Psychopharmacology (1992) 108 : 485-494

Psychopharmacology © Springer-Verlag 1992

Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease G.M.M. Jones 1' 2, B.J. Sahakian 4, R. Levy I, D.M. Warburton 3, and J.A. Gray 2 1 Section of Old Age Psychiatry, Department of Psychiatry, and 2 Department of Psychology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK 3 Human Psychopharmacology Group, Department of Psychology, University of Reading, Earley Gate, Reading RG6 2AL, UK 4 Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK Received March 10, 1992 / Final version April 8, 1992

Abstract. This single-blind, placebo controlled study reports on the effects of administering three acute doses of nicotine (0.4, 0.6 and 0.8 rag) subcutaneously to a group of Alzheimer's disease (DAT) patients (n=22), young adult controls (n = 24), and normal aged controls (n=24). The study extends our previous findings obtained using smaller groups of subjects. Drug effects were examined on three computerised tests: the first measuring rapid visual information processing, sustained visual attention and reaction time (RVIP task); a delayed response matching to location-order task measuring sustained visual attention and visual shortterm memory (DRMLO task); and a finger tapping test measuring simple reaction time (FT task). The critical flicker fusion test (CFF) was used as a measure of perception and the WAIS digit span forwards (DS), of auditory short-term memory. Tests were graded in difficulty, titrated to avoid floor and ceiling effects so that meaningful, direct comparisons between groups could be made. Nicotine significantly improved sustained visual attention (in both RVIP and D R M L O tasks), reaction time (in both FT and RVIP tasks), and perception (CFF task - both ascending and descending thresholds). Nicotine administration did not improve auditory and visual short-term memory. There were no consistent, overall patterns of difference in pertbrmance between smokers and non-smokers in the control groups, or between males and females in any group. Despite the absence of change in memory functioning, these results demonstrate that DAT patients have significant perceptual and visual attentional deficits which are improved by nicotine administration. The importance of measuring multiple abilities in future drug studies is emphasized and results are discussed in terms of nicotine's actions on attention, information processing and short-term memory. Key words: Nicotine - Alzheimer's disease AttentionInformation processing - Short-term memory Correspondence to: J.A. Gray

People suffering from Alzheimer's disease have been shown to have large reductions of nicotinic receptors in both neocortex and hippocampus (Perry et al. 1986, 1987). The status of the muscarinic receptors is controversial but they appear to be preserved in large measure, compared to their nicotinic counterparts (Perry et al. 1987; Mash etal. 1988). However, the significance of this result for understanding the cognitive deficits in Alzheimer's disease, and the possible treatment thereof, is not yet clear. It has been suggested that the cognitive deficits that characterise Alzheimer's disease largely rise from degeneration in forebrain cholinergic systems. This "cholinergic hypothesis" suggests that treating patients having dementia of the Alzheimer type (DAT) with cholinergic agonists might boost cholinergic functioning pre- and/or post-synaptically and so also cognitive functioning. Given current knowledge about the cholinergic system, trials using the cholinergic agonist, nicotine, are a novel but logical next step in searching for treatment approaches. The actions of nicotine are varied and complex. It not only acts post-synaptically, but recent evidence shows that it increases the release of acetylcholine (Clarke et al. 1986; Araujo etal. 1988; Richard et al. 1989). In animal models of DAT, involving destruction of the nuclei of origin of the forebrain cholinergic projection system, acute systemic administration of nicotine has been demonstrated to reverse otherwise enduring cognitive deficits, probably by increasing the ability to attend to informationally significant environmental stimuli (Hodges et al. 1990, 1991). A detailed review of the actions of nicotine is given in Wonnacott et al. (t990). Our earlier preliminary report (Sahakian et al. 1989) on the effects of administering three doses of nicotine subcutaneously (SC) was based on data from seven DAT patients and from young and aged control groups matched for sex and premorbid IQ. This paper reports on the full sample of patients and control subjects.

486

Materials and methods Sample

There were three groups: 24 " y o u n g " normal adults; 24 " a g e d " normal control subjects and 22 patients with DAT. There were equal numbers of males and females and smokers and non-smokers in each of the three groups, except for the DAT group, which had only nine smokers. Table 1 provides descriptive information for the patient and control groups. The National Adult Reading Test (Nelson 1982) was used to match the three groups for premorbid verbal IQ. Non-smokers were defined as being people who had never smoked, or who had quit more than 2 years prior to joining the study; this is the time required to reverse most of the risks and physiological changes induced by smoking (Royal College of Physicians 1983). People were considered to be smokers if they smoked currently. Even by this definition, several DAT patients had an ambiguous smoking status (see caption for Table 1). The young adults were students and community volunteers and the elderly controls were community volunteers and spouses of patients. Patients had been assessed at the Maudsley Hospital Memory Clinic (Philpot and Levy 1987) and diagnosed by a consultant psychiatrist, in agreement with a second psychiatrist, as having DAT, following the N I N C D S - A D R D A criteria for "probable Alzheimer's disease" (McKhann et al. 1984). All patients selected were considered to be in the mild or moderate stages of the disease and fell into stages 1 (n= 11) or 2 (n= 1:l) of the Clinical Dementia Rating Scale (CDRS), (Hughes et al. 1982).

Protocol

The study was conducted single blind, patients and control subjects being unaware of what dose, or whether nicotine or placebo was being administered. Written permission for participation in the trial was obtained from all subjects, including patients' spouses. Each person participated in two to five training sessions so that they had reached asymptotic performance on the learning curve for the computerized tests and were comfortable and familiar with them. Thereafter, they attended seven test sessions during which drugs were administered in the following order: an undrugged session for baseline measurements; the first placebo; three sessions with nicotine given in ascending dose order (0.4, 0.6 and 0.8 rag); a second placebo; and a final undrugged session for baseline measurements. Each test session lasted about 40 min; all training and test sessions were completed within a 2-week period. Nicotine doses were always given in ascending order; since this was, to our knowledge, the first trial of the SC route of administration, it was not possible to randomise the order of doses for ethical reasons. The placebo was administered as 0.5 mg normal saline and nicotine was given in the form of the hydrogen tartrate (2 mg/ 2 ml in NaC1 0.9% W/V). Nicotine and saline were injected in the upper, non-dominant arm. Data from the two baseline and two placebo sessions were summed and the two means calculated separately.

