Tobacco Documents Online

PHILIP MORRIS INCORPORATED CONFED3-NTIAL ts INTER-OFFICE C~ORRESPONDENCE RICHMOND, YIIRGINIA To: Fror: Dr. W. L. Dunn F. P. Gulliotta and C. J. Shuiltz Date: `1 r: 6-;E-tiC3®UC i'S February 4, 1981 Subject: . Th,e Effects of Ci arette Smoking on Pattern Reversal Evoked Potentials (PREPs3 Since its inception, one of the goals of the neuropsychology laboratory has been to identify responses of the human brain which change in a predi~ctable and reliable manner as a function of cigarette smoking. Over the 1!ast several months we have been conducting research on what appears to be such a response. This memo describes the first study we have completed on the effects of cigarette smoking on pattern reversal evoked'~ pot- entials (PREPs). In the 1960s David Hubel and Torsten Wiesel demonstrated that the visual system optimally responded to patterns and edges which moved across the visual field in very specific orientatiions. The system responded considerably less well to diffuse illumin- ation. Based upon this work, subsequent research showed that very relliable visual evoked potentiials could be obtained by employing shifting (reversing) checkerboard patterns. Their reproducibility was such that neurologists began testing their sensitivities to various pathophysiologies of the central nervolus system (CNS):. The response is currently used to diagnose a number of pathologic processes in the CNS, i~ncluding: optic neuritis, compressive lesions and multiple sclerosis.. Despite the great popularity of the PREP in cliinical medicine, there is a paucity of basic research on the topic. In particular, there have been very few reports of pharmacologic influences on the response. The data presented here strongly suggests the modifiiabiliity of the response by nicotine and nicotine d'epriv- ation. The PREP. has three principal components or peaks (see Figure 1). The fi~rst negative peak (N1) has a latency of. approximately 70 msec,' and its neural generators are postulated to be located, in striate cortex. The first positive peak (P1) occurs at approximately 100 msec, and it is believed to be.generated in occipital cortex. The second negative peak (N2), which is also thought to be of occipital origiini, has a latency of about 1510 msec.

Dr, V. .L..' Dunn Februa;ry._4 1981 OS ;. _. L 4 r1!12 V PR©DUCTS Altho~ugh the N,2 peak is quite variable within and between subjiects, both the N, and P1 components are characterized by a high degree of inter and intra subject reliability. There- fore, we have chosen to restrict our discussion to the data analyzed on these two earlier peaks. We believe that the nature of the changes reported herein, are quite robust and will endure in the light of future research. Ten, male R&D employees were used to assess the effects of cigarette smoking on PREP's. They were asked to abstain, overnight, from cilgarette smoking, and then were required to smoke, on seplarate occasions, cigarettes delivering either :14 mg (low) or 1.34 mg (high) nicotine, or to sham smoke (no nicotine) an unlit cigarette. Both cigarettes which were smoked we.re Marlboro blends, with very similar tar, CO and RTD values. PREPs were recorded, via a vertex-positive electrode, both before (pre) and after (post) smoking. Figure 2 ill!ustrates the effects of smoking on the amplitude of N1 component. As figure 2 indicates, pre-post values in the siio-(no nicotine) smoking condition were nearly identical. In the low nicotine condition there was a post-smoking amplitude decrease, but the effect was not stati'stically significant. In the high nicotine condition, the post-smoking amplitude de- cliined by 0.92 uv. This effect was statistically significant (t = 2.43 df = 9, p < .05). Figure 3 illustrates the effects of smoking on Py latency. In the sham smoking (no: nicotiine) cond'ition, there was a slight, but non signiifilcant post-smoking latency increase. In the low nicotine condition, there was a post-smoking decrease-iniP1 latency, but this effect also failedto reach statistical significance. In ni.ne out of ten subjects there was a post- smoking decrease in P1 latency in the high nicotine cond~ition. The average latency decrease, in this case, was 2.79 msec, and this effect was statistically significant (t = 3.08, df = 9, E < .0~5). One additional finding is worthy of note. In almost every subject, smoke deprivation apparently ind'uced abnormalities in the shape of the PREP waveform. It can be seen, in Figure 1, that the typical PREP is si,nusoidal in shape, with two distinct negative peaks at approximately 70 (N1) and 150 (N'z) msec., respectively, and a very prominent positive peak (P1) at approximately 100 msec. In Figure 4 are PREPs from three individuals followiing overnight deprivation (pre) and following the smoking of a high nicotin~e cigarette (poist). In the first examp,le, the entire pire-smoking, waveform is grossly distorted. In examples 2 and 3, there is an unexplained additional comp- onent occurring, at 125 msec. Finally, in all of the pre-smoking records, the N2 component is.not well defined. Post-smoking,

