IDENTIFYING PSYCHOPHYSIOLOGICAL PREDICTORS OF TOBACCO USE IN CHILDREN: A FIVE-YF-AR PROSPECTIVE LONGITUDINAL STUDY Research Proposal Dr. Verner J. Knott Royal Ottawa Hospital Submitted to Canadian Tobacco Manufacturers Council, Nov/1981. BATCo document for Province of British Columbia 12 November 1999 C71-- CP un CONTENTS 1. Introduction 1.1 Statistics 1.2 Psychosocial Factors 1.3 individual Differences Ii. State of the Organism III. Etiology of Tobacco Smoking III.I. Genetics 111.2. Morphology 111.3. Personality 111.4. NeurophysioloV 111.5. Prenatal mechanisms IV. Empirical Integration IVA. Need for a Longitudinal Study V. Tobacco and Stress Reduction: An Operational Framework V.1. Affect V.2. Performance V.3. Psychophysiology V.4. Neurophsyiology Vi. Summary, Rationale and Objective of Study VII. Significance of the Study VIII Methodology VIII.l.Subjects VIII.2.General Design and Procedures VIII.3.Psychophysiological Test Battery VIIIA.Statistical Analyses Bibliography BATCo document for Province of BritiSh Columbia 12 November 1999 NID cr, C;D Un IDENTIFYING PSYCHOPHYSTOLOGICAI; PREDICTORS OF TOBACCO USE IN CHILDREN:' A FIVE-YEAR PROSPECTIVE' LONGITUDINAL STUDY Verner J. Knott, D. Phil. I- INTRODUCTION 1. Statistics The recent report of smoking habits of Canadian school children by the Department of National Health and Welfare* (1980) has shown that students start experimenting with Cigarettes at an early age. The major conclusions regarding prevalence of the habit were as follows: - By age 12, one half of Canadian school children have at least tried smoking; - Regular smoking is established in the early teens by many Canadian students; - School aged boys experincnt with cigarettes earlier than girls, but girls begin reqular smoking earlier than boys. From the early teens, a higher proportion of girls than boys smoke daily; - By age 14, 15% of boys and 20% of girls are daily smokers and by age 17 these figures have increased ta--27% of boys and 30% of girls. No significant change occurs in the proportion of students who report daily smoking beyond this age. These figures are remarkably similar to the studies reviewed by Russell (1971) in which it was found that of those children who smoked more than one or two casual cigarettes before the age of 19, 80% went on to become regular smokers as adults. It is only the teenager who never attempts, or who has attempted no more than once and decided that he dislikes it and will not take it up, who has much chance of being a non-smoking adult. The matter is largely settled by the age of 19; if a person still is a non-smoker at this age he is unlikely to take it up. C=) see Brown, Cherry and Forbes (1980) for reference to above data r-I-)' C7 N C:) BATCo document for Province of British Columbia 12 November 1999 -2- 2. Psychosocial Factors But to establish the prevalence of cigarette smoking in children and adolescents does not explain how it is contracted. There is a general consensus that the motivating factors mediating the onset of the smoking habit are distinct from those factors maintaining the habit. This has been discussed by Russell (1971) and the argument will not be repeated here other than to say that after initiation to smoking has been mediated by various psychosocial motives, the pharmacological effects of nicotine take over as prime reinforcers. There is strong evidence that starting to smoke is related to social factors, particularly the influence of parents, siblings and peers (Mausner and Platt, 1971). The effect of the behavior of parents, peers and siblings on childhood smoking is presumably mediated partly through increased exposure to cigarettes, partly through imitation and example and partly through psychological and ' social pressures to smoke. Evidence for social factors such as parent's attitude and health education is to a great extent derived from cross-sectional correlational studies which give little insight into how these influences act on the school-going child. Evans, Henderson, Hill and Raines' (1979) review of the psychological factors reveals that smoking in children is related to lower levels of perceived (and real) academic achievement, to rebelliousness, anti-authority behavior, low self-esteem and that children who begin to smoke at an earlier age show a higher rate of sensation- seeking behaviors than non-smoking peers. 3. Individual Differences Although it is generally stated that social and psychological factors are responsible for the initiation of smoking, it is clear that no sharp line divides the biological from the psychological and sociological. The kinds of inner emotions that people experience in relation to environmental conditions and events is at the same time an expression of both psychological and biological factors. These -emotions and the environmental situations that are perceived as rewarding or aversive will determine, at least in part, a wide variety of behaviors including one's response to cigarette smoke (Jaffe and Jarvik, 1978). Individual differences in personality- and particularly in orientation towards the kind of psychological rewards offered by smoking are considered to be of paramount importance rNI) GrIl CX:> BATCo document for Province of British Columbia 12 November 1999 -3- in determining both smoker/non-smoker status and type of smoking behavior. This is illustrated with respect to early experimentation with cigarettes. The reasons most people give for their first experiments with smoking are curiosity, conformity, bravado or to appear grown-up (Horn, Courts, Taylor and Solomon, 1959). The first cigarette is almost invariably unpleasant. Nearly everyone has experienced the shock of the first inhalation, often accompanied by gagging and nauseousness - a physiological response which presumably has a pharmacological basis. On the other hand, nearly everyone who has continued smoking more cigarettes can recall the pleasantness of the light-headedness which followed inhalation, a sensory experience that could be made to recur following a brief time lapse between cigarettes. Tolerance is said to . develop to the unpleasant side-effects and skill is quickly acquired to limit the intake of smoke to a comfortable level, thus lowering the threshold for further attempts. Herein lies a possible cause of the virtual inevitability of escalation after only a few cigarettes (Russell, 1971). With curiosity satisfied by the first cigarette, the act is likely to be repeated only if the physical discomfort is outweighed by the rewards of smoking. If these motives are sufficient to cause smoking to be repeated in the face of unpleasant side-effects, there is little chance that smoking will not continue as these side effects rapidly disappear. What then is the nature of these rewards and what are their basis? There is a growing consensus that organismic-dispositional factors contribute to the development of the smoking habit but as to what extent such organismic factors can be attributed to genetic biological influences as opposed to acquired influences is as yet unclear (Battig, 1980). The emphasis on organismic trait and state factors in influencing smoking behavior has been expressed in varying degrees by a number of reseachers. In attempting to extract meaning from their highly variable data on .studentsl McArthurr Waldron and Dickinson (1958) hypothesized 0 ... that starting to smoke i-.- largely brought about by one's social environment but that reactions to smoking ... seem to depend in good part on the personal needs that the newly established habit is able to gratify (p. 272).11 Seltzer (1962) paraphrased these observations in biogenetic terms: "Rather than a superficial habit overlaid indiscriminate- ly upoa various persons, smoking appears to be a response to a wide variety of personality and behavioral characteristics which have their origin, in part, in the biologic and genetic CIO BATCo document for Province of British Columbia 12 November 1999 -4- make-up of the individual (p. 43) Dunn (1973) made similar references to organismic variables with specific references to early experimentation with cigarettes: "...it is likely that we shall ultimately find that the critical mechanisms involved- in smoking require the synergistic presence of some other factor, such as anxiety or possibly some constitutionally determined reactivity. The observation that only about half of those whotry smoking cigarettes go on to take up the habit certainly suggests some kind of interaction process. Smoking apparently is not sufficiently pleasurable among the disinterested half of the tryers for the aversiveness of smoking to be overridden. Smoke is smoke - whether its inhalation is pleasurable is dependent upon what the individual brings to the situation ... Whether or not the total experience is judged by'the smoker as. positive or negative might in time prove to be associated with biochemical, endocriziological, or neurophysiological variables which are either constitutionally fixed or shaped by experience prior to initial experimentation with tobacco smoke (p. 101-102)." Il- STATE OF THE ORGANISM The average pack-a-day smoker takes 8-10 puffs per cigarette and absorbs approximately 50-150 ug of nicotine per puff. Each dose of nicotine reaches the brain within 7 seconds and exerts widespread and varied central and peripheral nervous system effects (both stimulation and depression, all of which are potential reinforcers) , via its capacity to affect the actions of and release of important neurochemical transmitters (Russell, 1976). For the average smoker the behavior is reinforced approximately 50-70 thousand times a year and this consumption level would tend to suggest that organismic factors of a markedly compelling nature are operative in the inception and persistence of smoking behavior. While environmental cues and contingency factors play a crucial role in tobacco usage, a comprehensive analysis of smoking also must take into consideration the effects of tobacco in relation to organismic variables. The mode of interaction between a pharmacological agent and ongoing organismic state is of critical importance therapeutic- ally but its study has also proved valuable in furthering an understanding of target physiological systems by the known actions of such psychoactive drugs (Irwin, 1968). A similar approach can be taken in tobacco research, namely to determine tobacco's effects on the organism, taking into consideration ongoing states, so as to elucidate possible mechanisms and C:> sought for effects by the individual. Nicotine, as a chemical,. r1_J does not affect behavior directly but rather interacts with C7*1 other chemicals at'a cellular level to produce changes in BATCo document for Province of BritiSh Columbia 12 November 1999 tissue, organ and systemic functioning. The resulting alteration in physiological state then determines the limits and manner by which the individual copes and interacts with his environment. Thus the mode of action of nicotine at the biochemi6al and physiological levels may provide useful information of its possible dissimilar effects in smokers and non-smokers that may result in differential behavioral patterns of consumption. The issueis raised as to whether smokers are unique in their reasons for selection of and response to tobacco and hence consume this substance in an effort at modifying or manipulating a target system (or systemq). Their consumption therefore would have ultimately behavioral consequences that alter and possibly increase coping capabilities (Mills, 1978). Such an interpretation of tobacco usage has an obvious teleological flavor-insofar as it presupposes that smoking serves at least a potentially adaptive purpose. As will be elaborated upon more fully later, there is some indication that this may indeed be the case for some