the interst£mulus interval conslsCently Keuerated an artifactual, vertex- neF~stlve field, havens 8 ~me course resembling that o£ the ~ (19)o Although eye movenmnt can be m~nimtsed by •skin8 subjects to fines on a spot, blinkir~ may still occur, and contamination of the ~Y record£nK is st£11 • problem. In order to try and compensate for this ve have applied • correction ~ each CNV result obtained° This approach was eu~ested by Dr. C~o Binnie (the neurophyslolo~cal consultant to Group R. & D. Centre) s and ~s bued o~ the method of IL~llyard and Gel•robes (16). The area trader the t~ace representlnK eye movement potentials eas muursd and d~vided by a factor of ~hre• (mince, on Iv•raKe, only one ch~rd of ohm total activity due co my@ movement is expected to be detectable ac the electrodes usad for ~rV recording). This number was then added to or subtracted from ~lle area under the C~V trace, as ~proprimte. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O',, c~

-11- This type of cortect£on ks, of nacess~ty, £a£rly crude but it was considered that results obtained in Ch£s ray would be of value. Ashton et a.__~. (II) assumed that any eye movements would be el•Liar before end a£cer smoklng ~z~d, consequently, did noc attempt Co correct Chelr results for eye movement artefact. Tecta and Rm~lton (17). studyinK the effects of mmphetm~Lne showed that, even o~e ot t~o houc8 a~ter druK adm£uLscratlou, subjects 8hc~ed £e~er eyeblinks ~d ocher eye movement arte£sct8 andwere able to fixate on • spot luch more easily than before treatment. Zt has a18o been reported chac ,4~azepam (Val£,~) may cause z~ductlon in eye movements (18). Our scudles sho~ chac eye movements may be greatly affected by smokin& and an example of the results obtained for one subject Ls ~ven (Table 2). The ef£ecC of smoking on eye movement is discussed in more decaL1 in the Appendix to this report. TABLE 2 ~LE_ OF_ _C~IANGES,, _ _ ]lq. EYE MOVEI~ENT A.RTEFACT ]BEF,OKE _AND AFT..ER' SD4OI~,C " Be£ore Smoking Eye Hovement Artefact CNV 1 12.07 71.5 2 75.73 53.3 3 54.07 6.7 in , L t am m, _ j /, -17.9 83.7 $ -23.1 64.9 6 -23.7 84.5 7 -11.4 70.5 8 -5.6 65.6 7or both the Eye Movement Artefact end the C~7 the chanees are 8isnifiem~t at the 951 confidence level. BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0'%

-12- The correction of our ~qV mlasura~nts ~or eye movezmnt arte£ac~ has resulted in several negative results. The meaning of these is not clear since the way in which the CNV's are drawn demands Chat a cont~ent neKatlve variation be represented by a posLtlve number. When the complex computer-assisted amalysie of the EEC records of o~r subjects is completed it is ~nltkely that snomal£as of this nature will arise. The negative results are probably due to large corrections being applied, based on traces obtained from the BTO~h~C laboratory computer vhich was not calibrated £oz larks voltales. This vould cause inaccuracies in the results obta£ned. In the computer .analysis, however, any CNV's which ere ~rossly contaminated vith eye movement potentials can be rejected, and the zemain/~@ responses averaKed. Our work shows chac smokins can cause • chats• in the CNV magn£tude of dif£erent individuals. For the majority of our subjects ~4ho shoved a sCatlstically sIsnlf£cant charge, th~s was an /zscrease. These results are slm£1ar to chose reported by Ashcon ec a..._.1. Our zesults, however, are less statlstlcally s~snlfLcant than Chelrs. Ashton et a__.__~ll, have cl~med, in addition, chat pu££inK on an ux, lit clEar•tie had no ef£ect on CNV maKnitude, vherees we have shown that this can a~fect some Lndivlduals. The inched of estlmating the magnitude o£ the CgV's was si~Llar in both st~d£es, except tha~ ve have corrected for eye ~ve~nc ar~afsccs. We therefore believe chat the zssults of Ashton et a._.~l, can only be realls~ically considered as demons~rat£ns the eg£ects of s~ok£n~ on the comb£ned ma~n£tudes o£ the CNV and o£ rye movement potential. Consequently it eppure that their conclusions should be created ~ith conslde~able caution. cr~ CF~ C7~ CO BAT Co LTD - MINNESOTA TOBACCO LITIGATION

