Biological Psychology 33 (1992) l-22 0 1992 Elsevier Science Publishers B.V. All rights reserved

Cholinergic processing

activity and constraints

Enoch

Roy Halliday

Callaway,

SFVAMC116T,

and Hilary

0301-0511/92/$05.00

on information

Naylor

4150 Clement St., San Francisco, CA 94121, USA

In humans, close relationships are found between cholinergic activity and constraints placed on information processing operations. This is true for all operations where the effects of cholinergic activity have been studied. Studies of vigilance, memory, problem solving, stimulus processing and response processing are cited as illustrations. These studies suggest the hypothesis that cholinergic activity controls constraints in all information processing operations. Alternative hypotheses are proposed and experimental tests are suggested. Keywords:

acetylcholine, pharmacology,

anticholinergics, cognition, psychology, scopolamine.

event-related

brain potentials,

performance,

1. Introduction A narrowed focus of attention has been associated with arousal in general (Callaway & Stone, 1960; Callaway & Thompson, 1953; Easterbrook, 1959) and with increased cholinergic activity in particular (Warburton, 1987). In the process of relating our recent work on scopolamine to other work reported in the literature, no human studies were found which were inconsistent with the hypothesis that cholinergics narrow the focus of attention, and that anticholinergics broaden it. There are, however, several problems with the term “focus of attention”. First, attention suggests a primary enhancement of processing for items at the focus in addition to any advantage gained from constraints on (inattention to) the processing of items outside the focus. Evidence for change in constraints on the processing of items outside the focus of attention is much more persuasive than is evidence for specific change in processing at the focus of attention. Secondly, since “. . . everybody knows what attention is.. . ” (James, 19501, preconceptions about attention interfere with taking a review of the literature as an operational definition. A special term like “constraint on information processing” helps to underline this special meaning. It is this special operationally defined meaning that allows the formulation of alternative hypotheses framed in terms of informaCorrespondence 94121, USA.

to: Dr. E. Callaway,

SFVAMC116T,

4150 Clement

St., San Francisco,

CA

2

E. Callaway rt al. / Cholinergic actirity and information

processing

tion processing. At the conclusion, several such alternatives are suggested along with possible means for testing them. The idea of linking cholinergic activity to constraints on information processing in general may seem implausible. In the studies to be reviewed, different sorts of constraints are found to be operating at different stages of information processing. They probably involve different neural circuits and different neurophysiological processes. Generalizing across such different operations is risky. It is even more risky to try linking acetylcholine, which is involved in many different operations at the molecular level, with a single principle at the information processing level. Evidence that scopolamine acts on several relatively independent systems can be found in the scopolamine dose-response studies of Kopelman and Corn (1988), where there were poor correlations between the various drug-induced changes. While one might expect to find more than one sort of information processing change mediated by acetylcholine, there does not seem to be evidence for that in studies of human information processing. Most of the literature on humans relevant to the present hypothesis is cited, although the volume of literature has required some selectivity. The enormous relevant literature on neurochemistry, anatomy, pharmacology and animal behavior has been virtually ignored. Nevertheless, an attempt was made to include potentially adverse evidence, and some studies offering specific support for alternate hypotheses are given when, in the conclusion, the alternative hypotheses are discussed. Table 1 lists and identifies drugs that are referred to in the body of the paper.

2. Scopolamine

and stimulus

processing

High doses of scopolamine produce a distracted, delirious state followed by amnesia. In lower doses, it interferes with the processing of sensory data so as to make target detection slower and less accurate on vigilance tasks and to impair subsequent recall of items presented while under the influence of the drug. Thus, in everyday language, scopolamine affects stimulus processing by impairing attention. The effects of scopolamine on both memory and vigilance tasks will be shown to be more specific than the term “impair” suggests. More specific ways for localizing drug effects to stimulus processing will also be considered. However, this does not imply that antimuscarinics act only on stimulus processing, and the effects of acetylcholine on motor responses will be discussed later. Latencies of event-related brain potentials (ERPs) provide one way of determining when a drug effect has occurred in the temporal order of information processing (Gaillard, 1988a). If the latency of a component is slowed, then some operations preceding that component must have been