smokers. However, before proceeding further, a conceptual framework is proposed so as to allow the reader to establish a context or perspective for the position to be outlined. If, as pointed out earlier* the organismic state is an important determinant of tobacco consumption, then it remains to be elucidated as to what target physiological system or systems the person seeks to modify and toward what altered state the individual is striving. Irwin (1968) summarised some of the more salient organismic conditions from psychopharmacological studies. All of the factors - including wakefulness, arousal, activity, endurance, biosocial. drives, set, responsiveness to stimuli, information' processing and autonomic, neurophsyiological and endocrine functioning have been investigated in tobacco research and have been suggested as reasons for consumption at one time or another (Dunn, 1973). A person who voluntarily takes a drug often does so with the intention of altering one or more of the organismic -variables mentioned above.The point.to be made here is that the motivation for and effect sought can vary between individuals and serve diverse functions in a given person in different situations. This fact is of paramount importance in the study of smoking motivation. First, it emphasizes multiple causality in the onset of the habit and illustrates how consideration of organismic states precludes unidimensional etiological cc CD L.14 BATCo document for Province of BritiSh Columbia 12 November 1999 -6- mechanimsms as explanations for all smokers. A second point is that in addition to motivational needs and sought for, altered organismic states that tobacco can induce, another factor for tobacco use may be intrinsic physiological disturbance that is rectified by tobacco. Thus a pre-smoker Person wh6 is defective in one aspect of physiological functioning may seek tobacco with essentially medical intent, much as a person with adrenocortical insufficiency craves salt (Wilkens and Richter, 1940). Thus, the study of tobacco consumption must incorporate into a comprehensive explanatory system in understanding of the state of the organism which under appropriate environmental circusmtances (cues and contingencies) leads to experimentation and repeated use of tobacco by an individual for its perceived and/or real effects in modifying coping capacity through its mediating action on target physiological systems. III- ETIOLOGY OF TOBACCO SMOKING From the preceeding discussion it is apparent that the motivation for using pharmacological substance can vary between individuals, and that a given chemical may also possess unique effects for certain individuals, whose organismic state dispositionally distinguishes them from others. Among the results obtained in animal research in the last few years there has been numerous indications that psychogenetic inheritance can influence the made of action of pharmacological substances affecting the central neuropsychological systems and of substances having other kinds of effects as well (Broadhurst, 1977). Although Battig (1980) has cited animal evidence indicating response variability to nicotine as a function of psychogenetic strains, the extent such a disposition in man can be observed and attributed to genetic biological factors is open to question. Of the limit-less number of organismic variables that can lead to physiological and behavioral disruption and thus possible use of tobacco, the concept of disturbed arousal has probably received the most attention (Thornton, 1978; Remand and Izard, 1979). Disturbances in arousal mechanisms have been implicated in a variety of psychopathological conditions such as hyperactivity (Hastings and Barkley, 1978), anxiety and depression (Lader, 1975), sociopathy (Quay, 1965) and schizophrenia (Venables, 1977). Arousal disturbance has been theorized to be an etiological factor in children who as adults are at risk for these disorders. The question is raised as to whether tobacco may also have anarousal syndrome as an etiological substrate. The tentative hypothesis advanced is that within a population of children there exists a subgroup whose symptoms of arousal disturbances is premorbidly extant. Such persons will exhibit higher probabi- lity of acquiring the tobacco habit an the basis that initial experimentation with cigarjettes will result in C:) r\-) 0-1 co _`1 CD 0 N 41- BATCO document for Province of British Columbia 12 November 1999 -7- alterations of organismic states which %bill be perceived subjectively and behaviorally as reinforcing. The evidence implicating a premorbid difference in smokers and non-smokers is briefly reviewed below. 1. Genetic. Many studies that have implicated biological factors in the initiation of smoking behavior attribute the behavior to a genetic predisposition. Studies of twins are among the most popular means of assessing genetic factors. Initial twin studies by Fisher (1958) showed that monozygotic twins were more concordant in their smoking behavior than dizygotic twins, data by Shields (1962) on monozygotic twins reared apart indicated frequency of concordance in smoking Ftatus which was significantly different from chance expectancy. Subsequent studies however have both supported and denied a significant genetic influence on smoking behavior (jarvik, 1979) and an example of negative results is shown in a study by Cederlof, Friberg and Lundman (1977) in which the results of their monozygotic twin series speak strongly against the constitutional hypothesis. The presence of a substantial number of discordant twins in these studies indicates that genetic factors do not operate exclusively to determine smoking tendencies. As an example, an estimate of the amount of variance with regard to smoking in Shields' (1962) sample which can be accounted for by genetic factors is somewhat less than 33%. It seems reasonable to conclude that genetic factors operate significantly, but by no means exclusively, in the tendency to smoke; and they may do so in a wide variety of modes, including personality characteristics, and social and psychological needs and values, rather than simply by producing an inborn craving or need which nicotine satisfies (Kety, 1973). This line of thought parallels Eysenck's (1980) conclusions on his most recent twin studies: "Our data do make us question the simple-minded exploitation of the twin design and its conventional genetic interpretation in relation to smoking. In particular, although we agree that dizygotic twins are less alike than monozygotics in aspects of the smoking habit, we are not so sure that the similarity of twins for onset and consumption of tobacco is purely genetic... All in all, therefore, the picture emerges from the whole body of data that the onset of smoking and the consumption of cigarettes are governed by both genetical and environmental factors (p.. 281, 313).". GN co --_j (Z3 CN BATCo document for Province of British Columbia 12 November 1999 2- Morphology Although the above studies suggest the existence of genetic mechanisms in the development of tobacco smoking, they give no clue as to what they might be. They only indicate that the smoker differs in some significant xespect from his non- smoking peers. Early morphological work by Seltzer (1963). suggests that smokers differ from non-smokers on a variety of anthropometric measurements (e.g. height, weight, head circumference, etc.) . On every single measure examined, smokers were found to exhibit larger mean, dimensions than the non-smokers. As the measures involved a strong genetic component, Seltzer concluded that smoking behavior may have a constitutional basis. Although this data suffer from the fact that they may have been affected in turn by the smoking habits of the subjects investigated, this is not true of such studies as Thomas and Cohen (1960) on ability to taste phenyl~thiourea (PTC), a trait which has been demonstrated to have a genetic basis; they found that heavy cigarette smokers showed a significantly higher porportion of tasters than did non- smokers. Although the functional significance of these findings is questionable, this is not the case with Seltzer's (1967) most recent longitudinal work. Here, future smokers, compared to future non-smokers, were found to have smaller tidal air values, an increased frequency of sighs and swallows, greater respiratory rate, a somewhat higher recumbent pulse rate, more palpitations, more sinus arrhythmia, more constipation, more loss of appetite, and a greater frequency of urination. Tne future non-smokers, an the other hand, exhibited a consistent lack of physiological reaction to stress, suggesting that smokers are more prone to patterns of reducing anxiety which involve physiological change. This is in good agreement with the alleged tens ion-re ducing properties of smoking (Gilbert, 1979). 3. Personality The possible existence of a constitutional difference between smokers and non-smokers suggest a relationship between personality and smoking. Of the numerous measures available, the majority of research in the smoking area (Eysenck, 1980) has focused on three major dimensions: extravers ion- introversion (E); neuroticism-stability (N); and psychoticism (P). Each major dimension is a combination of intercorrelations between traits. Thus individuals with high scores E show traits such as sociability, impulsiveness, carafreeness, activity, etc. High N individuals exhibit such traits as worry, tenseness, anxiety, emotionality, etc., and high P individuals exhibit cx:) 0 N cr*% BATCO document for Province of BritiSh Columbia 12 November 1999 -9- such traits as emotional coldness, hostili-ty, egocentricity, lack of superego control, etc. There is good evidence 'air the genetic determination of these major personality variables and the behavioral manifestations of these personality traits would seem to be mediated through various anatomical and physiological features of the organism (Eyseck, 1967). In arousal terminology, extraverts seem to be characterised by low resting levels of cortical arousal, whereas introverts have relatively high resting levels of cortical arousal; these levels are presumably mediated by the ascending reticular formation. Relative to extraverts who are hypothesized as exhibiting strong inhibitory tendencies, low cortical arousal and hypo-sensitive responsivity to stimuli, introverts are hyp6thesized to exhibit weak inhibitory and strong excitatory tendencies resulting in relatively high cortical arousal and hype r-sens i tivity to stimuli. Differences in emotionality, characteristic of N, are governed by the visceral brain, a limbic system, coordinating the activity of the sympathetic and parasympathetic autonomic systems. Physiologically, high neurotic/anxiety subjects tend to respond more strongly to stimuli, show greater variability in'response, and take a longer time to recover after the response. As far as psychoticism is concerned, the evidence suggests some degree of hormonal control, related to sex hormones in general. Physiologically, individuals with high P scores and individuals exhibiting psychopathic behavior tend to exhibit low tonic resting levels of arousal and concomitant hyper-reactivity to stimuli and stress situations. Although inconsistencies are apparent, reviews of the smoking literature are in general in agreement that smokers exhibit higher scores an E, N and P dimensions (Matarazzo and Saslow, 1960; Eysenck, 1973; 1980; Kozlowski, 1979), and on average there seems to be a positive correlation between these dimensions and the degree of smoking within the smoking population. As with other studies and other variables however, whenever differences are reported between smokers and non-smokers, .it is usually impossible to determine whether the differences reflect consequences of smoking or possibly have a causal relationship to smoking behavior. This objection applies to a lesser extent to studies on child smokers and to studies where personality assessments were obtained prior to smoking onset. Powelgi, Stewart and Grylls (1979) examined E, P, and N dimensions on a sangle of 808 middle-class children between 7 and 16 years of age. More than half of the boys and girls 01 ~1 CO ON BATCO document for Province of British Columbia 12 November 1999 _10- had tried smoking cigarettes by the age of 15 years. Of the children who tried, they were found to be'. particularly extreme on the P, N and Lie dimensions and high on the E dimension. The authors concluded that this pattern is identical to that of children who misbehave and do not conform in a general sense. Similar studies indicating that rebelliousness and antisocial traits were correlated with smoking in children and persisted into adult smoking (Jamison, 1978; Steward and Livson, 1966). Cherry and Kiernan's (1978) longitudinal study is of particular interest in that their data pertains to personality dimension pre-dating the smoking habit for those who took up smoking after 16 years of age. It is clear from their data, that those who become smokers are both more neurotic and more extraverted than those who do not, and that the two personality dimensions-are independent and additive in their effect on the likelihood of becoming a regular smoker. 