t~ish ! L~ AJhCon eC 81. (11) interpreted the chmnKes £n ~ maKn£Cude miter smoking as being due co nlcoc£ne, acting either as • stimulant or • depressant, the unde of acclon varying from person to person. However Tecce and HamiZCon have proposed • tyo-process mdel (17) co account. for changes ~ ~ m~itude (Figure 2). TIGU1~ 2 TWO-PROCESS MODEL slsh Low H~gh ATTENTION High AROUSAL Zn this model it is assumed that the ms6nitude of CNV has • positive relationship with attenClon to the second sc/mulus ($2). Attention is considered Co be a process ~hlch £•cilltates the selection of relevant sC:l~aaul4 from the internal or external envlrou~ent, Co r_he exclualon of :£z'~'elevant stium14. Arousal ~ be viewed as a process th&C enerJliSeS behaviour unselectively and mffects only the intensity o£ response. It is possible to combine these two processes m,d advance the hypothesis that attention improves with increased arousal up to an optimum level and becomes impaired rich further physiological activation. The ~mplicac£on BAT Co LTD - MINNESOTA TOBACCO LITIGATION O t...rl O ClO

-14- (4) that the zet£culer foz~acion of the brain, (which is £mportm~t for the functions of wakefulness m~d alertness (20)), is ~nvolved in the :@enesls of the C~V is consistent wlch this ~o process Cheoret4cal mode2. The use of Tecee'e m~del sugKeecs, as an aXternative to Ashton's hTpothes4s, the follov£nK ~nterpreCat£on of the effect of suok4ns on the CNV. For ~e majority of our subjects the statis~cally s£~=icant change in the maKn~cude of oqv observed afCez mmok~nK was ~n increase: for these subjects £c follows Chac smoking £s mctinK as a stimulant, w~th the ~pllcat£on that these subjects were in 8 :elatlvely low, or normal, state of arousal before smok4ng. For may subjects vho vere in a high state of arousaZ before smok£ns, a decreaJe in C~V magnitude would be expected a~tez mmok4n8 (assun~ng Chat emok~nK acts as a stimulant, the h48h state of arousal vould be further ~ncreased). A1ternat~vely a decreaJe i~ the maKnltude of ehe C~TV ~ould occur 4f the subjects became bo=ed and pve less actenC£0n to the S2 sisnal. Two subjects showed e4Kni£icanC changes 4n C~V maKn~tude a~te~ 84m~lated smoking. These results may be explained Lf puff~z~ on an unlit c~garetce chanKes the level of arousal, by psycholog4cal rather than by pharmacolos£cel means. When the present zesults have been analysed in more detail it m~y be possible to decide between the poes£bil£~e8 discussed above (i.e. ~dtecher ~4cot£tte shows m~-phaeic oz b~-phas~e properties). It £s hoped that the validity of Teece's model in the smoking siCuaClon can be tested more thorouShly by conslderat~on of the data re~at£uK to the resCln8 EEC, the subject:' personellCy and 8mokLr~ behav£our. BAT Co LTD - MINNESOTA TOBACCO LITIGATION O ¢.j'1

-15- $wklng Behavi, our A~ already ment£oued, Ashton et a l, (ll) found that r.heir more txtraverted subjects showed ~ :Lnccemse in C~TV ma~tude aisoc~ated with a slow nlcoClne intake, whereas their more introverted sub~ecCs shoved a decrease in CNV magnitude associated wlch a faster nicotine intake.. We therefore decided to examine the smoking dace obtained previously for the I0 subjects who showed sceC£stically SignLflcanc changes in CNV magnitude after smoking a Benson and Hedges K.S.F.T. The dace are shown in Table 3. In vLew of the small number of subjects whose C~V chm~es are signiflcant, no firm conclusions can be dra~n from Table 3. However, the results suggest that there is no relationship between smoking bchavlour and direction of Ch'V change. If this result 4s cqnfix~med in r.ha more detailed ~alysis, it will be i~ con£1£cc with the £ind£n~ of Ashton et al. mmmammammm Xt ks also proposed Co examine the relationship between personality and direction of CNV changer thle and a knowledEe of the subjects' smokin~ behavlour may enable us to sec up a model in which varfous clusters of smokers nay be dis~nKuished,. ,S~,Z)K~O PAPJ~ETEP~ Average £or 7 subjects showing an increase in 466 CgV msuituda AversEe for 3 subjects showlng 8 decrease 4. 499 (2IV mgn~tude Averase of all subjects Cakina. part in the 503 experiment Total Volumm of Smoke (mr) TLme A1LSht (,sus) 395 #2O 367 Smoke (ml/sac) 1.18 1.19 1.37 BAT Co LTD - MINNESOTA TOBACCO LITIGATION CO