3

E. Callaway et al. / Cholinergic actkity and information processing Table 1 List of drugs referred

to in the paper

”

SCOPOLAMINE [hyoscine]: Antimuscarinic (Ml and M2) with greatest affinity for central receptors (Larson, Pfenning & Richelson, 1991). Pre-synaptic activity also results in increased acetylcholine release ATROPINE [belladona]: Antimuscarinic similar to scopolamine but with relatively greater affinity for cardiac receptors. Thus it causes tachycardia while scopolamine causes bradycardia. [esterine, Antilerium]: Non-specific cholinergic agonist that acetylcholinesterase (the enzyme that removes acetylcholineb

PHYSOSTIGMINE versably poisoning SARAN

[nerve gas]: Anticholinesterase;

ARECOLINE

[betel nut]: Muscarinic

[Sansert]: Serotonin

METHYSERGIDE

PROPRANOLOL

agonist.,

blocker

antagonist,

[ Inderal]: Beta noradrenergic

DIAZEPAM [Valium]: Benzodiazepine GABA (an inhibitory neurotransmitter). [Arkan]:

Similar

D-AMPHETAMINE [Dexadrine]: noradrenergic and dopaminergic. METHAMPHETAMINE METHYLPHENIDATE peripheral cardiovascular PIMOZIDE

but irreversible.

stimulus

with central

release

of acetylcholine

nicotinic

anatgonism.

“minor

to diazepam A short

Used to

to reduce non-specific

antagonist tranquillizer”

that acts to enhance

but with slower

acting

stimulant

[ Methadrine]: Like amphetamine,

that

onset

and shorter

is (among

but possibly

other

responses

to

duration

of

things)

both

more of a euphoriant.

[Ritalin]: Also similar to amphetamine in many respects, effects and releases monoamines from a different store.

[Orap] Dopamine

and

used to treat migraine.

[Catupres]: Alpha 2 noradrenergic agonist that acts pre-synaptically activity. It also reduces acetylcholine release and so is an effective

CLONIDINE noradrenergic anticholinergic.

LORAZEPAM action.

Nicotinic

[ Incersine]: Ganglionic

MECAMYLAMINE treat hypertension.

by re-

agonist

Nicorette gum]:

NICOTINE [tobacco, catecholamines.

like physostigmine

acts

but has less

(D2) antagonist

a Alternate names are in brackets, with US trade names italicized. Sources are Physicmz’s Desk Reference, 1991 Edition and E.F. Reynolds (Ed.), Martindale: The Extra Pharmacopoeia, 29th Edition. (1989). London: The Pharmaceutical Press.

slowed. The P300 is of particular interest in identifying effects on stimulus processing. It is a vertex-positive component with a latency of around 300 ms. It appears to occur during or after stimulus processing, and before response processing. Thus, making stimuli more difficult to discriminate will slow both reaction time (RT) and P300 latency. Requiring a more complex response will also slow RT but does so without changing P300 latency (McCarthy & Donchin, 1981). P300 is slowed by scopolamine (Callaway, Halliday, Naylor,