4. Neurophysioloqy Although admittedly the scalp recorded electroencephalogram (EEG) and the event related potentials (ERPs) observed in the EEG are gross measures of brain activity, they provide the best and most direct measure currently available for assessing the functional state of the central nervous system. The heritability of the EEG and ERPs has been firmly established. Twin studies have indicated that there is a significant genetic determination of EEG (Lykken, 1975) and of ERPs (Dustman and Beck, 1965). From these studies, it appears that approximately half of the variance of the EEG and ERP is genetically determined. In relation to the preceeding discussion on personality and its biological basis, there is evidence indicating that variations along the various behavioral dimensions such as extravers ion-in trove rs ion (E) may be reflected in neurophy- siology. Gale, Coles and Blaydon (1969) have reviewed the literature on the EEG and have added their own important .studies; they conclude that the evidence from the EEG is fairly convincing. Introverts tend to have higher alpha frequencies and lower amplitudes (i.e. higher arousal levels), extraverts lower alpha frequencies and higher amplitudes (i.e. lower arousal levels). Studies of ERPs have shown shorter latencies and greater amplitudes (i.e. greater C7 N c0 --_j C:) 0111 c0 BATCO document for Province of British Columbia 12 November 1999 _11- arousability) for introverts, longer latencies and lesser amplitudes (i.e. lesser arousability) for-'extraverts (Stelmak, Achorn and Michaud, 1977). The ability to monitor brain activity makes it possible for researchers to examine the relationship between subjective states, behavioral changes, individual differences, psychotropic drugs and the electrophysiology of the central nervous system. In the field of tobacco smoking, interest has focussed primarily on investigations on the acute effects of tobacco an EEG and ERPs (Thornton, 1978; Rdmond and Izard, 1979). Relatively few studies have examined the question of whether smokers exhibit quantitatively distinct EEG and ERP characte- ristics from non-smokers. If specific EEG and ERP activity are characteristic of the smoker, those may point to a possible predisposing neural mechanism underlying smoking motivation. As is true in most research areas howevdr, what appears to be an easily answered question do smokers show distinguishing EEG and ERP characteris tics turn out to be difficult to investigate. This question can break down into a series of questions requiring investigation, some of which present difficult methodological problems which make clear-cut answers hard to obtain. For example, with respect to EEG, one could make the general question more complex by asking whether the differences observed are (a) widespread or predominantly localised in specific brain areas; (b) stable during both resting and activated (eg. task oriented) conditions and (c) related to the degree of smoking (i.e., light, moderate and heavy smoking) and length of abstinence? It is not within the scope of this section to consider all the studies that have been carried out in this area. For our purposes it is best to avoid the many controversies attendant upon this area and we shall simply and briefly present two studies on EEG alpha activity and two studies on visual ER?s which reflect the inconsistency of the results to date. Brown (1968, 1972) found that all active smokers and former heavy smokers exhibited significantly higher resting alpha frequencies than non-smokers and former average smoker groups. The abundance of alpha activity present in the EEG was similar for all groups except that for very heavy smokers who exhibited significantly half the amount of alpha per unit of time. As with Brown's findings on alpha abundance, Knott and Venables (1977) observed no significant differences between smokers and non-smokers, but in contrast to their data on alpha frequency, these researchers found that non-smokers, in contrast to Brown's smokers, exhibited the higher resting dominant alpha frequency. With respect to ERPs to visual stimuli, I Brovin (1968) observed that smokers exhibited slower latencies and smaller amplitudes than non-smokers. Knott and Venables ON CC) CD C111 BATCO document for Province of British Columbia 12 November 1999 -12- (1978) however observed contradictory repults in that smokers showed faster latencies and larger amplitudes to visual stimuli compared to non-smokers. As with the previous studies on personality differences in smokers and non-smokers, these EEG and ERP findings are based on a single testing of subjects with a long history of tobacco smoking and the temporal or causal relation between electrocortical findings and smoker vs. non-smoker differences is unclear. Two rival interpretations may be uggested: (1) the electrocortical patterns precede tobacco moking and may be related to possible neurophysiolgoical : and psychological states which predispose individuals to smoking; or (2) the electrocortical patterns are a neurophsyiologycal consequence of prolonged smoking. Again, as with the preceeding personality studies it is.clear that a longitudinal study is necessary in order to choose between the rival hypotheses. S. Prenatal mechanisms . The predisposing factors thus far discussed have been those most possibly related to genetic inherited biological mechanisms. There is, however, an additional and obviously different possibility for predisposition i.e., the prolonged exposure to the fetus to high levels of tobacco smoke in utero. It is now widely accepted that maternal smoking in pregnancy is associated with reduced foetal growth and therefore with an increased incidence of infants who are small for dates(SFD) (Simpson, 1957). As Scarr (1969) has observed an association of low birth weights (less than 2,500 grams) with deleterious effects in later brain and intellectual development, there has been an,increasing research interest on the long-term effects ofsmking in pregnancy on the child. Whereas Hardy and Mellets (1972) found no difference in intellectual functions up to the age of 7 years between children of smokers and non-smokers, others have found significant differences in reading, mathematics and general ability skills between the ages of 7-11 years, with children of mothers who smoked exhibiting the slower development (Davie, Butler, and Goldstein, 1972; Goldstein, 1972; Butler and Goldstein, 1973). These latter findings were confirmed more recently in 7 year olds where children of mothers who smoked during pregnancy exhibited: a higher (non-significant) frequency of neurological abnormalities, including minimal cerebral dYsf=ction and abnormal and borderline electroencephalogram C=) (EEG); lower scores in general on the Wechsler Intelligence r,-) C) BATCo document for Province of British Columbia 12 November 1999 -13- Scale for Children (WISC), and more specifically on sub-tests of vocabulary, block design and coding; higher adverse scores on Haggerty -Olson -Wick man Behavior Rating Schedule scored by teachers; Igram. and Hunter, 1977). Denson, Nanson and McWatters (1975) have also noted an association between hyperkinetic children and smoking in that mothers of me thy lphenidate-sens itive hyperkinetic children were reported as smoking two to three times as many cigarettes as the mothers of normal controls. These studies are in marked disagreement with Lefkowitz's (1981) recent findings which failed to find any significant differences in the 10 year old offsprings of mothers who smoked and did not smoke during pregnancy. Measures of physical, intellectual, affective and personal and social functioning were similar for both groups of children. At this stage one can only speculate on the possible biological mechanisms which may be operative in pregnancy and thus responsible for the developmental differences observed between children of smoking and non-smoking mothers. Carbon monoxide (CO) crosses the placenta during pregnancy and the CO concentrations of the fetus of smoking mothers is significantly higher than in the fetus of non-smoking mothers. As Co has a much higher affinity for hemoglobin than oxygen, relative hypoxin may be a major biological factor operating in the fetus. Nicotine may eert an effect at various levels. For example, tobacco smoking is known to reduce appetite and smoking mothers may exhibit reduced food consumption relative to non-smoking mothers and this may impair the nutritional state of the fetus. Nicotine also causes vasoconstriction and may constrict the uteroplacental vessels, thereby placing the fetus in a state of relative hypoxia. Nicotine may also operate on a more direct level by acting on neuronal systems within the developing brain of the fetus. Although all these factors may operate alone or in combination, Yerushalmy (1971-,1972) has raised the important question of whether differences between the outcome of pregnancy in smoking and non-smoking women might be due to the characteristics of smokers rather than the smoking per se. For example, Yerushalmy (1972) reported that the prevalence of low birth weight infants was higher for non-smoking women who later became smokers than for women who never smoked. This is suggestive that the low birth weight was due more to the smoker than to the smoking, in accord with the genotype hypothesis. Yerushalmy (1972) also observed that low birth weights were significantly less prevalent among infants of smoking women who later stopped smoking than among infants of regular rIJ Or" co --.I BATCO document for Province of BritiSh C01urnbia 12 November 1999 -14- continuing smokers. The birth weights of infants of smoking women who were to become ex-smokers were rather comparable to the higher birth prevalence among infants of non-smoking women. This is also compatible with the theory that low birth weight is more a consequence of the smoker than of smoking. IV. EMPIRICAL INTEGPATION 1. Need for a longitudinal study The preceeding discussion has focussed on traits of the organism as being important determining factors in tobacco use. in searching for organismic conditions.that result in a higher probability for tobacco use the quest~ion is posed as to "what is given". Central to this is the suscep- tibility of the individual. As poorly understood as are most mechanisms involved in the development of smoking behavior, the nature