Product Design
1620 - Electrophysiological Studies 1620 - Electrophysiological Studies - 830000 Annual Report
Abstract
Reports on experiments using pattern reversal evoked potentials (PREPs), evoked potentials to olfactory and trigeminal stimulants (EPs) and electrotrigeminograms (ETGs) to explore the effects of smoking on the central nervous system. Demonstrates that smoking produced a decrease in PREP P100 latencies over time. States that maximal central nervous system effects are achieved while smoking, but quickly dissipate. Explores effects of nicotine delivery on P100 latencies.
User-Contributed Notes
Fields
- Author
- Charles, James L., Ph.D. (PM, R&D VP, Pharmacologist, Industry Expert)Vice President of Research and a scientist for Philip Morris, Inc. Vice President of Research for Philip Morris, Inc. in 1986 and then again from 1992 to 1993.
- Gullotta, Frank Paul, Ph.D. (Tobacco chemist, Philip Morris, Cologne, Germany '94)Developed and used EEG techniques to study relationship between nicotine addiction and blend properties. Worked moved off-shore in 1986 to avoid discovery.
- Hayes, C. S. (PM R&D)
- Warfield, Al H. (PM)
- Recipient
- Carpenter, Robert D., M.D. (PM R&D Biological Inhalation Research)Defense
- Central File
- Charles, James L., Ph.D. (PM, R&D VP, Pharmacologist, Industry Expert)Vice President of Research and a scientist for Philip Morris, Inc. Vice President of Research for Philip Morris, Inc. in 1986 and then again from 1992 to 1993.
- Daylor, Frank L. (PM Gen. Products Development. Mgr., R&D)Was involved in flavor development for Philip Morris; worked for PM Research and Development in Products Development 1962-93.
- DeNoble, Victor J., Ph.D. (PM Behavioral Research (1980-84))Associate Senior Scientist at PM Behavioral Research (83). Senior Researcher at Philip Morris from 1980-1984. Performed in-house PM rat studies on nicotine and addiction; was later fired by PM because of sensitive nature of what studies revealed about nicotine addiction.
- Ellis, Cathy Lynn, Ph.D. (PM VP of Worldwide Scientific Affairs)Director of Research at Philip Morris U.S.A. in 1994. In 1997 was Senior VP of R&D at PM (2505370877). Osdene protégé.
- Farone, William Anthony, Ph.D. (PM Former Dir. of Applied Research, Anti-Tobacco Expert)Hired to make safer products and to find business alternatives outside the tobacco industry for PM.
- FAustini, D. Dr.
- Ferguson, Robert N. (PM R&D 1975, Principal Scientist March '97)Robert Ferguson joined PM in April 1974. Prior to 1997 appointment was a Research Scientist. He worked for Philip Morris' Research and Development located at Box 26583, Richmond, VA, 23261 in 1975. [Source: Butler 2021648905-13, (P.O.)]
- Gullotta, Frank Paul, Ph.D. (Tobacco chemist, Philip Morris, Cologne, Germany '94)Developed and used EEG techniques to study relationship between nicotine addiction and blend properties. Worked moved off-shore in 1986 to avoid discovery.
- Hausermann, Max (PME R&D VP c. 1977, Chemist)Position at PM was above Thomas Osdene and Bill Farone. Hausermann (a chemist) reported to senior VP Operations. Was Vice President at Fabrique Tabac Reunine R&D (owned by PM). He was fully knowledgable re INBIFO and Osdene programs.
- Hayes, C. S. (PM R&D)
- Hellams, Ralph D. (PM R&D)Defense
- *Ikeda, R. M. (use Ikeda, Robert M., Dr.)Associate Principal
- John, Judith E. (PM scientist)Judy E. John was a Philip Morris Scientist. (PMI's Introduction to Privilege Log and Glossary of Names, Estate of Burl Butler v. PMI, et al, April 19, 1996)
- McCuen, Robert W., Ph.D. (PM Microbiologist)Defense
- *Meyer, L. F. (use Meyer, Leo F.) (Employee at Philip Morris)
- Osdene, Thomas Stefan, Ph.D. (Director of Science and Technology, Philip Morris [1986])Ph.D. in Organic Chemistry. Ten years of research when he started with PM in 1965. Worked in Chemical Research Division of PM 1965-66; Chemical and Biological Research Division 1966-69; Director of Research 1969-1984, also assumed independent position as Director of Research and Extramural Studies during these years; became Director of Science and Technology in 1984, reporting directly to Philip Morris USA Executive VP Mark Serrano. Involved with Center for Indoor Air Research (CIAR) 1988. Attended PM's Operation Downunder Conference in June, 1987. Retired 1993.