4

E. Callaway et al. / Cholinerglc actiuity and information

processing

& Schechter, 1985) and this is reversed by physostigmine (Meador, Loring, Adams, Patel, & Davis, 1987). P300 is speeded by nicotine (Edwards, Wesnes, & Warburton, 1985). Age also affects P300, slowing it with advancing years. There are, however, many drugs that alter information processing but do not slow P300. For example, methysergide is a serotonin antagonist that impairs memory but does not slow P300 (Meador et al., 1989). Pimozide (Halliday, Naylor, Callaway, Yano, & Walton, 1987) reverses the speeding of RT produced by amphetamine without changing P300 latency. A second way of locating a drug effect is by looking for interactions with task variables. If a task variable slows a particular process and the drug slows the same process, then it will be likely that the combination of drug and increased task demand will slow responses more than the simple sum of the slowing produced by each alone. For example, stimulus evaluation is a stage of stimulus processing slowed by making the stimulus more complex or unfamiliar, and is distinct from an earlier stage of stimulus processing which is slowed by reducing contrast. Response selection is a stage of response processing that is slowed by making the response more complex. It is distinct from a later stage of response execution that is slowed by increasing the physical demands of the response (Myers, Osman, Irwin, & Yantis, 1988; Smith, 1968). Interaction between stimulus complexity and an experimental manipulation indicates an action on stimulus evaluation. Interaction with response complexity indicates action on response processing (Gaillard, 1988a; Pieters, 1983; Sanders, 1980; Sternberg, 1969). Barbiturates (Frowein, Gaillard, & Varey, 1981) and aging (Halliday, Callaway, Naylor, Gratzinger, & Prael, 1986) both interact with stimulus complexity, slowing responses to complex stimuli more than they slow responses to simpler easier ones. For a more detailed review of issues involved in timing information processing components, see van der Molen, Bashore, Halliday, and Callaway (1991). Since scopolamine slows P300, and has been said by some authors to produce effects on memory that resemble those produced by old age (Bartus, Dean, Beer, & Lippa, 1982), we expected scopolamine to interact with stimulus complexity and produce a disproportionate slowing of responses to harder stimuli. This prediction was tested with the task described below. 2.1. The stimulus

eualuation-response

selection task (SERS)

The subject is seated in a comfortable chair facing a computer display screen with the response buttons supported on the subject’s lap so they can be comfortably operated by the index and middle fingers of both hands. The fixation display (see Fig. 1) is on whenever a display with a target is not on. A trial begins with a display containing a target “X” in one of the four horizontal positions. This target is made more complex and difficult to detect by displaying stars in the other three positions. Stimuli that are either easy or

E. Callaway et al. / Cholinergic aciicity and information processing

I

.)(.

.

I

I*x**I

3

lIl@ma

Fig. 1. The stimulus

J evaluation-response

selection

task.

hard (more difficult to perceive) are presented randomly. In each block of trials the subject is instructed to respond to the stimuli in one of two specific ways. One way of responding is judged to be “easy” and requires that the subject press one of two outside keys depending on whether the target’s position is left or right of center. The other response is more complex and is judged to be “hard”. It requires that the subject press one of four keys corresponding to the relative position that the target occupied. Blocks of easy and hard responses are alternated. The target remains on for 1852 ms or until a response is made. Then a feed-back tone informs the subject when an error has been made and such trials are discarded. The interval between target display onsets is 2100 f 100 ms. The task illustrated in Fig. 1 combines easy or hard stimuli with easy or hard responses producing four task conditions: (1, easy stim. + easy resp.; 2, easy stim. + hard resp.; 3, hard stim. + easy resp.; 4, hard stim. + hard resp.). Hard (more complex) stimuli slow stimulus evaluation so another variable that slows stimulus evaluation should interact with stimulus complexity. By the same additive factors logic, hard (more complex) responses slow response selection, so a variable that slows response selection should interact with response complexity. Increasing stimulus complexity and increasing response complexity both slow RT. However, P300 latency is only increased by stimulus complexity. In several studies, older people had longer RTs and P300 latencies than younger adults (Halliday et al., 1986). In addition, the hard stimuli slowed both RT

6

and P300 consistent with age interacts 1978).

E. Callaway

et al. / Cholinergic

actidy

and information

processing

latencies more in older subjects than in younger subjects. This is with other studies that have reported a reduction in P300 latency (Pfefferbaum, Ford, Wenigrat, Roth, & Kopel, 1984). Age also significantly with stimulus complexity (Simon & Pouraghabacher,