~./ ATTORNEY Dr. W. L. Dunn -3- 4e~~RPIQ;118 however, each waveform assumes a more or less sinusoidal and normal appearance. Our data are interesting in several respects. First, using noninvasive techniques, we have presented evidence which suggests where and how cigarette smokinig is influencing the human brain (i.e., the N1 and Pi PREP components are believed to be gener- ated in striate and occipital cortex respectively, and were affected differentially). Second, we have demonstrated a human CNS response which varies systematically as a function of nicotine delivery. Finalliy, we have shown how a system which participates in the processing of visual iinformation is affected by cigarette smokiing and smoke depriva~tion. Research currently under way is aimed'. at determiining how the'PREP responds to suistained visual stimulation (habituation study) and how the response is influenced by other classes of centrally' active compounds (caffeine study). fiw Enclosure cc: Dr. Dr. Mr. Dr. R. T. J. R. Seligman Osdene Charles Fagan Behavioral Research Laboratory

ATTORN...r.y ~~ . The PREP FIGURE 1. Representative PREP recorded from vertex - positive lead. Me.g!ative up. .,

f`t'CG"'!' VJ !!-1!'IS`:..1 t V'JCC L.nAlVVC.J VI' IV 1 ; , ozq%6szoz NO LOW HIGH SMOKING CONDITION (NICOTINE) FIGURE 2.. Figure.illustrates effect of Smoking on N1 ampljtude. The effeGt is

r"rcc-t"u0 I Hd"irL.L i uvc t..nH/vuL-0 ur !v 1 I N M U 0 V LOW HIGH SMOKING CONDITION (NICOTINE) . FIGURE 3. Figure.'illustrates effects o€ smoking on PI latenqy,, The effect is statisticcL

_ - A_ _ r I 1 ' - - - - - - - - - - _ - k-.. _ ' - ' - -- - - - - II- _ - -' - - - - - - f - - ~ - ~ - ' 1 I I - - i - r ~ -r . . . . . - ~ - - - - - - - - - - - - - - - - - ' - - - - - - - - R - - - - - - - - - - - ET I - - j-~- I - ~ - t I Y - j ~ Z 1 ' - . - -- _ t I 1 - ! - ~ T ~ - - - _ - _ I ~ ''/ J - - _ ' t . _. ... .. ._ . ... _ _ ._. . _ . . ., . _ .. . . . S2 S3 - + - -- T r - .-~ I ~. ~. t I , - - -- 1 - - - _ - 7 -7 ~ . . . -. _ - -- - . FIGURE 4.8 PREP's ff'rnm three subjects following overnight smoke deprivation .. (pre) and.following, the smoking of a high nicotine cigarette (post) . ' ' 2Q25986f 22

r'KC"'i'UJ 1. LH I GVI, T lsf1HlVVcJ ur r i Ez99esSzoZ NO LOW HIGH .. SMOKING CONDITION (NICOTINE) FIGURE 3. Figure illustrates effects of smok.ing on P1 latency._ The effect is statistic-

, 3 ... PRE-nOST LATENCY CHANGES OF P i , NO LOW HzGH, FIGURE 2.. Fi aure i l 1 ustrate Sef9lc~aft smo'ki'nlg ron=N~Im~pf i tu~ N"fifie~ ef'~~cti'?s