of increased individual susceptibility has been perhaps the least adequately explored. As observed in the previous discussions, this is probably true because of the theoretical and methodological difficulties in such studies. These difficulties revolve about the following points: (1) there is evidence that increased susceptibility may be genetic, neurophysiological, developmental, physiological, psychologic, social or the consequence of prolonged tobacco use; (2) it is literally impossible to separate out the effects of these various influences because they all operate concomitantly; (3) the effects of prolonged tobacco use are particularly difficult to parcel out because the characteristics of tobacco smokers can only be determined in smokers who by definition show the effects of prolonged consumption of tobacco. These points emphasize the difficulty of developing etiological findings from studies based on individuals who are already smokers and they stress the long recognised need for the implementation of a longitudinal study which carries out its -measurements on a defined population prior to acquisition of smoking behavior. in a "real time" prospective longitudinal study where the goal is to examine predictors of specific future events or behavior, the researcher selects an appropriate aged child sample at time 1, examines its members for fxequency of the target behavior (eg. smoker vs. non-smoker status)p collects measures which are to be used as predictors and then waits for a suitable follow-up period to measure GN C=) N) BATCO document for Province of British Columbia 12 November 1999 -Is- again at time 2 the frequency with appropriate statistical relationship of the proposed with the presence or absence of the target behavior. Then, procedures, one examines the predictors collected at time I of the target behavior at time 2. Robins (1980) has detailed the theoretical and technical aspects of working within longitudinal studies of normal and pathological development and it is obvious from their presen- tation that there are certain methodological advantages in the longitudinal approach in the tobacco area: (1) the subjects are not yet smokers; they have not experienced the epiphenomena of long-term smoking. Thus their reactions on tests and measures are not heavily colored by these epiphenomena; (2) the researchers, relatives, and the subject himself do not know that he will become a smoker. This relieves the data of a certain part of the burden of bias; (3) the information gathered is current, -not retrosepctive; (4) the data- are uniformly and systematically obtained. This is in contrast to retrospective studies which make use of childhood records concerning adult smokers; (5) one advantage of the longitudinal method is that the ideal controls for the children who become smokers are the children (matched for sex, sociocultural status, etc.) who remain non-smokers. Such controls are an integral part of the design. In summary, we have criticized research into primary etiology based on smoker populations because the resulting observations are so heavily contaminated by nonprimary phenomona. Research on primary etiology is research into causes and the longitudinal approach is one of the best approximations to this goal. This is not to say that the prospective approach is without problems. A long-term longitudinal study of a relatively large sample faces certain problems including maintaining the sample, loss of key personnel, appropriateness of measures, etc. In addition, the longitudinal procedure yields correlative data and it is extremely difficult to securely construct unequivocal causative statements without experimental manipulation. Experimental manipulation is the method of choice in research of the cause of a behavior. With this in mind, of the masses of research an the already smokers and the effects of tobacco on smokers there is doubtless much which does relate to etiology. Information on premorbid characteristics would be of great value in culling these etiologically relevant findings. In this manner the two methods may be mutually supportive. all BATCo document for Province of BritiSh Columbia 12 November 1999 - 16 - V. TOBACCO AND STRESS REDUCTION: AN OPERATIONAL FRAMEWORK Having observed the need for longitudinal investigations in researching etiological mechanisms in smoking behavior, one must formulate a parsimonious scientific framework or theory of susceptibility and proceed to test the hypothesis it generates. The hypothesized increased response to tobacco smoke of the Susceptible individual can be designated as an element in the -development of acquisition of the habit, regardless of whether that increased response is duo to biochemical, physiological, neurophysiological, or psychological mechanisms. In each or any Of these cases, the change is presumably from an aberrant state to a nore "normal" one or from a "normal" state to a more "pleasant" one, and this change is translated into a psychologically rewarding experience. Thus within this frame of reference physiological processes are'translated into psychological reactivities on which the principles of the reward conditioning paradigm are fully operative. This may be conceptualized as a psychophysiological paradigm. Under these circumstances each successive rewarding experience strengthens the conditioned response (smoking) and the habit develops. Given a susceptible population, the question still arises: Why specifically do they smoke? Clues to the reasons why smokers smoke have been obtained by investigating the acute effects1of tobacco inhalation on psychological and psychophysiological functioning. 1. Affect A key to the understanding of smoking behavior is to be found in the management of affect. If you ask smokers why they smoke, overwhelmingly they respond in sedational terms. In a study by Meyer, Friedman and Lazersfeld (1973), smokers were asked, "Why do you smoke?" The question could be interpreted historically (How did you get started smoking?) or instrumentally (What do you get out of smoking?). of 126 respondents, 76 interpreted the question instrumentally. Of this group, 64% answered in sedational terms, that is, with such replies as, "It relaxes me," "it calms me down," and so on. Not a single respondent answered in terms that could be coded as indicating arousal, such as "it stimulates me," or "It bucks me up." And these are typical results. Aqu6 (1973) asked smokers to fill in a mood Adjective Check List before and after smoking a cigarette at different times of the day. Although there were interactions with time of day and test conditions, in general smoking was found to increase feelings of relaxation and decrease feelings~ of aggression, anxiety and tension. These effects were greatest for high nicotine cigarettes. Tomkins (1962) has classified a number of types of smokers in the smoking population. many of the smokers are "nigative affect' or sedative smokers. They smoke when the negative affect (distresst anger, worry, fear, shame, contempt, etc.) gets to a certain intensity or when they feel that negative affect is increasing to a high level or indeed when they anticipate negative ----4 affect will increase in the near future. Russell, Peto and Patel (1974) found that many smokers report smoking when anxious or angry; BATCo document for Province of BritiSh Columbia 12 November 1999 - 17 - the proportions were 74% of hospital workersk 93% of patients at a smoking clinic and 88% of a group of university studnets '(War- burton and Wesnes, 1978). The outcome of these studies strongly parallel the findings an individual differences which were discussed earlier and which indicated that smokers tend to be characterized by higher neuro- ticism (anxiety) scores on personality tests than non-smokers. Thomas (1978) found that smokers and non-smokers could be differentiated an personality scores with smokers exhibiting higher anxiety and anger scores than non-smokers. In addition very heavy smokurs (over 60 cigarettes per day) have boen found to be more aggressive and anxious than heavy smokers (40-60 day) and the latter felt greater negative affect than average (15-20 day) smokers. Non-smokers felt the least anxious and aggressive. It is important here to keep in mind that these anxiety differences do not seem to be a consequence of smoking as the prospective study by Cherry and Kiernan (1978) showed that young people with high neuroticism (anxiety) scores were more likely to start smoking than more stable adolescents. This is supported by McKennell's (1970) findings that situations of .nervous irritation" were common occasions for smoking among adults and adolescents and by Henderson, Lewis, Howell and Rayner's (1981) study of a secondary school population where a significant positive association was found between the probability of a neurotic disorder and use of tobacco. That this association was significantly stronger in female adolescent smokers is of particular interest in that it concurs with Frith's (1971) observation that a greater proportion of female smokers than male smokers reported a desire to smoke in high-arousal situations. A common picture of smoking as a stre iss reducer emerges from these studies and they are to a great extent supported by Lindenthal, Myers and Pepper's (1972) study on the relationship between smoking, psychological states and stress. Here, life crises were signifi- cantly related to psychologi~6al impairment.and a significant positive association was observed between frequency and intensity of life crises, degree of psychological impairment and smoking intensity. These authors concluded that their data supported the notion that smoking served as an adaptive behavior for coping with life's exigencies. mills (1978) has discussed the possible role of tobacco as a coping mechanism in high-arousal situations and there is a growing consensus that tobacco functions as a psychological tool in the attenuation of stress (Stepney, 1979, 1980). Warburton and Wesnes (1979) have suggested that tobacco (nicotine), like anxiolytics, acts as a negative reinforcer by reducing the unpleasant emotional experience of anxiety/arousal provoked by the internal or external environment.. Anxiolytics, however, do not exhibit similar biochemical or electrophysiological actions as ON nicotine and furthermore, anxiolytics are of little aid in 03 smoking cessation. In an attempt to elucidate specific mechanisms _-1 of action, a great deal of research has focussed on behavioral and physiological concommitants of tobacco-induced stress reduction. BATCO document for Province of BritiSh Columbia 12 November 1999 2. Performance Studies on the effects of cigarette smoking on human performance suggest that nicotine and smoking may enhance behavioral efficiency on sensorimotor and cognitive functions by increasing arousal. Improvements in sensorimotor tasks following smoking or oral ingestion of nicotine tablets have been repeatedly observed in long-term vigilance and signal detection tasks which in Kahneman's (1973) terms, require sustained mental effort (Frankenhauser, Myrsten, Post and Johansson, 1971; Mangan and Golding, 1978; Tong, Leigh, Campbell and Smith, 1977; Wesnes and Warburton, 1979; Myrsten and Andersson, 1978; Waller and Levander, 1980). These improvements are considerable, if Comparisons are made between deprived smokers and non-deprived Smokers. Typical non-smoker performances, however, usually lie between these two extremes. Both Battig (1980)' and Stepney (1979) have commented that it is difficult to interpret these results as the observed differeaces may be attributed to a Performance reduction caused by nicotine deprivation, to a performance improvement induced by the administration of nicotine, or to both of them. Indications that improvement may actually