- Pages, Robert Alex, Ph.D. (PM scientist & researcher, c. 1980s)Robert A. Pages gave a deposition that was 25 pgs with one exhibit in the Carlisle v. Philip Morris Inc., et al case on 10/30/86 and he gave another deposition that was 207 pgs on 9/23/88 for the Rothgeb v. ATC, et al case. He was a Scientist and he worked for Philip Morris, Inc. and was born on 10/10/41 and is in infirm health. (PMI's Revised Initial Disclosure, June 27, 1996) (PMI's Introduction to Privilege Log and Glossary of Names, Estate of Burl Butler v. PMI, et al, April 19, 1996) Robert Pages, who gave depositions in 1986 and 1988, is apparently in poor health. (Alexandra Wagner, Ness, Motley letter to Grant Kaiser, 1/10/97)
- Spielberg
- Spielberg, Howard L. (PM Research Professional)Research Professional
- Tafur, Susan (PM Biochemical Research Division Head, c. 1980)Head of the biochemical research division in the early 80's
- Taylore, F.L.
- Thomson, Richard N. (PM Development Director, scientist)Defense
- Turano, L. R. (PM Researcher)Research Professional
- Warfield, Al H. (PM)
- Warfield, A.H. Dr.
- Yu, T.Biological Effects of
- Hypothesis
- Neurobiology
- Sensory effectsTechnologies used to measure, control, or alter sensory effects
- Keyword
- Electrophysiology
- Central nervous system (CNS)
- Trigeminal chemoreception (Trigeminal nerves)
- Pattern Reversal Evoked Potential
- Electrotrigeminogram
- Ofactory/Trigeminal Evoked Potential
- Additive
- Vanillin
- Methyl salicylate
- Menthol
- Limonene (d- Limonene)
- Carbon dioxide
- Smoke Constituent
- Nicotine
- Design Component
- Flavorant
- Named Organization
- AIR Products
- Givaudin
- Technology/Method
- PREP
- Electrotrigeminogram
- Olfactory/Trigeminal Evoked Potential
- Subject
- Menthol (Additives)
- nicotine technology
- CNS/Brain (Effects)
- Sensory Effects—Taste (Effects)
Document Images
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THIS REPORT 13 C0l/FIDENTIAL TO THE BUSINESS OF THE
COWANY: IT SHOULD BE CAREFULLY HANOLED. IS NGT
TRANSFERABLE TO ANOTHER IlDIYIDIML. AND IS NOT TO
BE PFIOTCCOPI ED.
If tM report has s.rv.d-Its purpase and Is no
longer n..d.d, pl.ass rartnrn It (ow.d1af+Ny to
the C.ntra 1 Ft l* at the R.a..rei: Canter for
-I@aord k.Min9 purposs and d.sfrvct(on.
7t~
~.:
4
ILIP MORRIS
Accession Number: 83-127
Copy Number:
Issued To: ~ 1. C!,l-YtcJ111 ~4
A
.
RES EA R C H CENTER
RICHMOND, VI RGINIA
,
,
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.
,CiiARGE NO- & TITLE: 1620 - Electrophysiological Studies
'",:TYPE REPORT: ® ANNUAL :. Q SEMIANNUAL
.
3
-DISTRIBUTION:
BY
SUPERVIS® BY
,
Dr. M. Hausermann
"rt
.~
Dr. W. A. Farone
Dr. T. S. Osdene '
Dr. J. L.
;, . Mr. F. L
Dr.
DATE: June 29, 1983
r
0 COMPLETIOIV . 0 SPECIAL
PERIOD COVERED: July 1982 - July 1983
REPORT TITLE: 1620 - Electrophysiological Studies -- 1983 Annual Report
APPROVED BY
Mr. L. R.
Mr. L. F.
Mr. R. N.
p C.t~. : -.
F. P. Gullotta and C. S. Hayes
.