2.2.1. Unexpected effect of scopolamine Scopolamine was expected to slow stimulus evaluation since, like aging, it slows P300, and its effects on memory are similar to changes seen in old age (Flicker, Serby, & Ferris, 1990). Thus, scopolamine was expected to interact with stimulus complexity, and to slow responses to complex stimuli the most. In two experiments it did the opposite and slowed RTs to simple stimuli more than those to complex ones. In the first experiment (Callaway et al., 1985>, twelve women (aged 19-33 years) were tested before and after placebo, 0.6 mg and 1.2 mg oral scopolamine. The drug slowed both RT (p < .02) and P300 peak latency (p < .05). The drug slowed RT less for hard stimuli than for easy stimuli, although this interaction was not statistically significant. In the second experiment (Brandeis, Naylor, Halliday, Callaway, & Yano, 19901, artificial pupils were used to compensate for the effects of scopolamine on pupil size and accommodation. As before, scopolamine significantly slowed both P300 and RT. Again, there was greater slowing of RT when the stimulus was easy rather than when it was hard and this time the interaction of drug and stimulus complexity was significant (p < .02X Thus scopolamine does the opposite from age, which interacts positively with stimulus complexity. In other words, age slows stimulus evaluation, but scopolamine does something else. It makes “easy” stimuli “difficult”. 2.2.2. Distraction time One special way scopolamine may slow RT is by reducing constraints on non-essential operations carried out during the stimulus-to-response interval. By definition, non-essential operations can be constrained to varying degrees without changing response accuracy. Time spent on non-essential operations can be estimated with a measure called Distraction Time. Distraction Time is estimated by analyzing an entire set of RTs (as opposed to dealing only with the mean value). The results reported here were obtained using a Poisson-Erlang model proposed by Pieters (1985). The actual procedure involves iterative curve fitting using the entire RT distribution, but can be thought of as decomposing RT into Processing Time and Distraction Time. Processing Time is assumed to be almost the same from trial to trial, because the time actually required by the task should not change much from trial to trial after learning is complete. In addition to this Processing Time, each single reaction time may include a number of Distrac-

7

E. Cullawa~ et al. / Cholinergic uctiliry and information processing

120

m

Eosy

stimulus

m

Hard

stimulus

100

.-. : F -hCY .c al E 0, L : _

80

60

40

20 -L

0

-20

REACTION

PROCESSING

DISTRACTION

REACTION

TIME

TIME

TIME

TIME

SCOPOLAMINE [DRuC(POST-PRE)-PLACEEtO(POST-PRE)]

[Ok%JNC]

Fig. 2. Increases in reaction time (and its components) produced by scoptilamine and by age. Responses to easy and to hard stimuli are shown separately. Data on age are from Halliday et al. (1986), those on scopolamine from Brandeis, Naylor, Halliday, Callaway. and Yano (in press).

tion Times. Thus an observed reaction time is the sum of the constant Processing Time and varying Distraction Times (Halliday, Gregory, Naylor, Callaway, & Yano, 1990). Figure 2 illustrates the effects of scopolamine and contrasts them with the effects of aging (age 18-30 compared with 65-75). Making the stimulus more complex increases Processing Time, but actually reduces Distraction Time. Perhaps the complexity of the target requires a more concentrated focus, thus reducing attention to non-essential operations. Scopolamine has no effect on Processing Time, but increases Distraction Time, principally in response to easy stimuli. Thus scopolamine is relaxing constraints on non-essential Distraction Times and this effect is seen most in responses to easy stimuli where Distraction Times are most prevalent. In this case scopolamine increases distraction and makes behavior more variable.

3. Vigilance The hypothesis that scopolamine relaxes constraints on information processing arose from a consideration of the results just cited and from a review

E. Callawuy et al. / Cholinergic activity and information processing

8

of the literature. First, consider the impairment in performance of vigilance tasks produced by the drug. If doses are moderate, we can reject the hypothesis that the effects are due to global impairment, or to lapses or “absences”. This is because the drug-induced decrements are not seen in very simple detection tasks, and are best seen in vigilance tasks “. . . having minimal memory requirements but depending heavily on selection and processing of information” (Warburton & Wesnes, 1985). The inference that the effect of scopolamine is related to its anticholinergic activity is supported by the fact that the effects of physostigmine are opposite to those of scopolamine (Warburton & Brown, 1972). The effects of nicotine are also opposite to those of scopolamine and can reverse the effects of scopolamine on a vigilance task (Warburton & Revel& 1984). Nicotine can also improve performance of patients with dementia of the Alzheimer type on a rapid visual information processing task (Shakian, Jones, Levy, Gray, & Warburton, 1989). Other relevant studies have been reviewed and discussed by Rusted and Warburton (1989). If, as is hypothesized, the decrement in conventional vigilance performance represents a failure to constrain and focus selection and processing, then such a decrement should be seen only in detection of targets at locations on which attention would prudently be focused. Lessening of constraints on the deployment of attention with an anticholinergic should then not necessarily impair detection of targets coming from outside the focus of attention. That is illustrated in a study by Dunne and Hartley (1986). They used a vigilance task with two sets of targets. One set occurred in high probability locations, the other in low probability locations. Scopolamine decreased detection of targets in high probability locations (the location to which most attention should be aliocated for best results), but it actuahy increased detection of targets in low probability locations.