Test s e s s i o n s

Test sessions of 40 min were used, since work on the pharmacokinetics of subcutaneous nicotine injections has shown that this covers the period of maximum physiological activity of nicotine (Russell et al. 1990). All of the following tests were administered during each session.

Tests

In view of the distinctive distribution of nicotinic receptors, particularly in regions such as hippocampus, sensory and frontal regions

of the cortex (Zilles 1990), tasks were selected which are thought to be especially sensitive to functions subserved by these regions. Tests of rapid visual information processing (RVIP), delayed response matching to location-order (DRMLO), simple and complex reaction time (in the RVIP, D R M L O and finger tapping tests) critical flicker fusion (CFF) and digit span were included. The approximate duration of the individual tests was: RVIP, 7 min; finger tapping, 2 min; digit span, 5 min; CFF, 5 rain; D R M L O , 15-20 rain. Tests were always given in the same order and, unless a subject asked for a break, tests were conducted consecutively and continuously. More extensive details of the computer tests and the instructions to subjects given for each test are contained in Jones (1990). R V I P task. The first of the two computerised tasks, the RVIP task, was primarily a test of attention and information processing with a small working memory component. Our version was substantially modified and simplified from that of Wesnes and Warburton (1984). Subjects were asked to detect only consecutive, ascending odd or even sequences of digits (i.e. 2,4,6; 3,5,7:4,6,8 or 5,7,9) from a pseudo-random string of numbers from 2 to 9. Digits were presented on the computer screen at the rate of 100 digits per minute and responses were registered by button press. The test took 7 min, of which the first minute was not scored, subsequent scores being for successive 2-min intervals. In order to titrate performance in the three groups to an approximately equivalent level, which was not at ceiling and could show improvements, the RVIP task was individually graded in difficulty. This meant that young subjects were generally asked to detect all four sequences, aged subjects were asked to detect between two and four sequences and DAT patients were asked to detect only one sequence. Correct detections or hits (h), failures to detect a sequence (misses) and false alarms (f) were recorded in addition to reaction time. D R M L O task. The second computer task tested both attention and short-term memory in the form of a delayed response, matching to location-order task. In its simplest form, this was a modified version of the delayed response test used in experimental animals by Dunnett (1985) and Sahgal (1987a). In this task, subjects (1) first demonstrated that they had attended to a " m o d e l " sequence of "yellow happy faces" presented consecutively in one of four adjacent boxes on a touch sensitive visual display unit (VDU), by touching the boxes as they appeared. Following a delay of 0, 4 or 16 s, they were asked to (2) recall the correct location-order of the sequences by pressing the touch sensitive V D U again. The first component of the test is a measure of sustained visual attention, the second a measure of short-term visual memory. The number of errors made in attending to the sequence and in recalling it were recorded; in addition, the time taken both to attend to (i.e. copy) the model sequence and to recall it from memory were also recorded. Twenty sequences of varying lengths were presented at each delay interval. An attentional error was recorded automatically if an "empty window" instead of a "' happy face" was pressed when a new model sequence appeared on the screen. Any sequence recalled incorrectly on the first attempt was scored as a memory error, and these were summed over all time delays. This D R M L O task, like the RVIP task, was individually graded in difficulty to titrate performance in the three groups to approximately equivalent levels. The young and aged subjects were generally shown sequences of two to six stimulus locations, while DAT patients were shown model sequences of one to four. CFF test. C F F has been used in psychopharmacological studies as an indirect measure of arousal, a simple vigilance task, and a simple visual perceptual task (Smith and Misiak 1976; MacNab et al. 1985; Warburton 1989). The ability to determine when a light starts or stops flashing comprises two distinct processes: one involving seeing a change against a moving or " n o i s y " background, another which detects change against a comparatively still or " q u i e t " background. Thus, ascending and descending thresh-

487 olds were each measured five times and the two means separately calculated. In healthy, alert, subjects these thresholds lie close together, whereas in DAT patients they vary markedly. This is the rationale for examining the thresholds separately and looking at the difference between them, rather than calculating the usual mean of the combined thresholds.

Finger tapping test. The computerized finger tapping test is a test of motor speed or simple reaction time and has previously been shown to be sensitive to the effects of nicotine in normal subjects by West and Jarvis (1986). In our study, subjects were asked to tap on the space-bar of the computer keyboard as quickly as possible with one finger of their preferred hand for a total of 100 taps. The overall mean tapping rate (in taps per minute) was automatically calculated by the computer programme.

Digit span. Digit span (taken from the Wechsler Adult Intelligence Scale, WAIS 1955) has been referred to at various times as a test of working memory, short-term memory and attention. Regardless of the label, it is frequently measured and thus is useful for making comparisons with other studies. Digit span (forwards only) was measured.

Reactions to injections. Reactions to the injections were measured by recording the total number of symptoms reported during each session in which nicotine or placebo was given. Subjects were asked to report any symptoms in response to the injections, both at the time the injection was given, and again at the end of each test session. From pilot work it was determined that possible effects could include: a feeling of pressure at the injection site (the same as for any injection), sweaty palms, light-headedness, muscle ache in the arm around the injection site, radiation of the ache down the arm to the palm of the hand and fingers for up to 10 min after the injections, and feelings of nausea. Each symptom reported was given a score of one.