A. H. Vlarfi ld
. L. Charles
~Dr. R. N. Ferguson
Dr. A. H. Warfield
Ms. J. E. John
TRICTED I~I~~I~~~RUTION
afur
~~~ ~~~: Mr. R. D. Hel l ams
Mr. H. L. Spielberg
Dr. R. M:
Mr.
Dr. D. Faustini
Dr. C. K. Ellis
R. D. Carpenter Ms. C. S. Hayes
R. A. Pages .Manager Biochemiq~l F P. Gd11e**a
Central File -
KEYWORDS: Pattern Reversal Evoked Potential (PREP); Electrotrigeminogram
(ETG); Olfactory/Trigeminal Evoked Potential (EP); Cigarette Smoking;
Nicotine; Feeling Factors; Central Nervous System (CNS); Trigeminal Nerve;
Limonene; C02; Methyl Salicylate; Vanillin; Menthol
.
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SUMMARY
. .,.. . i;~~.
' Etdd
xperimens were conucte em 1 o i n
p y g pattern reversal evoked_, -otenti a1 s~i
. .
,_-.W.-~~y1 . .~.`;
~tr,: ~.(PREPs ), evoked potenti al s to ~ol factory ' and tri gemi nal ~~st.imul ants (EPs ) and
h electrotrigeminograms (ETGs). ~n~if ~f'u< o! 4~ t3l.
-; x`ri~ ,~~~- w
` : r } r ; r'y tt- t't ~
Three PREP studi es were com 1 eted and a fourth i s i n pro ress ~~ ~`~~
. P The goal
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of each of these studies has been to systematic,ally, explore' the effect`s -of
t ti~
µ /~ ~~`h y4 ~-
~
.' s:."~~ .' ~ ~A?r
h ~, ..~ , . cigarette smoking on ,1 central nervous'system Vactivity In'th Rt t B`
.eeurnoase-
~` ~RwS:~~rx
"
n+~.t! line studyit was demonstrated that smoki~rodcdr statitiall'if
,ngpueascysgni-
; >I ,;.
'n1
^' `~o`latencies wliich endured''
icant decrease in PREP Plofor10 mi: post sm king.
^lY
However, Ploo latencies did not return to pre-smoking baseline levels unti60
..;.: :.i".A.
min. post-smoking. A second study examined the relationship between cigarette
smoking and`P1oo latencies over a four hour period. It was demonstrated that
1.:
~~
'
when su
b ects are allowed free access to cigarettes, Ploo latencies are main
~
hi
tained below pre-smoking values. Th
e t rd study i nvestigated the effects
o f
~
cigarette smoking on P100 latencies on a puff-by-puff basis. ' It was ascer-
tained that maximal central nervous system effects are obtained while smoking,
,. .
and that the effects begin to dissipate by the time the cigarette is extin-
.. ..
guished. An the Dose/Response study the effects of a range of nicotine
,; ,
.. . ,_ . .~. .. : -
deliveries (0.1717
1.65 mg/cigarette) on P100 latencies are being examined.
. ... ,
Research
on EPs was initiated in several studies. In a flow rate experi-
~~~'
ment, it was determined that a flow rate of 134 ml/sec produced reliable
. . . . ~ . . . ~ ., . . . . ~. . .. :... . ~_ ~ ,. . ~ . ' _ . . ...~ r. _.
responses to all stimuli under study. A series of experiments was carried out
on EPs to limonene, methyl salicylate and combinations of these odorants with
. S:
C02. It was demonstrated that the stimuli were differentiable in terms of
latency, amplitude and waveform morphology. In a series of concentration/
response studies (in progress), the manners in which EPs change with different
appear to
_stimulus concentrations are being investigated. These 'studies
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: . ... ~'~': . .. ....: , ,. ~ - .: . ,: . .. .... . . ..~ _
.~ '~ . : .. . . .. . . . . . . . . ~ .. , ~ . . . . .. .. . ' ~ .. -. ->.~ n-
indicate that EP waveform characteristics accurately reflect stimulus inten-'
? L 1 ti S i t
µy.
~4,
r.~
}d
~ n' Outsi de EP studi es performed by G. Kobal i n Erl angen, W. `.Germany, were
f
discussed. Kobal recorded EPs to vanillin, C02, menthol and.the combination of.
~`vanillin and COZ, ~The results of Kobal's experiments were found to basically `
~IhV
~s~{"~.Wr~,<~~u:' by~ i y
~f agree with experiments performed at R&D.