4. Memory 4.1.

Evidence for the role of cholinergic activity

A link between cholinergic activity and memory has been established in three ways. Firstly, the specific effects of anticholinergics on memory are reversed by cholinergics and vice versa. Secondly, there are drugs that influence memory yet have minimal effects on cholinergic systems. These drugs do not counteract the effects on memory of the drugs that do act on cholinergic systems. Thirdly, when cholinergic activity is reduced in nature, memory is impaired. The interactions of cholinergic agonists and antagonists need only a few examples. Thus, with respect to the first point, there are a number of relatively specific anticholinergic drugs that impair memory

E. Callaway et al. / Cholinergic actiuity and information processing

9

(Ketchum, Sidell, Crowell, Aghajanian, & Hays, 1973). The effects of anticholinergics on memory are reversed by physostigmine. Both physostigmine (Davis, Hollister, Overall, Johnson, & Train, 1976; Davis et al., 1978) and nicotine (for review, see Warburton, 1990) can improve memory. We have not found any attempt to reverse antimuscarinic memory deficits with nicotine. There are several illustrations of the second point (e.g. the usual absence of such reciprocal interactions between drugs acting on cholinergic systems and drugs acting primarily on other neurotransmitter systems). Aminergic stimulants can improve memory. This has been reported for methylphenidate by Peeke, Halliday, Callaway, Prael, and Reus (1984) and for methamphetamine by Mewaldt and Ghoneim (1979). Amphetamine can relieve the drowsiness produced by scopolamine, but it makes the scopolamine-induced memory deficit worse (Drachman, 1977). However, Mewaldt and Ghoneim (1979) did find a reversal of scopolamine’s effect on memory by methamphetamine. The memory deficit produced by scopolamine is not reversed by a benzodiazepine antagonist, while the deficit produced by lorazepam (which is counteracted by the benzodiazepine antagonist) is not counteracted by physostigmine (Preston et al., 1989). Physostigmine also does not reverse the memory impairment produced by diazepam (Ghoneim & Mewaldt, 1977) even though it has been reported to reverse benzodiazepine-induced sedation (Ghoneim, 1980). The third point has to do with the fact that reduced cholinergic activity (inferred from studies of human tissues) is found in a variety of conditions that are associated with poor memory. In patients treated with drugs that have anticholinergic actions, the degree of memory deficit is correlated with the anticholinergic activity of the serum (Perlick, Stastny, Katz, Mayer, & Mattis, 1986; Tune, Strauss, Lew, Brethinger, & Coyle, 1982). Old age, senile dementia, Alzheimer type (SDAT), Down’s syndrome, and Lewy body type dementia are all associated both with impaired memory and with reduced cholinergic activity (Bartus et al., 1982; Broks et a1.,1988). Since normal aging, SDAT and anticholinergics all depress cholinergic activity and cause problems with remembering, anticholinergics have been used to model aging and SDAT (Drachman & Leavitt, 1974). 4.2. Evidence of constrained information processing Delayed free recall is most vulnerable to anticholinergic-induced impairment. Items learned before the drug is given are recalled under scopolamine and such memories appear to decay no more rapidly than normal. Digit span is also normal. Thus scopolamine seems to affect the processing of data into long-term storage. It interferes with the focusing of that storage so that data related to the target item (depth of processing) are inadequate for free recall.