Statistics Repeated measures multiple analysis of variance (MANOVA: SPSS x version 2.2) was used to examine the results. After ascertaining initially that nicotine was having significant effects, by covarying the mean baseline value against the four values of the mean placebo and three nicotine doses (where placebo was used to model 0.0 mg nicotine), a more stringent analysis of the effects of nicotine was completed. In the analysis reported here, the effect of the mean placebo value (mean of the pre- and post-drug sessions) was covaried against the three doses of nicotine. This analysis was performed for each of the measures recorded in the tests already described. The MANOVA analysis generated effects due to group (young, aged, DAT), drug (comparing the mean of the three nicotine sessions against the mean of the two placebo sessions), and dose (comparing 0.4, 0.6 and 0.8 mg nicotine against each other). The partitioned dose effects, and the linear and quadratic components of dose, were further assessed by subsequent univariate Ftests. In addition, in order to examine differences between groups further, contrasts of DAT versus aged controls, and of aged versus young controls, were specified in the program. One-way analysis of variance was used to look for differences between males and females, smokers and non-smokers in each of the three groups. The DAT group was broken down into patients in Hughes et at. (1982) stages J or 2, and comparisons were made by one way analysis of variance. Sahgal's (1987b) computer program for non-parametric Signal Detection Analysis (SDA) was used to calculate A and B, according to the formulae of McNicol (1972). Non-parametric SDA measures were calculated because the assumption of underlying normal distributions and equal variances of the effects of signal and nonsignal events are not usually met in vigilance situations (Loeb and

Table 1. Age, sex, pre-morbid IQ (NART scores) and smoking status measures, used to match the groups

N, total Mean age Males Females CDRS stage 1 CDRS stage 2 NART score Male smokers Female smokers

DAT

Aged

Young

22

24

24

60.0_+ (SD) 6.0 11 tI 11 11 114.5-+9.3 3* 6**

65.5+5.6 12 12 -121.0-+5.6 6 6

27.7--+7.9 12 12 120.4+_3.2 6 6

* One of these males smoked only 1 cigarette per day and did not inhale ** One of these females smoked 1 cigar per day without inhaling; two other females in this group had stopped smoking 1 or 2 cigarettes daily between 12 and 18 months prior to joining the study Alluisi 1984). Recalling that f stands tbr false alarms and h for hits, the equations used were: A'=0.5 + [ ( h - f) + ( h - f)2]/[4 x h (1 - t ) ] B"= [(h -- h 2) -- (f-- fZ)l/[(h -- h e) - ( f - f2)]

Results Males versus females Y o u n g males h a d significantly l o n g e r digit s p a n s t h a n y o u n g females ( t = 2 . 5 ; d f = 2 2 ; P < 0 . 0 5 ) in all test sessions. In a d d i t i o n , a g e d m a l e s m a d e significantly fewer e r r o r s o n the D R M L O t a s k t h a n a g e d females (t > 2 . 2 ; d f = 22; P < 0 . 0 5 ) in all test sessions, e x c e p t at the 0.6 m g n i c o t i n e d o s e ; in this session t o o , h o w e v e r , the sex difference a p p r o a c h e d significance (t = 2.0; d f = 22; P < 0.07). T h e r e were n o o t h e r sex differences o r i n t e r a c t i o n s between sex a n d n i c o t i n e t r e a t m e n t .

Smokers versus non-smokers N i c o t i n e d i d n o t exert overall c o n s i s t e n t d i f f e r e n t i a l effects o n s m o k e r s a n d n o n - s m o k e r s in a n y o f the g r o u p s , o n a n y o f the t a s k s m e a s u r e d , w i t h the f o l l o w i n g two exceptions. In the a g e d c o n t r o l g r o u p , s m o k e r s h a d significantly h i g h e r t a p p i n g rates t h a n n o n - s m o k e r s o n the c o m p u t e r i z e d t a p p i n g test w h e n t h e y were given n i c o t i n e ( t = 2 . 2 ; d f = 2 2 ; P < 0 . 0 5 ) b u t n o t f o r the m e a n baseline or p l a c e b o values. I n the y o u n g c o n t r o l g r o u p , n o n s m o k e r s h a d significantly faster r e a c t i o n times t h a n s m o k e r s o n the R V I P task, b u t o n l y for the m e a n p l a c e b o v a l u e ( t = 2 . 6 ; P < 0 . 0 3 ) . T h e r e were n o significant differences b e t w e e n the b a s e l i n e a n d p l a c e b o scores o n a n y m e a s u r e , a n d n o significant q u a d r a t i c effects o f nico t i n e dose.

Rapid visual information processing task T h e severe i m p a i r m e n t o f p e r s o n s w i t h D A T o n the R V I P t a s k was m o s t e v i d e n t in their a b i l i t y to d e t e c t

488 Table 2. Test responses (means ± SD) in the young, aged and DAT groups during un-injected (baseline), placebo, and nicotine conditions. Measures 1-4 are from the RVIP task; measures 6-9, from the DRMLO task Mean baseline

Mean placebo

0.4 mg nicotine

0.6 mg nicotine

0.8 mg nicotine

Young adult controls (N= 24) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Hit probability Sensitivity index (AI) Bias index (Bn) Mean reaction time (ms) Tapping rates (taps/min) Total memory errors Total attentional errors Mean time to copy model Mean time to recall model from memory CFF (ascending-descending threshold) Digit span forwards Total number of symptoms

0.76± 0.10 0.94_+ 0.02 0.95± 0.05 408 ± 67 423 ±55 7.5 _+ 4.8 0.1 _+ 0.6 4.1 _+ 0.4 5.4 _+ 0.7 - 0 . 7 _+ 2.0 7.3 ± 1.3 -

0.76-+ 0.13 0.94± 0.02 0.94-+ 0.05 413 ± 77 424 +58 6.7 ± 4.9 0.0 ± 0.0 4.0 _+ 0.6 5.4 ± 0.7 - 0 . 6 ± 1.9 7.5 ± 1.4 0.42± 0.8

0.75_+ 0.13 0.94± 0.03 0.95± 0.07 418 ± 72 427 ±48 6.8 ± 5.8 0,0 ± 0,0 4.0 ± 0,7 5.2 _+ 0.6 - 1 . 2 ± 2.6 7.4 _+ 1.7 1.02_+ 0.80