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f~ Initial studies were carried out on. the .ETG. ETGs to.high concentrations
a:.Jf: t'.. ..4:. - . . .
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limonene methyl salicylate and CO were recorded 4'
. ..~.. ,. . . ... / , .. -.-..: }..::K'. . " ~,..:~.
...t. . .. . . . ..-. . . ... ~l .-, , .
~xPl_ans,for future PREP, EP and,ETG studies were discussed.-
SUMMARY...::':.:....`
.DEFINITIONS AND ABBREVIATIONS..:::..:'o:.:.'::...
aIII. 1INTER-INDIYIDUAL DIFFERENCES IN EVOKED
- .J~ ~ ~t~: .. -.
.... . POTENTIAL RESEARCH...:..:..:...:...°...:..::.:::
PATTERN REVERSAL EVOKED POTENTIAL (PREP) STUDIES...:.:':
,. ....
General Considerations....:....:...:..:.......:...
Return to Baseline Study......'....:.
<,.
~..~.. rtj 0r,
~
:::::.....:..
`Smoking Over a Four Hour Period.........
Puff-by-Puff Analysis of Cigarette Smoking......'..
_, ... , ., . .
....::..::...:..:....::
Conclusions............ :`:.........
EVOKED POTENTIALS TO OLFACTORY AND TRIGEMINAL STIMULANTS (EPs)...
General Considerations .............:........................ 26
Flow Rate Determinations..................................... 29
EPs to Limonene, Methyl Salicylate, C02 and Combinations.... 31
...,:
Concentration/Response Study......: ......:...:.....`.:.':::.::
Electrotrigem:inograms (ETGs): Prel,iminary Studies..:.::..:.
. EPs - G. Kobal......... :...... :..` ::.......... .:........
.....
Conclusions.......................... .........:........:.:.:..
VI. PLANS............ ........ .......................................... 50
VII. ACKNOWLEDGMENTS ...............:.................................. 52
VIII. REFERENCES ....................................................... 53
,. .. _ . .- . _. ..,. . . . .,y _
, A ~4i1OV.:
w,`DEFINITIONS AND ABBREVIATIONS
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.
, Amplitude-Evoked Potential -";The height of some component of the multiphasic
evoke po en.ia wave orm, measured either from a zero baseline, or `with
.:
respect to another component
.. . . .. ~ .- ,..,... . - _ _.... __ .. , . . . ...'tiS?q
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Central Nervous System (CNS) The brain and spinal cord.
n~s~i~t ~~'':'~~ ~~ ~I~l~~ ~r~ea 9V~i~~n
.~>~~j~~+~d~°L?Si~x~ ka~e'
~.~. ~,~ ° dF}S'T~R t~¢~~ r9~tfk~~{bPi73 'fl+T ~y~~ ~~MR .~ 1 F t9..~ ~' ` r SL4
v.. +a:a q.~ .., ~ .. . .t _ ... ~' ,
Component/Peak-Evoked Potential ="One 'wave of the multiphasic'evoked potential
,
wave orm. t is usua y measured in terms of polarity (P or N) and either its
'normal latency (e.g., P100) ) or its ordinal relationships to other peaks (e.g.,`,t~~
< P
l a.t"'{1
y~ } ; ~{!'.
45
(r 1^
dtf)N ~c~:~?tFr i~. A F ~ ~~
!"
: El ectroencephal ogram t( EEG )=-A record of the 'ongoi ng el ectri cal 'acti vi ty rof 'the
u,
. rain. It iusua y recorded from the scalp via gold or silver-silver ;
~ chloride electrodes positioned over the brain areas under study. ~'
Electrotrigeminogram (ETG) -"A record reflecting the hypothesized depolariza-
ion potentia o the frnerve endings of the trigeminal nerve (cranial nerve
V). In this case, the ETG refers to the negative potential recorded from the
i nner 1 ateral regi on ( regi o respi ratori a) of the human nose.`a
.?J ty;~f
`
EP - In the context of this report, EP will be used to refer to the electrical
response of the brain to olfactory and trigeminal stimulants.
rl,l1J0q:i.