-16- REFERENCES J | I. B-A.T. Report No. RD. IISO-R, 3.10.74. 2. Walter, W.G.~ Cooperp Ro, ~dr£dge, VoJ.p NcCallum, W.C. and Winter, A.L. "Contingent Ne~jative Variationz An Electric Sign of Sansory~4otor Association and Expectancy in Cbe Human Brain". Nature, 203, 380, 1954, 3. Low, }i.D. and StoLlen, L. '~NV and ~DG in Children; Haturatlonal Characteristics and Findings in the HCD Syndrome". Electroenceph. clin. Neurophyslol., Suppl., 33, 139, 1973. Axduin£, A., Hancia, H., Hechelse, K. "Slow l~tential G~anges Elicited in the Cerebral Cortex by Sensory &nd ~tlcular Stimulation,. Arch. Ital. Biol., 95, L28, 1957. Tecce, J.J. "Contingent Negative Variation and Lndividual Differences". A=ch. Gen. Psychiat., 24, 1, 1971. Donchin, E., Gerbrandc, L.A., Lei£er, L. and Tucker, L. "Is the ContinKent NeKat~ve Var£ation cootinKent on a Motor Response?". Psychophysiolo~y, 9, C2), 178, 1972. Otto, D.A. and Lei£ec, L.A. t'~e ~f~ect o£ ~di£yin8 ~asponsa and Performance Feedback Parameters on the CNV An Humans','. Electroenceph. clin. Naurophysiol., Suppl., 33, 29, 1973. Walter, W.G. "Slow Potential Chanses in the Human Braln associated with Expectancy, Decision and InCention". Cobb, W., Nogucuttl, C. (F~s.) ~ie Evoked Potentlalsp Amsterdam, Elsevier PublishinK Co., 1967, pp. 123-130. Low, H.D., HcSharry, J.W. "F~ztber Observations of PsycboloKical Factors involved in CNV Genesls". Elmctroancaph. clln. Neu~ophysiol., 2~5, 203, 1968. ~o ~o e v o 9o 8AT Co LTD - MINNESOTA TOBACCO LITIGATION C~ C~ O C~ C~

-17- IO. Dongler, M. NClinieal Applications of the CNV". Electroenceph. olin. Neurophysiol. Suppl., 33, 309, 1973. 11. Ashcon, 14., Idillman, J.E., Telford, R. and Thompson, J.W. "The Effect of Caffeine, N£erazepam and Cigare=ee Smok£ng on the Contingent Negative Variation ~n Man". Elactroenctph. clin. Heurophysiol., 37, 59, 1974. 12. Groll-Knapp, E. "Effects of Low Carbon }~uoxlde Concentration on ViKilance and C~puter Analysed Bra~n Potentials". St&ub-~IxLh&It., 32, 60, 1972. 13. Eyeenck, H.J. and Eyeenck, S.B.G. '*Eysenck Personality IJaventory'. University o£ London Press, London, 1972, 14. Lynn, R. "An Achievement M~tlvanion Questionnaire'~. Brit. J. Psycho1., 60, 529, 1969. 15. B-&.T. Report No. RD.11Og-R, 7.6.74. 16. Hillyard, S.&. and Calambos, R. "Eye Movement Artefact in the C~4V". Electroenceph. olin. Neurophyeiol., 28, 173, 1970. 17. Tecta, J.J. and Hamilton, B.T. "CNV Reduction by Sustained Cosniclve Activity (Distraction)". Electroenceph. clin. Neurophysio1,, Suppl., 3~3, 229, 1971. 18. BroughCon, E., Mier-Ewert, K. and Ebe, M. "Visual and Somato-Sensory Evoked Potentials of Photosensitive Epileptic Subjects durln8 Wakefulness, Sleep and £ollowin$ £.v. Diezepam (Valium)':. ElecCzoeuceph. ~l~n. Neurophys£ol., Suppl., 21, 619, 1966. 19. Low, M.D. et el.."Neurololy"(~L~nneap.). 16, 771, 1966. 20. Ho=uzz~, G. and Maf;oun, H.W. "E=ain Stem P4t£cular ¥orsmt£on and Act:ivation of the EEG". Elactroencaph. c11n, Neurophyglol., 1, 455, 1949. 0 C2~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