0.79_+ 0.10 0.94+ 0.03 0.95± 0.07 404 ± 64 436 ±53 7.8 -+ 5.3 0.0 ± 0.0 4.0 ± 0.7 5.2 ± 0.7 - 0 . 7 _+ 1.8 7.3 -+ 1.1 1.71_+ 1.42

0.81± 0.12 0.95± 0.03 0.91± 0.09 391 ± 76 419 ±74 9.5 _+ 6.9 0,0 ± 0.0 4.0 ± 0.6 5.2 ± 0.7 - 0 . 5 ___ 1.5 7.6 ± 1.1 1.33 _+ 2.01

0.79_+ 0.16 0.94_+ 0.04 0.88± 0.05 420 ±69 379 ±39 10.0 ± 7.9 0.3 ± 0.7 6.1 ± 2.4 5.5 ± 0.9 --1.5 ± 2.8 7.1 ± 1.2 0.33± 0.56

0.76± 0.17 0.94± 0.04 0.92± 0.06 413 -+62 380 _+43 10.5 _+ 8.9 0.3 _+ 0.9 6.1 ± 2.5 5.3 ± 0.7 --1.6 _+ 3.0 6.9 ± 1.2 0.42_+ 0.58

0.80_+ 0.15 0.95_+ 0.04 0.93± 0.10 405 -+67 382 _+42 10.4 _+ 8.2 0.2 _+ 0.6 6.1 _+ 2.3 5.2 ± 0.8 --1.4 ___ 2.5 7.0 -i- 1.2 0.75_+ 0.80

0.81± 0.17 0.95_+ 0.05 0.91± 0.12 394 _+66 393 _+44 11.0 _+ 8.0 0.3 ± 0.8 6.1 ± 2.5 5.3 ± t.0 --2.6 _+ 2.t 7.3 _+ 1.0 0.88± 0.80

0.52+ 0.24 0.87_+ 0.07 0.86_+ 0.17 713 ± 224 325 ± 64 26.1 -+ 10.0 13.0 + 20.1 9.9 + 4.7 7.0 _+ 2.7 7.5 ± 9.2 4.6 -+ 1.7 0.23± 0.61

0.56_+ 0.24 0.88_+ 0.07 0.87_+ 0.10 630 -+ 185 322 4- 52 25.4 _+ 8.5 10.4 -+ 18.1 9.2 ± 4.2 6.6 _+ 2.5 4.5 + 4.8 4.5 _+ 1.8 0.27± 0.88

0.62_+ 0.22 0.90_+ 0.06 0.86_+ 0.14 647 -+ 162 336 ± 60 24.5 _+ 9.9 8.7 ± 12.5 8.7 ± 4.0 6.8 ± 2.1 3.4 _+ 4.2 4.5 ± 1.5 0.86_+ 1.83

0.63± 0.22 0.90_+ 0.06 0.88± 0.15 682 -+212 335 ± 52 24.5 _+ 10.1 6.2 ± 10.2 8.1 ± 3.3 6.3 ± 2.3 4.2 -+ 3.2 4.8 ± 1.6 0.25± 0.55

Normal elderly controls (N = 24) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. t 1. 12.

Hit probability Sensitivity index (AI) Bias index (Bn) Mean reaction time (ms) Tapping rate (tips/rain) Total memory errors Total attentional errors Mean time to copy model (s) Mean time to recall model from memory CFF (ascending-descending threshold) Digit span forwards Total number of symptoms

DA T patient group (N= 22) 1. Hit probability 2. Sensitivity index (A~) 3. Bias index (BH) 4. Mean reaction time 5. Tapping rate(taps/min) 6. Total memoryerrors 7. Total attentional errors 8. Mean time to copy model 9. Mean time to recall model from memory 10. CFF (ascending-descendingthreshold) 11. Digit spanforwards 12. Total number of symptoms

0.76± 0.16 0.94± 0.04 0.93_+ 0.10 414 _+64 378 -+44 11.9 _+ 8.6 0.56_+ 1.3 6.3 ± 2.8 5.4 ± 0.9 --2.0 ± 3,8 7.t ± 1.2 --

0.50+ 0.23 0.86_+ 0.07 0.86_+ 0.14 700 _+214 314 ± 75 25.8 -+ 10.9 12.0 _+ 19.0 9.9 ± 4.8 7.6 ± 3.5 6.7 + 7.4 4.7 _+ 1.6 -

only one target sequence, c o m p a r e d to c o n t r o l subjects, who detected b e t w e e n two a n d four sequences simultaneously. N i c o t i n e significantly i m p r o v e d hit rate i n this task [F(2, 6 4 ) = 1 3 . 5 6 ; P < 0 . 0 0 1 ] b u t did n o t alter the n u m b e r o f false alarms. This is f u r t h e r reflected by signal detection analysis, which shows t h a t n i c o t i n e gave rise to a significant i m p r o v e m e n t in the accuracy o f detecting a target stimulus as m e a s u r e d by the sensitivity index (A') [overall effect o f n i c o t i n e : F(2, 64) = 9.63; P < 0.001 ] (Fig. 1). This effect showed a linear increase with d r u g dose I F ( I , 6 5 ) = 2 7 . 6 ; P < 0 . 0 0 1 ] . H o w e v e r the B" index was unaffected. I n signal d e t e c t i o n analysis this i m p r o v e m e n t in A', c o u p l e d with a lack of c h a n g e in B", is a g o o d i n d i c a t o r t h a t n i c o t i n e affects stimulus selection, rather t h a n response threshold, c o n s i s t e n t with a n influence on, e.g., a t t e n t i o n rather t h a n m o t i v a t i o n . W h i l e the D A T g r o u p i m p r o v e d m o s t m a r k e d l y o n this meas-

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ure [DAT versus aged: F(2, 64)=2.98; P<0.05], aged and young controls did not differ significantly from each other in their reaction ( F = 0.14). Although overall reaction time on this task was not significantly reduced by nicotine, there was a significant reduction in reaction time measured in the first 2-min block of this test [F(2, 64)=3.9; P<0.02]. There was also a group xdrug interaction [F(2, 63)=3.25; P < 0.05], indicating a reduction in mean reaction time at the 0.4 mg dose of nicotine for the DAT group alone (Fig. 2). All three doses of nicotine prevented the increase in reaction time (possibly due to attentional fatigue) that took place in the final 2 rain of the test during baseline and placebo performance.