~
Evoked Potential - The electrical response of the brain to the onset (usually)~"
o a sensory stimulus. In general, evoked potentials are small multiphasic
waveforms which must be signal averaged to extract them from the ongoing (and
much larger) EEG. r
~.St
ci' FAijk 4tf'F 7
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=``xthatf'
Feeling Factors In Cigarette Smoke `= The qualities of cigarettesmoke;
can be c assi ie as spicy, peppery, cool, warm, pungent, etc. Feeling factors~
are commonly thought to be mediated by stimulation of the trigeminal nerve in
both the nasal and oral cavities.
msec - milliseconds
Latency-Evoked Potential - The time from stimulus onset to the occurrence of
some component pea o the evoked potential waveform.
py - microvol ts
~~
i ... , , . .
Olfactory Evoked Potential (OEP) - A somewhat inaccurate, but generally use
e
ermi to escri e t e cor i ca y recorded response to stimul ation of th sense
of smell. The sense of smell includes olfactory (stimulation of olfactory
z' receptors) and trigeminal (stimulation of free trigemi'nal nerve endings in the
"it) Ihd OEPfltdd/or fel
resp raory mucosa components.n oter wors,s re ec oor ane
ing factor stimulation. In this report, the term EP will be used in place of
OEP.
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er
+F `h, s ' ~ ~ r~;.. R i; ~JC}~ ~r
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.
Pattern Reversal Evoked Potential (PREP) - The corticallyrecorded response of^
~.V <{ : e visua sys em to a s i ing pa ern(usually a checkerboard). The PREP is
the most stable and reproducible electrocortical response yet recordable ~an<
humans r
tiif"v;y?1 trf6 ri ~.
~ t. _ . . . . 'r ~
. . . .. . . .
P ,"P -PREP -^ The primary (largest) positive component of the PREP. ''_Its
ypica atency is 100.0 ± 4.0 msec Th
e The latency of the P exhibits system- '~
. o
atic.changes in response to the smoking of cigarettes of ~iffering nicotine r_1
deliveries.
r.,y.
l ~~ ~ t . tt ~f
-. .. .~ .
oE f# .+
~
'Psychophysical Data - Data which relate psychological stimulus scalesto
p ysica sUmu us scales (e.g., perceived loudness to sound wave amplitude).,11VN
~4Jitry `!i(y~ r~ ta~fw 1 j~~~ 14~yr 4~ifi' t}
-'
Signal Averaging Evoked Potential - The process by which an evoked potential c~
s extracted from t e ongoing . Since the 'evoked potential is time-locked
to stimulus presentation, it can be computer-summated. The ongoing EEG (and
artifacts).is random with respect to stimulus presentation and is averaged to
zero.` The.number of stimulus presentations necessary to record a clear evoked
potential varies with the signal (evoked potential) to noise (EEG and arti-
facts) ratio.
. . A ia
.. ~ :~..~C
Trigeminal Nerve - The fifth cranial nerve, widely distributed throughout the
ea . ntense stimulationof the trigeminal nerve is associated with the sen-
sation of pain and reflexes such as tearing, salivation and inhibition of res-
.piration. Modest trigeminal stimulation may be pleasurable and is associated
with feeling factors such as spiciness, pungency, cooling, warmth, etc.
II. OBJECTIVES
The overall objectives of Project 1620 (Electrophysiological Studies) are
to: (1) gain further understanding of the electrophysiological consequences of
cigarette smoking, with a particular emphasis on nicotine; and (2) develop and :
-.-a".r_V"
utilize new techniques which will permit the quantification of physiological
responses to smoke constituents and tobacco flavorants. Specific objectives
II.
A. To utilize the PREP to study:
. Pattern Reversal Evoked Potential (PREP) Studies
nervous systemiactivity.
smoki ng
the role of nicotine in smoking behavior.
and
central
Evoked Potentials to Olfactory and Trigeminal Stimulants-(EPs)
A. To develop an EP program to study: -
11 central nervous system responses to current and new or
alternative tobacco fl avorants.
2. feeling factors in tobacco flavorants and smoke consti-
tuents.
1. gain direct knowledge about irritative factors in whole
smoke and'smoke constituents.
III. Electrotrigeminograms (ETGs)
A. To develop an ETG program to:
2. gain additional insight on the role of the trigeminal nerve
with respect to feeling factors in tobacco flavorants and
smoke constituents.