reflect on nicotine-enhancement effect is seen in Heimstra, Fallesen, Kinsley and Warner's (1980) study which showed that Vigilance tasks were not affected by smoking deprivation and also by Wessnes and Warburton's (1978) study which made use of nicotine tablets and found improvenents in the performance of non-smokers as well. Studies on cognitive functioning, or more specifically learning and memory, have indicated that smoking exerts adverse effects on short-term memory and improves long-term retention as measuerd by delayed recall (Andersson and Post, 1974; Andersson, 1975; Myrsten and Andersson, 1978; Williams, 1980). As studies on learning and arousal agree that high arousal during learning leads to improved ultimate memory (Kleinsmith and Kaplan, 1963; Berlyne, Borsa, Hamacher and Koeing, 1966; Walker and Tarte, 1963) but leads to detrimental effects an immediate recall, the results of the above tobacco- learning studies were interpreted on the basis of the arousal- in cre as ing properties of smoking. Although this proposed general arousal mechanism seems to be an adequate hypothesis for these tobacco-induced performance changes, an alternative second-order interpretation based on Easterbrook's (1959) data suggests that increased arousal may function by narrowing the focus of attention (i.e., subjects sample a smaller range of potentially distracting, irrelevant external and internal stimuli and focus selectively on relevant stimuli) . This increased ability to attend CO BATCO document for Province of BritiSh Columbia 12 November 1999 _19- selectively to certain relevant asPects of -the stimulus f 'ield while simultaneously inhibiting responss to other aspects of the field may account for Andersson and Hockey's (1975) findings that smoking reduces the incidental learning of irrelevant stimulus material. The results imply that attentional processes are affected by cigarette smoking in the same way as by other Arousal-increasing events. Easterbrook's hypothesis, proposing that the range of cues are reduced in states of high arousal, was supported by these findings. This increased selectivity of attention by tobacco may well be the basis of the frequent reports by smokers that smoking improves their concentration and that not smoking results in extreme difficulty in concentration. As with the cognitive studies, tobacco-induced inprovement in vigilance performance has frequently been interpreted within arousal theory, and indeed there is a solid body of data supporting relationship between arousal and vigilance (mackworth, 1969; Tong, Henderson and Chipperfield, 1980). However, this data may also be interpreted specifically within an attentional framework as Mangan and Golding's (1978) results indicated conclusively that smoking improves vigilance performance by decreasing the subjects errors of commission (false positive) rather than by improving his detection rate. The notion that the attraction of tobacco may lie in its ability to screen or block out disruptive, distracting effects nf irrelevant input on ongoing tasks and performance has been forwarded by a number of researchers (Dunn, 1978; Knottv 1978t 1979; Warburton and Wesnes, 1978, 1979; Wesnes and Warburton, 1978). The empirical basis for this approach is based in part on studies which have shown that tobacco does not appear to have any consistent effect on short-term performance proficiency under conditions conducive to good performance (Dunn, 1978; Stepney, 1979), but it does seem to offer an advantage under conditions likely to interfere with performance. Initial support is forthcoming from studies which show that nicotine reduced the distractibility on the Stroop task (Wesnes and Warburton, 1978) and that tobacco smoking counteracts the decrement in reaction time performance observed under distracting noise conditions (Tong, Knott, McGraw and Leigh, 1974). In contrast to Warburton and Wesnes (1979) who emphasize the impact of tobacco an performance as being an enhancement of signal or relevant target information, due to increased arousal, both Dunn (1978) and Knott (1978, 1979) have emphasized the inhibitory role of nicotine and tobacco in dampening down the impact of hyper-arousal responsivity on task performance ON Co. _-.4 C:D BATCO document for Province of British Columbia 12 November 1999 -20- induced by disruptive, distracting input. An initial study by Dunn (1978) on the disruptive effects of frustration on anger and performance proficiency in a complex perceptual-motor task supported this notion. Here, smokers and non-smokers displayed the same increases in anger, but the performance proficiency scores of the smokers were significantly superior to the scores of both deprived and non-smokers during the anger-inducing period. In Dunn's word's, "... the smoker is unwittingly triggering a physiological response sequence when he smokes which has the effect at the psychological level of improving his coping efficiency in face of otherwise disruptive influences... I am suggesting that ... the subjects emotional or affective arousal had reached a level such as to impair ongoing task performance and that the arousal did in fact impair the performance of the non-smokingand placebo subjects. The smoking subjects, however, were invoking protective physiological mechanisms that had the psychological effect of insulating ongoing performance from the disruptive influence of excessive arousal. Smoking may be having a negative or inhibitory effect upon the intrusiveness of excessive affective arousal upon ongoing behavior (p. 22). 11 This data is to a great extent supported by studies which clearly show that nicotine can play a significant part in reducing the disruptive effects of stress (electric shock) on behavior in animals (Stepney, 1979, 1980). Recently, based on his elactrocortical findings which suggested that tobacco "normalized" central nervous system activity of smokers to a level comparable to that of non-smokers (Knott, and Venables, 1977, 1978), a "filter model" was proposed by Knott (1978, 1979) to relate the relative attentional deficits in deprived smokers and improvement by tobacco to the frequently reported sedational or stress-reducing effects of smoking (Gilbert, 1979). The model hypothesized that (a) relative to non-smokers, smokers deprived of tobacco exhibit an inefficient central filtering mechanism for gating out irrelevant, distracting stimuli and experience input more readily and more strongly and as a result are characterised by a distressed state of relative stimulus overload inappropriate for efficient performance and (b) the attraction of tobacco smoking may lie in its ability to normalize control of stimulus input thereby relieving distress and improving performance and subjective well-being. The filter mbdel runs parallel to findings of greater irritability to intense stimulation and reduced pain thresholds, i.e.f greater sensitivity to pain, observed in smokers relative to non-smokers and subsequent increasing pain thresholds and decreases in stimulus irritability following smoking (Nesbitt, 1973; Schachterf 1973, 1978; seltzer, Friedman, Siegelaub and Collen, 1974).Initial behavioral support for smoker vs. non-smoker differ4inces on susceptibility to distraction effects was C:=> CO C:D cc BATCo document for Province of British Columbia 12 November 1999 -21- observed by Knott'S (1980) finding that high intensity auditory noise significantly impaired smokers performa *nce on a choice reaction time task but had no effect on non-smokers. A subse- quent (1981&)study further indicated that female smokers, who have been reported to have their greatest distraction induced deterioration in choice reaction. Although this data is colored by possible secondary phenomena such as long-term tobacco effects and influences of deprivation, they may be suggestive of predispositional factors relating to the onset of the smoking habit. 3. Psychophysioloqy All of the evidence from the performance studies provide strong support for the notion that tobacco smoking reduces rceived stress by inhibitinq indiscrimate arousal responses to -sruptionsby internal and external input.This neat pic:ture is complicated, *however, by what is probably the least 6quivocal, best established fact about the physiological consequences of smoking - namely that it seems to lead to widespread increases in nervous system arousal with the most obvious alternations being exhibited within the peripheral autonomic nervous system. Larson, Haag and Silvette (1961) have remarked that there are so many peripheral effects of nicotine that the cantial effects seem to be obscured. Similarly, the Surgeon General's Report (1964) showed that "Smoking I to 2 cigarettes causes in most persons, both smokers and nonsmokers, an increase in resting heart rates of 15 to 25 beats per minute, a rise in blood pressure of 10 to 20 mm Hg systolic and 5 to 15 mm Bg distolic, and an increase in cardiac output of about 0.5 I/min/sq.m. (p.318) In short, there are a host of transient increases in physiological responses to smoke inhalation and they include elevated heart rate, elevated coronary flow, elevated blood sugar level, lower cutaneous temperature in the extremities, increased blood flow in skeletal musculature, a reactive release of adrenalin and alterations in electrical potential patterns of the brain (Dunn, 1973), all of -hich are customarily associated with increased states of arousal : activation or emotionality. As theories of emotion view increased autonomic arousal as an essential component of emotional processes, and as tobacco increases physiological arousal yet fre5uently reduces behavioral effects of arousal and self-repcrt measuies, an intriguing paradox pervades the motivational literature. Recently~ there have been an increasing number of studies and theories (Gilbert, 1979; Schachter, 1973) that pertain to the resolution of these apparently contradictory findings and there is a general picture emerging which indicates physiological evidence for tobacco induced arousal reduction as apparent in specific electraphysiolo- ical measures and eliciting this response it is important to look' C= at the effects of nicotine, not in isolation, but in conjunction with the situation in which the nicotine is administered, and also C_ in relation to the personality of the subject. The combination of these three factors (amount of nicotine taken in, arousal- producing situations and low or high-arousal organism) determines the outcome of any tobacco experiment. BATCO document for Province of BritiSh Columbia 12 November 1999 -22- Neurophysiological studies in animals are in general agree- ment that the effects of small and medium does of nicotine on the central nervous system (CNS) arc biphasic, there being a marked sequential effect, with a primary arousal phase being followed by a secondary depression effect on electro corticograms (Schaeppi, 1967; Goldstein, Beck and Mundschenk, 1967). There is also evidence that while small dose of nicotine increase arousal, larger doses may decrease arousal. Thus, Armitage, Hall and Sellers (1969) found that doses of 2 mg/kg every thirty seconds for twenty minutes, given intravenously to cats, caused desynchronization of the electrb- cardiogram indicating cortical activation, and an increase in the release of cortical acetylcholine. However, a larger dose given less frequently (4 mg/kg every minute for twenty minutes) caused sometimes an increase and sometimes a decrease in cortical activity, such changes being accompanied by an increase or a decrease in cortical acetylcholine output. On this basis and on the basis of the previously discussed distraction based stress hypothesis, one would expect that the action of tobai:co or .nicotine on the human EEG should mimic the action of anxiolytics but the electrophysiological