Tapping test Nicotine also increased motor speed as measured by the finger tapping test in all three groups [F(2, 63)=3.6; P < 0.03] (Table 2).

Delayed response matching to location order task In the attentional phase of this task, only the DAT group made errors in any number and these were significantly

reduced by nicotine [F(2, 64)=3.5; P<0.04]. This occurred linearly as a function of dose [F(I, 64)= 5.75; P<0.02; Fig. 3]. DAT patients were significantly impaired on the short-term memory component of this task compared with both young and aged control subjects [F(2, 64)= 3.79; P<0.03]. Though the aged group made more errors than the young controls, this difference was not significant ( F = 0.02). Nicotine did not significantly alter short-term visual memory performance as measured by number of memory errors in this task for any of the three groups [F(2, 64) -- 0.50; Table 2]. The overall mean time (across the 0,4 and 16 s delay conditions) taken to copy a model sequence during the attentional phase of the task was significantly reduced when nicotine was administered [F(2, 64)=3.42; P < 0.04]. This effect occurred only in the DAT group; group by drug effect [F(2, 64)=2.81 ; P<0.03; Table 2]. In contrast, the overall mean time taken to recall the model sequence, an indirect measure of short-term memory performance, was unchanged by nicotine [F(2, 64)= 0.1]. However, at the 0 s delay, nicotine significantly reduced the time to recall the model in the DAT group only [F(2, 64) = 3.68; P < 0.03].

Critical flicker fusion Nicotine improved the ability of patients to detect a flashing or flickering light, as evidenced by the reduction in the difference between ascending and descending thresholds (Fig. 4); the mean ascending threshold value decreased significantly [F(2, 37)= 3.61 ; P<0.04] and the descending threshold increased [F(2, 37)=3.90; P < 0.03] (Fig. 5). There was a strong group by drug effect for the change in ascending threshold [F(2, 37)=8.71; P<0.01], indicating the largest improvement for the DAT group. Furthermore, the variability (standard deviation) of the five measures of the ascending threshold was also significantly reduced by nicotine in the DAT group [F(2, 61)=3.72; P<0.03]. Even so, CFF threshold differences remained substantially higher in the DAT than in the control groups (Fig. 4).

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Table 3. Test responses (means _+SD) in the D A T sub-groups. CDRS Stages 1 and 2, mild and moderate: Hughes et al. (1982). ( N = m g of nicotine; X BASE = mean baseline value; X PLAC = mean placebo value) Test

X Base

X PLAC

N 0.4

N 0.6

N 0,8

Stage 1 SD

302.3 70.6

317.2 66.3

318.4 56.0

324.4 62.3

320.8 45.3

Stage 2 SD

323.2 78.2

331.5 76.5

324.9 49.2

347.4 59.2

346.0 55.6

Tapping test (taps /min ) Tapping

Rapid visual injormation processing task measures RVIP A'

RVIP B"

Mean RT

Prop'n hits

False alarms

Stage 1 SD

0.884* 0.068

0.900" 0.062

0.903" 0.064

0.922" 0.063

0.927 0.053

Stage 2 SD

0.840 0.062

0.837 0.066

0.848 0.057

0.872 0.054

0.879 0.067

Stage 1 SD

0.846 0.161

0.855 0.218

0.875 0.131

0.815 0.163

0.856 0.176

Stage 2 SD

0.862 0.120

0.854 0.117

0.866 0.073

0.891 0.110

0.896 0.116

Stage I SD

686.0 186.0

628.4 * 145.0

615.9 148.9

610.8 188.6

644.8 160.5

Stage 2 SD

712.0 235.4

788.5 259.9

644.2 222.0

679.1 181.7

717.3 252.7

Stage 1 SD

0.57 0.23

0.63 0.20

0.65 0.22

0.72 0.22

0,74 0.19

Stage 2 SD

0.41 0.21

0.41 0.23

0.46 0.22

0.53 0.18

0.55 0.21

Stage 1 SD

0.017 0.021

0.017 0.031

0.016 0.017

0.013 0.014

0.015 0.023

Stage 2 SD

0.015 0.015

0.016 0.015

0.016 0.011

0.015 0.017

0.013 0.014

Touch screen errors and RT's (0, 4, and 16 s delays) Total mere errors

Total att'n errors

Stage 1 SD

23.8 14.7

25.5 12.8

26.1 10.6

25.0 12.5

26.6 11.9

Stage 2 SD

27.8 4.9

26.6 6.5

24.7 6.1

24.0 7.4

22.4 8.0

Stage i SD

7,1 10.8

10.7 13.5

5.8 4.9

7.0 7.2

5.4 6.8

Stage 2 SD

16.5 23.0

15.4 25.6

17.1 24.4

10.2 16.1

7.0 13.2

Stage 1 SD

36.4* 7.6

39.3* 9.1

35.2* 6.1

35.6* 7.6

34.4 7.4

Stage 2 SD

26.5 6.2

27.5 4.7

18.3 8.4

23.6 3.8

27,1 6.2

Stage 1 SD

28.4" 9.0

29.0 12.1

29.8* 9.2

31.7" 10.0

29.5 12.6

Stage 2 SD

19.4 5.1

21.0 4.1

20.0 3.4

20.2 4.5

22.6 2.3

Stage 1 SD

8.6 7.2

10,0 6.7

5.5 5.1

3,9 4.6

5.0 6.1

Stage 2 SD

5.7 5.1

8.3 516

3.3 4.6

2.5 3.5

3.7 5.9

~el SD

5.1 1.5

5.2 1,5

5.2* 1.7

5.0 1.6

4.9 t.4

~a~ 2 SD

4.2 1.6

3.8 1.7

3.6 1.8

3.9 t.2

3.9 1.5

Critical flicker fusion measures (thresholds) ( Hz ) Ascending threshold

Descending threshold

Asc.-desc,

Digit span Digit span

* A significant difference between the 2 groups, P_<0.05

491 35.0

, J \ r~ .J 0

30.0

"I-

LU e-

25.0

p-

20.0

i

_ _

BASELINE

t

I

~

t

PLACEBO

0.4rag NIC

O,6mg NIC

O.Smg NIC

TREATMENT

Fig. 5. Mean ascending ( - + - ) and descending ( - / , - ) CFF thresholds as a function of nicotine (NIC) treatment in the DAT group