'1. the relationship between cigarette
-3-
III. Inter-Individual Differences in Evoked Potential Research"
;=.~'':Large inter-individual differences are found in all electrophysiological =-`,
~
^
studies on humans. ' No studies of which the authors are -aware
have
failed *to
'
find a statistically significant difference among individuals,``irr
espective of
`
7
,.~~~~3~?~
~~
nneeihlp traatmpnt affarte 't~yL~l~.10.5~: E.:;;~cyu~(:~^~! ~';G D :,~I~~~.1
$, ~.~..ri..
,,V ven this fact, differences among individuals must be treated statis-
C ; .. . ~ , . ~~
tically. The design of choice "in most experiments is a`repeated measures
analysis of variance.1 -~~;In the design, the error variability attributable to
individual differences is eliminated.
^
In other words,siibjects are handled
as ~
,
;
the variability associated with `
inter-indlviduai differences is isolated. Once isolated, the effects due to
the experimental treatments can"be dealt with without the 'inflated variability '`'
c~
due to differences amnna subiects.
A simple
respective of inter-individual differences.
example might serve to illustrate "how a' repeated measures ~T
analysis of variance allows for the analysis of experimental treatments ir-
S5
20
30
6
10
X = 14.0
Table 1
MEDIUM HIGH
8 10
25 - 30
32 38
9 12
14 16
17.6 21.2
In Table 1 are the hypothetical results of an evoked potential experiment ;
Yet, i f those differences are i sol ated i n the analysi s, , a stati sti cal ly
,~. SR,
' r'icant treatment
ff
t
ld b
e
ec
wou
e obtained andt would be s tht td
Veena scoresen :rG J i. - ..,.r.. ... - .
.~ t'-,.ii`. , ...w.~~.. .+,.'i~',:: .... . .. . ~ . . . . ~ .i . ~.a` . +u . ..~. ~~ ... ` . ..
,. . . ~
performed,~on, five subJects (S1-S5). ,.The subjects were tested using three
stimulVus` concentrations (low, medium, and high)
7~ Large~differences among,subJects are apparent, irrespective of treatment.
to increase with increasing stimulus concentrations. i~~.
.~ ~
T he stati'stical logic and assumptions ofthe re
eated measur
l
i
f
p
es ana
J t .J .. J, .
ys
s o
. - . .
.. .. ..
variance can be found in most books on experimental design. Here, it is suf-
ficient ficient to note that the analysis is very sensitive and statistically robust.1
l of the evoked potential experiments'performed at R&D employ experimen-
. ., ..
In
tal`desi9ns which statistically eliminate inter-individual differences. Hence
,::
it has been possible to detect differences among experimental treatments, even ;
.. ... . . . . . _
where large differences among subjects have been encountered.
5
.+ r
-5- .
General Considerations
~;., ; .~ ~ .. _ ..
rn e usetulness of the PREP for assessing the CN5 responses
cigarette smoking has been demonstrated in a~ number of studies 2,3.4 -4"=i
particular,`"it has been shown'that when"other variables are controlled'the o~V,~ti~:
effects that are obtained on the PREP appear to be attributable to nicotine:
...~- .. - : . _ _.. ~_. ~ .
Specifically, , cigarette -smoki'ng produces adecrease in the latency ' of the''-` "
primary positive component (P100) of the PREP. The magnitude of this
related- to nicotine delivery in "a"dose-dependent fashion. - -The P,n',;' latency
;
decrease appears. to be related to the stimulatingeffects of nicotine on the
visual system,5 and it may reflect a post-smoking facilitation of visual infor-
The
The effects of cigarette smoking on the PREP are extremely reliable,r
and the findings with respect to the P1oo~`have been replicated in numerous
studies over the last three years.2 ~3 ~4 ' iTherefore, 'it is now possible to '
conduct highly specific and systematic studies on the nature of the events that
occur in the brain as a consequence of cigarette smoking.
u t~ !'.In this report, four parametric experiments on the PREP and cigarette
smoking are described. In the first experiment, the issue of how long CNS
effects endure following the smoking of a single cigarette is addressed (Return
to Baseline study). - The second experiment investigates the nature of CNS
effects produced by repeated smoking (Smoking Over a' Four Hour Period study).
The third study involves a puff-by-puff analysis of smoking-produced CNS
effects (Puff-by-Puff Analysis of Cigarette Smoking study). Finally, a study
on the dose/response relationships between nicotine delivery and CNS effects is
described (Dose/Response study - in progress).
PATTERN REVERSAL EVOKED POTENTIAL (PREP) STUDIES
-6-