evidence does not strongly support this notion. In a pioneering comparison of nicotine and an anxiolytic (Murphree, Pfeiffer and Price, 1967), the means and variance for the total energy increased across the spectrum of EEG activity after the anxiolytic while there was a general reduction in means and variance across the whole spectrum for nicotine. It was concluded that the nicotine changes were more typical of a stimulant drug than an anti-anxiety compound. Sub- sequent EEG studies, reviewed by conrin (1980) have for the most part focussed on 8-12 Itz alpha activity and are in general agreement that tobacco smoking increases the dominant alpha frequency.Knott and Venables (1977) observed a "normalizing" effect of tobacco inhalation on dominant frequency. Analysis of pre-smoking activity revealed a slower dominant frequency on deprived smokers relative to non-smokers and non-deprived smokers and the immediate effect of smoking was to increase dominant alpha frequency in deprived smokers to a level comparable to non- smokers and non-deprived smokers. Instead of relatinq these findings to an arousal phenomcna, Knott and Venables cited a solid body of literature which suggested that dominant alpha frequency reflected a CNS scanning or gating process involved in stimulus-input and in cognitive processing (Lykken, 1975). As this tobacco-induced shift in EEG frequency may reflect improved cortical scanning and speed of cognitive processing, the authors suggested that smokers may smoke in order to achieve the psychological state of increased vigilance and attention associated with this shift. on this basis it would seem that this repeatable shift in dominant frequency induced by smoking may have particular functional significance in relation to both the distraction hypothesis discussed earlier and in relation to predisposing electrophysiological factors to the smoking habit. The dominant rhythm appears to reflect CHS maturation, appearing at 3 or 4 months of age at 3-4 Hz and increases to the adult frequency of about 10 Hz at about 10 years of age. This rhythm, although responsive to static factors, under normal circumstances remains constant day in and day out and month by month(Lindsley and Rubenstein, 1937). Is it possible, that the slower rhythm in CZ) r\-) 0-1 c0 -j CD CC) c::> BATCo document for Province of British Columbia 12 November 1999 deprived smokers represents a delayed CNS maturation, and hence a relatively inherent perceptual deficit which may 'set up' a need or predisposition for tobacco (or some Other substance. or activity) which is readily available and can specifically alter the rhythm at any given time? As it is reasonable to suppose that the satisfaction of tobacco smoking is ultimately dependent upon cerebral events, a number of studies have focussed on the measurement phasic potentials which sensory stimuli evoke (ERPs) in the cortex as a way of studying cerebral processes. The initial study by Hall, Rappaport, Hopkins and Griffin (1973) on visual evoked potentials showed that tobacco smoking increased amplitudes of late components (more than 80 ms after stimulus onset), changes which are consistent with the contention that tobacco increases arousal. Later studies by Friedman, Goldberg, Horvath and Meares (1974), and Friedman and Meares (1980) suggested that the tobacco effect may be modality specific, increasing late components of the visual 6voked poten- tial and decreasing late components of the auditory evoked potential. rhe reduction in late auditory evoked potential components is of interest in that Knott (1980) had shown that the performance of smokers as compared to non-smokers, was significantly more affected by high intensity noise. Knott and Venables (1978) observed a .normalizing" effect of tobacco smoking on visual cortical evokcd responses in that deprived smokers evidenced faster latencies and larger amplitudes (i.e. more sensitive) than both non-smokers and deprived smokers who exhibited comparable responsiveness. The authors suggested that a possible attraction of tobacco smoking may lie in its ability to function as a "chemical stimulus filter" thereby reducing the distracting effect of irrelevant, adverse stimuli on performance efficiency and emotional tonus. Complimentary results are provided by Vasquez and Toman's (1967) observat-ion-of a decrease in late E.R.P. amplitudes during smoking, an increase during abstinence. These evoked potential studies receive some support from an animal investigation by Pradhan and Guha (1976) who recorded from the auditory cortex of cats and observed that the initial effect of smoking dosages of nicotine (12.5 mg/kg) reduced I)oth amplitude and area measures of late components of the auditory evoked response. This appeared to be an apparent selective effect as nicotine produced general CNS excitation at the same time. . A number of additional electrophysiological studies have provided support for the notion that tobacco dampens CNS responsivity to stimul input and therefore they are of particular interest for the distraction hypothesis. Friedman, Horvath and Meares (1974) and Mangan and Golding (1978) found that tobacco smoking increases the speed of habituation of CNS (alpha blocking) and ANS (skin CD conductance responses) responding to repeated presentations of high intensity auditory stimulation. These authors suggested that a possible means of reinforcement of tobacco smoking may lie in its CO ability to stimulate CNS inhibitory mechanisms (without simul- taneous reductions in CNS excitatory processes) resulting in the "screening out" of irrelevant and irritating sensory input into cc consciousness. In this regard, it is interesting to note Mangan and Golding's (1978) observation that inhibition of momentary BATCo document for Province of British Columbia 12 November 1999 -24- spontaneous imbalances in autonomic arousal may be a physiological basis of tobacco induced improvement in vigilance performance. During their vigilance task, it was observed that false positives occurred most often immediately following a spontaneous skin conductance fluctuation. As smoking reduced both spontaneous fluctuations and false positives they inferred that performance improvement was due to the increased stability of the autonomic arousal system. The possibility that smokers may exhibit greater autonomic responsivity than non-smokers was confirmed by Knott (1980) who observed that smokers exhibited significantly higher resting skin conductance levels, faster response latencies, large response amplitudes and significantly faster and larger cardiac accelerations to a high intensity auditory stimulus. more recently Knott (1981b) has observed that female smokers relative to male smokers and female and male non-smokers, exhibit significantly higher resting skin conductance levels and larger skin conductance responses to high intensity auditory stimuli. This is in line with a previously discussed study which indicated that 'female smokers exhibit a more frequent craving in high arousal/anxiety situations. The contingent negative variation (CNV) is a small scalp- recorded negative potential which slowly builds up between a warning signal and an imperative signal (such as in a standard fore period reaction time task) requiring the subject to carry out some response, usually a motor response such as pressing a button. This slow cortical potential occurs in an expectancy situation is sometimes referred to as an expectancy wave. Tecce, Saviqnano-Bowman and Cole (1978) have proposed that two pro- cesses of arousal and attention become coupled under drug administration, such that over increase in attentional. demand will increase arousal, but an over increase in arousal will reduce attentiveness and so attenuate optimal CNV devclopment. The function of self regulated drug administration such as smoking is thus presumably to adjust this distracl:ion - arousal coupling to an optimal level according to task demand. As Ashton and Watson (1970) and Ashton, Savagel Telford, Thompson and Watson (1972) have shown that situational stress radically affects smoking strategies (i.e., increases puff frequency and thus nicotine dosage) this theory would preOict that individuals differing in Arousal levels would adjust their smoking parameters accordingly (e.g. puff frequency, duration, volume etc.) so as to bring CKV development to an optimal level. Studies an CNV, tobacco and individual differences have on the whole supported this contention and failure to take into account personality differences may have been the basis for the non-significant tobacco effect on CNV observed by Knott and Venables (1980). The initial study by Ashton, Millman, Telford and Thompson (1974) and a subsequent study by Eysenck and O'Connor (1979) showed that individuals C=) high in cortical arousal (introverts) exhibited consistent r__P CNV amplitude reductions (depression) following tobacco smoking C71 while individuals rated low in cortieal arousal (extraverts) 00 showed consistent increases in CNV amplitude (stimulation) ___2 following smoking. Estimates of nicotine intake (such as puff volume, frequency, butt analysis) indicated that extraverts co BATCo document for Province of BritiSh Columbia 12 November 1999 -25- took in more nicotine than introverts. Subjects who said they were relaxed by cigarette smoking tended to show a diminished CNV and these results parallel reports of a greater desire to smoke for tranquilization and stress-reduction in introverts (Gilbert, 1980). Subsequent studies by Ashton, Marsh, Millman, Rawlins, Telford and Thompson (1978) on effects of intravenous injections of various smoking does of nicotine on the CNV Produced a dose-response relationship in which smaller doses were found to have a stimulant effect and large doses a depressant one. On commenting on these findings, Stepney (1979). stated that smoking is capable of producing either stimulant or depressant CNS effects, depending on the smoker's environment and the dose of nicotine taken, and that the point at which the nicotine dose crosses over from having a stimulant effect to having a depressant one is within the range of dosc that can be obtained from a cigarette. This would give the smoker an extremely useful tool for arousal control. The notion that smokers may use cigarettes to obtain a specific effect on arousal in the context of the demands of a specific environment is supported by a study by Myrsten, Andersson,Frankenhaeuser and Elgerot (1975). Here, smokers who self-reported their strongest need to smoke under low- arousal conditions (low-arousal smokers) performed and felt better when smoking under laboratory tasks of low complexity and smokers who self-reported their strongest need to smoke under high-arousal conditions (high-arousal smokers), performed and felt better when smoking under laboratory tasks of high complexity. As with extraversion-introversion, one nay predict from the above studies that under conditions of stress and overload, high neuroticism scoring subjects should benefit more from smoking than low neuroticism scoring subjects. Studies by Kucek (1975) and'Warburton and wesnes-(1978) bear this out. In the former study, subjects were tested in an experiment under conditions of information overload and smoking had a beneficial affect on the performance neurotic subjects. In the Warburton and Wesnes study, an attentional vigilance task was employed and it was found that smoking helped high N scoring subjects, but not-1.9w N scoring subjects. The correlation between improvement and neuro- ticism was 0.68 which indicates the importance of personality in evaluating the effects of smoking on performance and stress reduction. Finally, an additional target physiological system implicated in tobacco-induced stress reduction is skeletal muscle activity. A number of studies have reported on the effects of nicotine and tobacco smoking on skeletal muscle tone in men. Webster (1964) reported a short-lived reduction in muscular tension in spastic patients after smoking a single cigarette and Domino's (1973) study showed a significant reduction of the patellar tendon reflex C7, (knee jerk) and associated clectromyographic (EMG) musculature cz> following tobacco smoking and oral administration of nicotine arousal. Hutchinson and Emley (1973) established that deprived smokers showed an increased frequency and force of spontaneous cc masseter EMG contractions and found that 5 mg of nicotine in water decreased the frequency and force of masseter EMG jaw BATCo document for Province of BritiSh Columbia 12 November 1999 -26- contractions to intense auditory stimuli in both smokers and non-smokers. This consistent picture is disturbed, however by Fagerstrom and Gotestam's (1977) study which showed that resting EMG activity of the trapezius neck muscle increased during tobacco smoking. One must conclude that nicotine, or at least tobacco smoking of varying nicotine content, has biphasic effects as far as EMG activity is concerned. Stimulant and depressant effects seem to be dependent on both the site of recording and whether or not one is focussing on tonic or phasic components. 