Digit span

Digit span forwards was unaffected by nicotine [F(2, 64) = 1.5; Table 2].

trol group reported the greatest number of symptoms overall [/:(2, 63) = 5.85; P < 0.005]. Of over 500 nicotine injections given during pilot work on this study, only three subjects, all non-smokers, reported feeling nauseous. A female control reacted to the low dose of nicotine; she was in the first year of menopause and reported suddenly having developed an intolerance to even minute quantities of alcohol. A male DAT patient, who had shown no adverse response to the highest dose of nicotine, reported feeling nauseous when he was subsequently re-tested on the medium dose. A 29-year-old male control reported feeling nauseous 14 min after the injection of 0.6 mg nicotine, and also anxious secondary to feeling nauseous; both these feelings abated about 25 min after the injection. A 51-year-old male DAT patient fainted 1 h after the 0.6 mg nicotine injection, though he had successfully completed the test session without reporting any symptoms. He had three additional fainting episodes during the next 24 h. After hospitalization for full investigations, including EEG and ECG, he was found to have a previously undiagnosed '° sick sinus syndrome".

C D R S stage 1 versus stage 2 DA Tpatients

Both sub-groups (CDRS, stages 1 and 2; Hughes et al. 1982) showed improvements on the measures which improved for the DAT group as a whole (Table 3). However, the A' measure improved significantly more for subjects in stage 1 at both the 0.4 mg (t=2.3; df=20; P<0.05) and 0.6 mg (t=2.5; df= 20; P<0.05) doses of nicotine, as did the ascending and descending CFF thresholds at these doses (t>2.2; df=20; P<0.05).

D A T versus control groups

Although nicotine positively influenced all three groups on a number of measures, the degree of change was largest for the DAT group on the following measures: RVIP task, A' [F(2, 64)=2.98; P<0.05]; RVIP task, mean reaction time [F(2, 64) = 3.25; P < 0.05] ; D R M L O task, attentional errors at all time delays [/'(2, 64)= 6.82; P<0.002]; D R M L O task, mean time to copy model [F(2, 64)= 5.89; P < 0.005] ; D R M L O task, time to recall model at 0 s time delay [F((2, 64) =3.68; P<0.03] ; CFF task, ascending threshold [F(2, 37)=8.71; P<0.01]; CFF task, decreased variability in ascending threshold [F(2, 64)=3.72; P<0.03].

Reactions to injections

Table 2 shows the mean number of symptoms reported by each group for each injection. Generally there were no reports of discomfort or other psychological symptoms, other than those felt during a routine subcutaneous iniection. On average, there was less than one symptom reported per subject. Significantly more symptoms were reported in response to nicotine injections than to placebo [F(2, 63)=7.03; P<0.002], and the young con-

Discussion This study reports on the effects of administering acute SC nicotine on measures of attention, information processing, perception and short-term memory in DAT patients and young and aged control groups. The results demonstrated that DAT patients have large perceptual and attentional impairments in addition to their reduced mnemonic abilities. Many studies have speculated about the presence of such impairments in DAT, yet quantitative evidence is only beginning to be reported (Hinton etal. 1986; Broks et al. 1988; Katz and Rimmer 1989). More detailed examination of these deficits is essential. Furthermore, in DAT patients, acute SC nicotine administration significantly improved perception, sustained visual attention, rapid visual information processing and reaction time measures. This confirms and extends our earlier findings with small groups of these same subjects (Sahakian et at. 1989). The improvement in A' (RVIP task), decreased attentional errors (DRMLO task) and the decreased response latency in the attentional phase of the D R M L O task, together suggest that nicotine exerts an effect on visual sustained attention and information processing, rather than on visual short-term memory. This interpretation gains further support from the results of the CFF and digit span tests, which showed that perception of ascending and descending thresholds improved with nicotine administration, while auditory short-term memory did not. The results of the RVIP, D R M L O and CFF tests are consistent with the notion that nicotine might reduce the signal to noise ratio for visual information processing tasks (Sahakian 1988). Our results showing improved speed of response on the RVIP and FT tasks also favour the attentional over the memory hypothesis of nicotine action. However, since only two simple tests of shortterm memory were carried out, until more extensive stu-

492 dies are conducted, the effect of nicotine on memory remains uncertain. Nicotine increased response speed in the first 2 rain of the RVIP task, overall response speed at the 0.4 mg dose, and appeared to prevent the fatigue in RT seen in baseline and placebo performance in the last 2 rain of this task. However the actions of this compound cannot be accounted for simply in terms of increased response speed. Importantly, on the same task, nicotine improved stimulus sensitivity (A') in DAT patients, without causing a slowing in either simple or complex reaction time, i.e. without a speed/accuracy tradeoff. Our findings, of improved attention but not memory, are also consistent with those of Newhouse et al. (1988), who administered nicotine intravenously (0.125-0.5 gg/ kg rain for 60 min) to 6 DAT patients. Though these workers did not examine attentional functioning, they did not find any major changes in memory. Since they used effectively larger doses of nicotine than we did and a faster administration route, it is possible that they exceeded a therapeutic window for nicotine. Many cholinergic drugs, e.g. physostigmine, can impair cognitive performance if this window is exceeded. This might also account for the increased ratings of anxiety and depression reported by their patients, which were not found in our study. Nicotine produced no consistent performance differences between smokers and non-smokers on any measure in either control group, with the exception that aged smokers tapped faster than their non-smoking counterparts when they were given nicotine. Increased tapping rate is consistent with West and Jarvis's (1986) report that nicotine significantly speeds up performance on this test, but it is puzzling that this effect was limited to the aged control group. Unfortunately, there were not enough smokers in the DAT group to allow for a meaningful assessment of the effects of smoking history in this group, nor for comparisons with the control groups. The absence of consistent patterns of differences between smokers and non-smokers in either the young or aged control groups makes it unlikely that there would be differences in the DAT group. However, this issue requires further careful study in view of the specific damage to cholinergic nicotinic receptors in DAT patients and epidemiological surveys of cigarette use in DAT patients. Jones et al. (1987) did not find a difference in relative risk of developing DAT between smoking and non-smoking groups, yet van Duijn and Hofman (1991), studying patients with the familial form of DAT, found a decreased risk of Alzheimer's disease as the number of cigarette smoked daily (before onset of the disease) increased. Such findings attest to the complexity of comparison between smokers and non-smokers among DAT patients. Future studies should pay special attention to the form and stage of the illness, as well as to specific details of the smoking history. In view of the great variability in performance in DAT patients, and the apparent selective effects of nicotine on certain cognitive functions, future drug studies should attempt to classify patients not only according to the form and stage of the disease, but also by the