-18- The effect of smoking o~ eye-movement i8 illustrated in Figures 3-7. These flguces show the changes in electrlcal potentlal due to eye movement, for me subject, under a vaciecy of conditions. The chanses ace reTaced to eye m~vement potenClal recorded durin8 the ~rst pre-smoklng CNV ~n. The results are expressed as a percentage change relative to the eye movement in the first ~qV run (pre-smoklng QqV 1). Zn Figure 3, whLch shows the effect of smoking a hilh "nicotine dellvery ~4garette the eye movement has ~creased in pre-emokins C~VSs 2 and 3 but is considerably ~educed /~=ediately ~tec smoking (Post Smoking CNV's 1, 2 and 3). It changes again (Post smoking CHV'8 & and 5) pcesuma])ly as the effects o£ r~cot~ne decline. When the subject smoked cigacettes rich a normal rLicotlne delivery (Figures 4 and S) the eye movements show a similar pattern to Chose observed when the hizh ~coCine c4garetce was smoked. However, in these cases the eye movemnt in Post Smokins 3 is large, presumably because the e££ects of smoking have d~n£n£shed more rapldly. Figure 6 shows a 81m£1ar graph plotted for results obtained from m~ experiment in which the subject si .mulated smoking. Figure 7 sho~s results obtained vhen the subject smoked a c£~acette vh£ch contained xw ~cotlne ('Roneyrose' tbsrbal Cigarette). ¥isu~es 6 and 7 do not show the same type of change in eye movement £mmediaceZy after smoking (or the simulation o£ smoking) as the others £11uscrsted. • n addition to examination of eye movement potentiaZ zecorded p in ~nterval between the S1 sad $2 sc~mul~, the number of eye movements ~s~ou~houC the CNV 8o~8ion~ h~ve bem~.coun~d. These seem to indicate that, £oc soma subjects, ac least, there are S~ificanC chaztges in total eye movement be£ore --~d a~ter smoking. BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0% ~o ~o

FIG. I RD. fIG4- R THE CONTINGENT NEGATIVE VARIATION VOLTAGE (~ V) SECOND 81"1M U LUS ~HE (SEC-= C, NV BAT Co LTD - MINNESOTA TOBACCO LITIGATION 0 O% O Oo

(HIGH riG. 3 EYE MOVEMENT NICOTI NE DELIVEAY CIGARETTE) R.O. IIG4-R [YE'HOVEMENT RELATIVE 1"O RUN ! 700 4OO 3O0 IOO 3 $ -I00 PRE- SMOKING POST SMOKING w 0 C~ 0 0 BAT Co LTD - MINNESOTA TOBACCO LITIGATION

FIG. 4 EYE PIOVEHENT (NORMAL NICOTINE DELIVERY ,CIGAR.ETT, E) EYE-MOVEMENT RELATIVE TO RUN I RD. I IG4-R 700 500 300 -I00, PRE- SHOKI NG CNV 8ERIE3 No- 0% O BAT Co LTD - MINNESOTA TOBACCO LITIGATION

FIQ. 5 EYE MOVEMENT (NORMAL NICOTINE DELIVERY ClGARETT, E) EYE- MOVEMENT RELATIVE TO RUN I (% CHANGE) I, 100 RD. IIG4-R 1,000 900 700 400 I00 0 POST 5r,1OKihl G BAT Co LTD - MINNESOTA TOBACCO LITIGATION (,.3"1 ",,.O

F'IG. G RD. II G4-- R EYE MOVEMENT ii ('$1MULAT.ED 5MOKI,NG) 8,000 PRE-SHOKING 111 4 POST ,SIOKIN Q BAT Co LTD - MINNESOTA TOBACCO LITIGATION ~NV SERI'ES N°. 0 c7~ 0

F~Ci.? EYE MOVEMENT (ZER0 ,NICOTINE DELIVERY CIGARETTE) EYE-MOVEMENT RE.LATIVE TO RUN I (70 CHANGE ) ~80 2G0 24o E2o ZOO 180 14.0 120 100 8O 60 40 Zo 0 -20 -40 -(,,o -.80 - I00 -I?-0 -140 -160 I 2 3 4 PRE-.~IOI~INP. POST' SMOKING BAT Co LTD - MINNESOTA TOBACCO LITIGATION RD. ! IG4-R CNV SERIES N'. (.j,--i c~ (3% cP~ ,,,.o

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