4. Neurophysiology Up to this point, the neurophysiological mechanisms relevant to the proposed filter model have not been discussed, and although at this stage of research it is recognized that discussion is purely speculative, some recent neurophysiological research is worth mentioning. Jasper (1958) and other researchers .(Dcmetrescu and Demetrescu, (1962) have implicated the reticular formation in controlling selective responsiveness to significant stimuli by preventing general alerting actions to ala incoming stimuli and this focus parallels the findings of investigations which found significant effects of nicotine on this CNS site (Domino, 1967) However, as with recent empirical data which has focused on the role of the limbic system in the control of attention, neurophy- siological investigations of nicotine action have also attributed the effects of nicotine to changes exerted by the limbic system. Here, employing electrophysio logical measures, Nelsen and colleagues - (Bhattacharya and Goldstein, 1970; Nelsen, Pelley and Goldstein, 1973) have provided evidence that the hippocampal limbic system is a major target area for nicotine, in that cortical activity under nicotine treatment is controlled more by the hippocampus than by the reticular formation. Based on Routtenberg's (1968) hypothesis that hippocampal activity inhibits the reticular formation, Nelsen (1974) hypothesized that the neurophysiological mechanisms underlying nicotine-seeking behavior lies in its ability to counteract inappropriate responding by the reticular formation, by its (nicotine) action on the limbic system. support for this hypothesis was observed in their animal investigation in which nicotine treatment was found to counteract decreased performance in selective attention which was induced by electrical stimulation of the reticular formation. On this basis, these authors suggest that a possible motivation underlying smoking behavior is its ability to reduce reticular excitation which is manifested in a hyper-stimulated anxious state inappropriate for effective behavior and to engender what might he considered a state of useful behavioral arousal. In relation to the filter model, it is interesting to speculate here whether the often reported relaxation smoking is related to inappropriate reticular hippocampal filtering or inappropriate hippocampal limbic control of reticular filtering' (or both) in deprived smokers relative to non-smokers. CID cc BATCo document for Province of British Columbia 12 November 1999 V3 :. SUMMARY, RATIONALE AND OBJECTIVE O'F STUDY An understanding of the etiological factors in the acquisition of the tobacco habit has remained elusive despite intensive study by researchers in the biological and social sciences over the past several decades. while each discipline has contributed important information on the factors which predispose an individual to acquire the habit, the necessary conditions for becoming a smoker have yet to be defined. While psychosocial factors play a crucial role in habit onset, the approach of this paper has been to examine the possible role of organismic trait and state factors in relation to pre- disposition to smoking. More specifically, the issue raised in this paper was whether within a population of children there are individuals who exhibit specific trait and trait arousal factors ?hich lead to experimentation with and repeated use of tobacco for its perceived and/or real affects in modifying physiological and consequent behavioral systems. In general, the literature which relied primarily on studies of adult smokers, supported an arousal interpretation in that: 1. in general, smokers tend to exhibit personality profiles indicative of physiological hyper-responsivity and there is evidence to suggest that these profiles pre-date the smoking habit; 2. in general, smokers report that they smoke to reduce byper-arousal and experimental studies support the contention that tobacco reduces both behavioral and subjective measures of arousal: 3. in general, and in particular for smokers assessed as exhibiting high-arousal profiles, tobacco smoking exhibits a negative inhibitory effect upon the intrusiveness of disruptive and excessive arousal upon ongoing physiological, behavioral and cognitive processes. A good portion of this paper has been aimed at presenting available evidence which may be indicative of disturbances in arousal processes. From the studies cited, it appears that although no specific target physiological system can be complicated in sm6king motivation, it appears that a host of CNS and ANS irregularities in the direction of hyper-responsivity may exist in smokers and thus may play a potential role in the onset of the habit. Integrally linked with this picture is the concept of defective filtering which implies certain characteristics ,of the individuals' attentional style that tends to augment the intensity and impact of information both from the internal and external world. For this type of individual the attraction of tobacco seems obvious, The mechanism of action of nicotine that has been proposed is not the same as negative reinforcement. Cz:) Negative reinforcement occurs when a drug terminates or reduces a negative affect. Thus an anxiolytic is taken during aversive events to enable the person to escape from the consequences or CP before these events in order to avoid them. Alcoholics seem to -11 drink for' this reason. CD co BATCo document for Province of BritiSh Columbia 12 November 1999 -28- In contrast nicotine enables the smoker to confront his problems and perhaps overcome them. Thus we would paraphrase nicotine's action by saying that nicotine is a drug of confronta- tion and not escapism, a sharpening drug not a blunting drug. In this way it is a unique anti-anxiety compound. it increases clarity of thought and decreases distracting, disruptive input as a consequence of its action on physiological systems (Warburton and Viesnes, 1979). In summary, the general trend toward hyper-responsivity in smokers supports the contention of a "physiological susceptibility" (acquired or inherited or both) for a coping behavior aimed at arousal reduction. Objective To investigate predisposing psychophysiological parameters in the acquisition of the tobacco habit by implementing'a 5-year longitudinal investigation which will: (a) examine psychophysiological measures in a population of children prior to the acquisition of the smoking behavior; and (b) use these measures as a data base for subsequent follow-up of the sample to identify predictive factors antedating the onset of smokers status. VII. SIGNIFICANCE CF THE STUDY In general it will provide objective, quantified information on motivationally critical relevant antecedant factors predisposing to the acquisition of the smoking habit. In particular, the study will provide objective information on general *stress responsivity" profiles of smokers prior to the onset of smoking and this will be informative as to whether a "stress-reduction need" is present prior to the acquisition of smoking as opposed to being a consequence of long term effects of smoking. The acquired data base, both psychological and psychophysiologi- cal will be an invaluable source of information for future studies into (a) motivational mechanisms - e.g. to what extent are adult smoking parameters, or difficulty in abstinence, etc. related to pre-smoking characteristics, and (b) health-disease oriented mechanisms - e.g. to what extent is pulmonary cancer in smokers related to pre-smoking characteristics and do certain individual "stress response" individuals exhibit a higher probability of PQ cancer proneness regardless of smoking habit, etc. cr.~ co co . BATCO document for Province of BritiSh Columbia 12 November 1999 -29- VIXI.METHODOLOGY 1. Subjects The study starts with a pool of children to be selected from various.schools of the Ottawa or Carleton School Board. In order to obtain permission to conduct research within the schools, a formal proposal including a statement of the problem area, theoretical framework, hypothesis to be tested, design and details of the procedures and school resources to be used will be submitted to the respective research committees. Following acceptance of the research proposal, individual principals of several schools will be approached for involvement and a study nrotocol and necessary consent forms will be sent to the homes or parental consent. Approximately 300 children (175 males) will be sampled at 11 years of age at Year I. Because of the expected higher .requency of daily smoking in females in the follow-up at Year V, a larger number of males will be sampled so as to ensure approximately equal outcome frequency distribution across sexes. Based on the 1980 statistics of the Department of National Health and Welfare, the composition of smokers, non- smokers at Year I and V should be similar to that shown below (Table.1). YEAR 1: AGE 11; M - 175; F = 125. NEVER SMOKED TRIED SMOKING SMOKE DAILY OTHER M F M F M F M F N 97.5 80.6 50.4 31.3 2.5 1.1 24.7 12.0 Other category includes unclassified cases, those who indicated they had smoked but for whom other details were not known. YEAR V% AGE 15; M = 175 1 F = 125. NEVER SMOKED TRIED SMOKING SMOKE -DAILY OTHER M F M F M F M F N 66.3 37.5 53.2 31.8 36.7 33.8 36.2 21.9 Other category includes unclassified cases, those who indicated' c0 they had smoked but for whom other details were not known. BATCO document for Province of BritiSh Columbia 12 November 1.999 _30- The 300 children will conform to the following criteria: (1) normal I.Q., i.e. at least 80 on either Verbal and/or Performance scale of the WISC; (2) living at home; (.3) no neurological or physical disease; (4) no psychiatric history; (5) no current.medication. In an attempt to control for socio- economic factors, the parents occupational status will be employed as a rough index to ensure a sample selection with equal distribution across social classes. 