pattern of cognitive strengths and deficits. Also, since our results show that both categories of DAT patients (CDRS 1 and CDRS 2; Hughes et al. 1982) improved when nicotine was administered, future studies should aim to include patients beyond the early and intermediate stages of the illness. As yet, however, no tests exist which would allow us to assess the effects of nicotine on cognitive function in these more moderate to severely affected patients. Although only those DAT patients were selected who were relatively early in the course of the disease (CDRS stages 1 and 2), their cognitive deficits were marked enough to make their performance on most tests incomparable with that of the control groups. Hence, the computerized tests were developed so that they could be scaled in difficulty, with each subject performing at a level that was challenging but not too difficult. This titration of performance allowed for a direct comparison of nicotine's effects on the RVIP and DRMLO tasks in the three groups. To our knowledge, this, and our earlier report (Sahakian et al. 1989), constitute the first study using the subcutaneous route of nicotine administration for large numbers of human subjects. Possible future consideration of this route as an alternative to administering nicotine by cigarette, on sugar cubes or in tablet form, necessitates careful examination of reported side effects. The subcutaneous route of administration seems to be a safe way to administer nicotine for acute nicotine studies at doses up to 1 rag. Care must be taken, however, with the injections themselves, especially if the subject has little adipose tissue, as nicotine can be a severe muscular irritant and can cause cramping sensations for up to 15 rain if injected too close to muscle tissue. The precise cellular and biochemical mechanisms underlying the effects of nicotine require further elucidation. It is possible that nicotine acts on remaining populations of cholinergic receptors and/or by modulating activity in ascending catecholaminergic systems, such as the coeruleo-cortical noradrenergic and mesolimbic dopaminergic projections (Brazell et al. 1990, 1991 ; Wonnacott et al. 1990). However, although the latter mechanism would suggest parallels with the effects of classical arousing agents, such as the psychomotor stimulant, damphetamine, or environmental white noise, the available evidence from other studies suggests that these agents produce cognitive effects distinct from those of nicotine (Hasenfratz etal. 1989). Warburton's (1986, 1988) "state" model of attentional processing suggests that nicotine maintains the cortex in a desynchronized state by driving the ascending cholinergic pathways, thus reducing fluctuations in cortical arousal and, hence, the frequent fluctuations in information processing that occur in the undrugged state. Nicotine may thus assist DAT patients who have impaired information processing by optimizing the functioning of structures which are necessary for attentional processes and by balancing cognitive resources to facilitate control over the subtle transitions between states which are necessary to meet the demands of rapidly changing activities of daily living.

493 In conclusion, the positive effects o f acutely administered nicotine in this large sample o f D A T patients are encouraging, especially given the previous resistance o f cognitive decline in this disease to p h a r m a c o l o g i c a l treatment. However, while these effects are o f theoretical interest, they fall well short o f the m a j o r changes in activities o f daily living, conversational ability or m e m o ry for current events which constitute real i m p r o v e m e n t for the family m e m b e r s a n d caregivers o f D A T patients. Nevertheless, o u r findings lend further s u p p o r t to a cholinergic hypothesis o f d e m e n t i a and suggest that p h a r m a cological e n h a n c e m e n t o f cholinergic functioning m a y p r o v e viable for patients m o d e r a t e l y affected by the disease. N i c o t i n e itself, or a related c o m p o u n d , m a y yet have a valuable role to play, a l t h o u g h the problems o f finding a safe, convenient and effective m o d e o f administration m u s t first be overcome. Nicotine c a n n o t be given chronically using the s u b c u t a n e o u s r o u t e ; and use o f the chewing g u m route for chronic administration has a weaker effect a n d poses other practical difficulties (Jones 1990; Jones et al. in preparation). It is possible, however, that the newer, and still experimental, routes o f nasal spray or skin patches, m a y provide a means for chronic nicotine administration with therapeutic effects.

Acknowledgements. This research was supported by British-American Tobacco Co. Ltd. BJS thanks the Wellcome Trust and the Eleanor Peel Foundation for support. We are grateful to Dr. M. Russell for his advice, piloting the pharmakokinetics of sub-cutaneously administered nicotine and for analyzing plasma nicotine levels for us; to Mr. L. Law, Dr. J. Evenden, Dr. M. Jarvis and Dr. A. Sahgal for computer program development and access to programs; and to Dr. Andrew Young for preparing the figures.

