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-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