2. General Design and Procedures The five year longitudinal design will consist of 5 stages as shown below: VEAR I -SMOKING ASSESSMENT AND TESTING YEAR II MONITORING IDENTIFIERS AND DATA ANALYS.IS.I YEAR III SMOKING ASSESSMENT YEAR IV MONITORING IDENTIFIERS YEAR V SMOKING ASSESSMENT, RETESTING AND DATA ANALYSIS II Year I will be concerned solely with the acquisition of three types of data: (1) descriptors; (2) identifiers; (3)-predictors. Descriptors: In essence, the descriptors are variables which are used as criteria for eligibility to enter the study sample, and one in the sample, for classification within the sample. in this case, the purpose of the descriptors are to elicit infor- mation on and factors related to the childrens' smoker vs. non- smoker status. Descriptors will be based on a standard pre- coded "smoking assessment" questionnaire which will elicit information on: -personal experience with cigarettes -circumstances surrounding and reactions to first cigarette -smoking habits of parents, siblings and friends -personal attitudes to smoking and reasons for and against, sm.oking -personal attitudes of parents, siblings, friends and school towards smoking -knowledge of health hazards arising from smoking %) 0 N co C--) co 13 ATCO document for Province of BritiSh Columbia 12 November 1999 _31- For the purpose of classification, children will be cate- gorized in Year I into one of four categories: non-smoker; experimental smoker; ex-smoker and regular smoker. In turn, each of the-smoker categories will be sub-divided to form groups reflecting variations in frequency of usage. In addition to these descriptors, all subjects will be required to give a sample of expired alvealor air in order to determine carbon monoxide levels. This measure will be used to assess the validity of the self-reports of smoking behavior in the children. Children categorized into any one of the three smoker categories will also be given a "smoking motives" questionnaire in order to assess the role of cigarette smoking an psychological factors. rdentifiers: The sole purpose of identifiers is to allow ease 3 t_1ooEa_U`on -of target sample at follow-up. Identifiers will be established an initial contact with the sample via i pre- coded standardised questionnaire which will elicit routine descriptive data such as name, home address, phone, school, parents work address and similar data for the closest relative. Predictors: Although the primary predictors in this study are psychophysiologically based, it is obvious from the literature review that there is significant interplay between physiological processes and psychological, social, behavioral and personality factors in determining future smoker vs. non-smoker status. On this basis, the test assessment of the entire sample will include the following procedures all of which will be obtained with appropriate consent: - Standardised psychophysiological testing of central, autonomic nervous system and behavioral reactivity. - Standardised pre-coded interview with parent having the major rearing responsibility. - Standardised personality testing with specific form on extraversion and neuroticism, dimensions. - Standardised coding of scholastic records and teachers behavior rating. - Standardised coding of school medical health records. - Standardised coding of obstetric records. Years II, III and IV will involve contact with the school and/or home to ensure identifiers are updated. Year III will also involve-contact with the sample pool for a repeated smoking assessment. This will involve the presentation of the identical pre-coded questionnaire and carbon monoxide sampling employed for identifying "descriptors" in Year 1. This repeated measurement will form the basis of a more detailed analysis.of early vs. late onset factors in the developmental processes cc Of the tobacco habit. BATCo document for Province of British Columbia 12 November 1999 - J.L - Year V, the follow-up period, will again involve presentation of the standardised "smoking assessment" questionnaires and carbon monoxide sampling. Having cbtained this information on smoker vs. non-smoker status, sub-samples of clearly defined non-smokers, ex-smokers, experimental smokers and regular smokers will be retested on psychophysiological measures in an attempt to relate change in smoker. status to changes in physiology. 3. Psychophysiological Test Battery The abundance of research procedures in psychophysiology reflects the popularity of these techniques as a means of testing models and underlying mechanisms of behavior. In comparison to clinical judgements and, for that matter, other biological measures in the clinic, psychophysiological measures are non- .nvasive, methodologically simple, make few demands on the subject and have the advantage of providing data that may not be directly observable. In a similar vein, the covert nature of the psychophysiological measurement is of potential and unique value in longitudinal studies of predictors in that, in contrast to more overt measures, it enables the investigator to examine aspects of dysfunction possibly before they become apparent to the outside observer, and even perhaps before they become apparent to the subject himself. The choice of target physiological response systems and procedural paradigms is to a large extent based on previous research and on the stance of the investigator. As there is no published psychophysiological data which can be used as a direct basis for a prospective study on smoking the battery of response measures and procedures to be employed are chosen on the criteria that they have been shown to be sensitive to (a) smoker vs. non-smoker differences and (b) effects of tobacco smoking. In addition to behavioral reactivity, the physiological response systems will include tonic and phasic components of: a. Skeletal muscular activity 1. Electromyographic (EMG) activity b. Autonomic nervous system activity 1. Electrodermal (SC; skin conductance) activity 2. Cardiovascular (HR; heart rate) activity C. Central nervous system activity 1. Electroencephalograms (EEG; power spectrum) 2. Event related cortical evoked potentials (ERP's) ON CO CD \10 CD 13 ATCo document for Province of BritiSh Columbia 12 November 1999 _J -1 - Each child will attend the ROH laboratory for one session. It is proposed that the measurements of ANS, CNS and skeletal muscular activity will take place during the.,one recording session-so as to offer the possibility of inter-relating and integrating these variables. The total session will be divided into fiVQ sections proceded and followed by time allowed for the placement and removal of electrodes.. The total testing time will be approximately 2.0 hours. Section 1: Examination of ANS and EMG Orienting (OR) and Defensive (DR) Responses Task: This will involve the presentation of a series of low and high intensity auditory stimuli for the purpose of.eliciting peripheral physiological features of *intake and rejection" to simple non-signal stimuli. Measures: Analysis will focus an both tonic and phasic (temporal and amplitude) components of SC, 11R, EMG and EEG alpha (8-12 Hz) responses. Section 11: Examination of cortical Augmenting and Reducing Task: This will involve the repeated presentation of auditory stimuli over four stimulus intensities for the purpose of examining the relative tendency of the CNS to .augment or dampen" the perceived impact of incoming stimuli. Measures; Analysis will focus on latency and amplitude measures of late components of the averaged cortical evoked response. Measures of SC, HR and EMG will also be examined as general indicators of tonic arousal. Section 11T: Examination of EEG During a Cognitive Stress Test Task: This will involve the 1 minute presentation of the Stroop Colour Word Test preceded and followed by 1 minute of rest. The purpose here is to elucidate correlates CNS processing during a task with inherent disruptive and distracting properties. Measures: Analysis here will focus primarily on power spectrum analysis of EEG from 0-20Hz and measures of SC, HR and EMG will also be examined as general indicators of tonic and task-induced arousal. Section IV: Examination of "Slow" Component Correlates of Cortical Potentials During a Choice Reaction Time Task: Effects of Distraction NJ Task: This will involve the presentation of two sets of 10 co three-choice reaction times. One set will be provantud alona and a ancand act will hci pronented in.combination with an additional distracting task. Each trial will consist of a presentation of a warning stimulus followed in 6 seconds by an imperative (go) stimulus. BATCo document for Province of British Columbia 12 November 1999 -34- Measures% Analysis will focus primarily on the slow cortical negative potential (contingent neg~ative variation) elicited between the warning and imperative stimulus. In addition to reaction time, latency and amplitude measures of evoked potentials to each stimulus will be examined and tonic and phasic components of SC, HR and EMG will be examined for the effects of distraction. Section V: "Attentional and Cocnitive" Components of Cortical Potentials During a Divided Attention Task Task; This will involve the presentation of a multi-channel divided attention task in which subjects will listen to a sequency of tones 0 types) delivered at a high presentation rate and at one of three spatial locations (channels) , left ear,,right ear . and an apparent position midway between lift and right ears. Subjects will be instructed to monitor one and two channels and detect slightly louder target tones in the monitored channel. Measures: Analysis will focus primarily on latency and amplitude measures of early (Nl) attentional and late (P3) cognitive components of the cortical evoked responses to attended (relevant stimuli) and non-attended (irrelevant stimuli) channels. Behavioral measures of reaction time and detection will also be examined and testing measures of SC, HR and EMG will be examined as measures of tonic arousal. General Psychophysiological Analytical Method It is proposed to acquire data from the polygraph channels in three steps: paper record; analogue tape; and computerised digitization. An analogue tape recorder is available from the ROH and a microprocessor is now set up for analyogue-to-digital conversion of eletrophysiological signals. Software programs will have to be developed further for easy-to-handle data acquisition, storage and analysis stages. 4,.. Statistical Analysis The data from the initial phase (Year I) of the study will be subject to multivariate analysis, in particular (a) principal component analysis - to determine the characteristics of the overall sample (and to compare the sample with currently available norms), and (b) discriminant function analysis with grouping on non-smoker vs. experimental smoker status so as to N.) determine the characteristics of each group. ON CC) Upon completion of the final phase (Year V) , multivariate __11 analysis will be performed. The data from the first phase of C=) the study will be subject to a discriminant function analysis 1110 with grouping as per smoking status as determined in the final %) BATCo document for Province of British Columbia 12 November 1999 phase in order to elucidate variables particularly relevant to the etiology of smoking. Principal component profiles of each smoking status group will be drawn from initial and final data in order to investigate the role of the various measures in the development of the final smoking status. rurther multivariate and univariate analysis will be performed as necessary to "explain' the data. C=) N.) C71- CO BATCo document for Province of BritiSh Columbia 12 November 1999 REFERENCES AGUE, C.: Smoking patterns, nicotine intake at different times of day and changes in two cardiovascular variables while smoking cigarettes. Psychopharmacologia, 30, 135-144, 1973. ANDERSSON, X.: Effects of cigarette smoking on learning and retention. Psychopharmacologia, 41, 1-Sp 1975. ANDERSSON, K. and HOCKEY, G.: Effects of cigarette smoking on incidental memory. Reports from the Department of Psychology, University of Stockholm, no. 455, 1975. ANDERSSON, X., POST, B.: Effects of cigarette smoking on verbal rate learning and physiological arousal. 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