References Araujo D, Lapchak P, Collier B, Quirion S (1988) Characterization of N-[3H] methylcarbamylcholine binding sites and the effect of N-methylcarbamylcholine on acetylcholine release in rat brain. J Neurochem 51:292-299 Brazell MP, Mitchell SN, Joseph MH, Gray JA (1990) Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat : comparison with caudate-putamen. Neuropharmacology 29 : 1177-1185 Brazell MP, Mitchell SN, Gray JA (1991) Effect of acute administration of nicotine on in vivo release of noradrenaline in the hippocampus of freely moving rats: A dose-response and antagonist study. Neuropharmacology 30:823-833 Broks P, Preston C, Traub P, Poppleton P, Ward C, Stahl SM (1988) Modelling dementia; effects of scopolamine on memory and attention. Neuropsychologia 28[5] : 685-700 Clarke P, Hamill G, Nadi N, Jacobowitz D, Pert A (1986) 3HNicotine and 125 I-atpha-bungarotoxin labelled nicotine receptors in the interpeduncular nucleus of rats. II. Effects of habenular deafferentation. J Comp NeuroI 251:407-4t 3 Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or flmbria-fornix on delayed matching in rats. Psychopharmacology 87:357-363 Hasenfratz M, Michel C, Nil R, Battig K (1989) Can smoking increase attention in rapid information processing during noise? Electrocortical, physiological and behavioural effects. Psychopharmacology 98 : 75-80

Hinton D, Sadun A, :Blanks J, Miller C (1986) Optic nerve degeneration in Alzheimer's disease. N Engl J Med 31518]:485-487 Hodges H, Allen Y, Sinden J, Lantos PL, Gray JA (]990) Cholinergie-rich foetal transplants improve cognitivie deficits in lesioned rats, but exacerbate response to cholinergic drugs. Prog Brain Res 82:347-358 Hodges H, Allen Y, Sinden J, Mitchell SN, Arendt T, Lantos PL, Gray JA (1991) The effects of cholinergic drugs and cholinergic-rich, foetal neural transplants on alcohol induced deficits in radial maze performance in rats. Behav Brain Res 43 : 7-28 Hughes CP, Berg L, Danziger WL, Cohen LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 40: 566-572 Jones GMM (1990) The cholinergic hypothesis of dementia: the effects of lecithin and nicotine on human memory and attention. Doctoral thesis for the University of London, UK Jones GMM, Reith M, Philpot MP, Sahakian BJ (]987) Smoking and dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 50:1383 Katz B, Rimmer S (1989) Ophthalmologic manifestations of Alzheimer's disease. Surv Ophthalmol 34:31-43 Loeb M, Alluisi E (1984) Theories of Vigilance. In: Loeb M, Alluisi E (eds) Sustained attention in human performance. Wiley, Chichester, pp 179-395 MacNab M, Folz E, Sweitzer J (1985) Evaluation of signal detection theory on the effects of psychotropic drugs on critical flicker-fusion frequency in normal subjects. Psychopharmacology 85:431-435 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS/ADRDA work group under the auspices of the Department of Health and Human Services Task force on Alzheimer's Disease. Neurology 34:939-944 McNicol D (1972) A primer of signal detection. Allen & Unwin, London Mash DC, Flynn DD, Potter LT (1985) Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science 228:1115-1117 Nelson H (1982) National Adult Reading Test (NART) manual. NFER-Nelson, Windsor Newhouse P, Sunderland T, Tariot P, Blumhardt C, Weingartner H, Mellow W (t988) Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology 95:171-175 Perry EK, Perry RH, Smith CJ, Purohit J, Bonham P, Dick D, Candy J, Edwardson JA, Fairburn A (1986) Cholinergic receptors in cognitive disorders. Can J Neurol Sci 13:521 527 Perry EK, Perry RH, Smith CJ, Dick DJ, Candy JM, Edwardson JA, Fairburn A, Blessed G (1987) Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases. J Neurol, Neurosurg Psychiatry 50:806-809 Philpot MP, Levy R (1987) A memory clinic for the early diagnosis of dementia. Int J Geriatr Psychiatry 2:195 200 Royal College of Physicians (1983) Smoking or Health. Pitman Med, London Richard J, Araujo DM, Quirion R (1989) Modulation of cortical acetylcholine release by cholinergic agents. Soc Neurosci Abstr 1512]:1197 Russell M, Jarvis M, Jones G, Feyerabend C (1990) Nonsmokers show acute tolerance to subcutaneous nicotine. Psychopharmacology t02: 56-58 Sahakian BJ (1988) Cholinergic drugs and human cognitive performance. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 20, Psychopharmacology of the aging nervous system. Plenum Press, London Sahakian B, Jones G, Levy R, Gray J, Warburton D (1989) The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatry 154:797-800 Sahgal A (1987a) Contrasting effects of vasopressin, desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats. Psychopharmacology 93:243 249

494 Sahgal A (1987b) Some limitations of indices derived from signal detection theory: evaluation of an alternative index for measuring bias in memory tasks. Psychopharmacology 91:517-520 Smith JM, Misiak H 0976) Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects - a review. Psychopharmacology 47:175-182 van Duijn C, Hofman A (1991) Relation between nicotine intake and Atzheimer's disease. Br Med J 302:1491-1494 Warburton D (1986) A state model for mental effort. In: Hockey GR, Gaillard AW, Coles MG (eds) Energetics of human information processing. Martinus Mijhof, Dordrecht, Netherlands, pp 217-232 Warburton D (1988) Psychopharmacological aspects of nicotine. In: Russell M, Stolerman I, Wonnacott S (eds) Nicotine: actions and medical implications. Oxford University Press, Oxford, pp 119-131

Warburton D (1989) Nicotine: an addictive substance or a therapeutic agent? Prog Drug Res 435:9-41 Wechsler D (1955) WAIS manual. Psychological Corporation, NY Wesnes K, Warburton DM (1984) Effects of scopolamine and nicotine on human rapid information processing performance. Psychopharmacology 82:147-150 West RJ, Jarvis MJ (1986) Effects of nicotine on finger tapping rate in non smokers. Pharmacol Biochem Behav 25:727-731 Wonnacott S, Russell MAH, Stolerman IP (1990) Nicotine psychopharmacology: molecular, cellular and behavioural aspects. Oxford Scientific Publications, Oxford University Press, Oxford Zilles K (1990) Codistribution of receptors in the human cerebral cortex. In: Mendelsohn FAO, Paxinos G (eds) Receptors in the human nervous system. Academic Press, London