IO

E. Callaway et al. / Cholinrrgic actil,ity and information

processing

This focusing of storage is part of what common language attributes to attention, and the connection between attention and recall is a matter of everyday experience. Recognition has the advantage of external cues provided by the test stimulus. Recognition of items learned under scopolamine is less affected than is recall (Ghoneim & Mewaldt, 1977; Petersen, 1977). This difference between recognition and recall, however, is relative rather than absolute. Nissen, Knopman, and Schacter, (1987) report reduced recognition after scopolamine, and Mohs and Davis (1982) found increased recognition by SDAT patients after physostigmine. In procedural memory (the memory of how to do something) each act serves as a cue to the next one. Thus, like recognition, it depends less on a network of stored associations then does free recall which involves semantic memory (the memory of a specific thing, such as a word from a list). Nissen et al. (1987) found no effect of scopolamine on procedural memory. But, like recognition, the resistance to scopolamine is probably one of degree and indeed an effect of scopolamine on procedural memory was found by Frith, McGinty, Gergel, and Crow, (1989). Thus the effects of anticholinergics on memory are much more limited and specific than the effects of any disease or even aging. For example, both SDAT and anticholinergics interfere with delayed recall of both verbal and non-verbal information learned under the influence of the drug or since onset of dementia. In contrast with SDAT, scopolamine did not interfere with verbal fluency (recall of old memories) or with a digit-symbol paired associate task (use of immediate memory). In other words, scopolamine interfered neither with retrieval of old memories nor with the functioning of immediate memory, while both these functions were found to be impaired in SDAT (Beatty, Butters, & Janowsky, 1986). The defects in memory produced by anticholinergics are more like those seen in old age than they are like those seen in the dementias (Grober et al., 1990). Differences between the effects of old age and those of scopolamine on the SERS task have been discussed above. 4.3. A limited resource used for free recall The particular vulnerability of free recall suggests that anticholinergics interfere with selecting and processing data into long-term memory. According to Rusted (1989), this is due to an effect on a central executive that has a limited capacity rather than to an effect on some global impairment of attention. She measured performance on tasks that called on free recall of words, short-term verbal memory (digit span) and visual memory (mental rotation). All three memory tasks were done alone and with two specific interfering tasks. The interfering tasks were (1) counting to interfere with digit span, and (2) tapping to interfere with mental rotation. Memory tasks, alone and with interfering tasks, were done with and without scopolamine.

E. Callaway et al. / Cholinergic acticity and information processing

11

Scopolamine impaired only free recall and showed no interaction with the interfering tasks. Tapping interfered with recall and mental rotation. Counting interfered with recall and digit span. Scopolamine interfered with free recall but did not interfere with either of the immediate memory tasks. That was expected from the literature. For the immediate memory tasks, only the modality-specific interfering tasks impaired performance, suggesting that each task called on a specific sort of attention (vulnerable to a specific sort of distraction). Both interfering tasks impaired some of the complex processing needed for free recall. That was also expected. The important observation concerned the absence of an interaction between scopolamine and the interfering tasks on free recall. If the interfering tasks distracted the subject (interfered with attention) and scopolamine also interfered with the same sort of attention, an interaction would be expected. The absence of an interaction argues against the idea that scopolamine impairs attention in a global way. The scopolamine-sensitive “central executive” postulated by Rusted is not taxed by counting, tapping, digit span or mental rotation. It is only concerned with the selection and processing of the data into long-term memory that will be needed for subsequent recall. 4.4. The consequences

of relaxing constraints

on processing

When subjects intend to remember something, they concentrate on processing data that are expected to facilitate recall of the target items. Loosening of constraints on processing should reduce storage of data relevant to the targets by permitting the processing of unrelated incidental items. It then follows that scopolamine, by reducing constraints on processing, should improve recall of incidental items at the same time as it is impairing recall of intended items. Dunne and Hartley (1985) report an experiment in which scopolamine actually improved memory. They used a dichotic listening task that required subjects to recall only words presented to one ear. They demonstrated the well-known fact that scopolamine impairs recall of words given to be learned. However, they found that incidental words (e.g. words that were presented to the unattended ear, and that the subject did not know would be asked about later) were recalled better after scopolamine than after placebo. In other words, when scopolamine reduced encoding of associations to the target words, the released resource became available for encoding associations to incidental words. The opposite sort of effect from a cholinergic agonist was reported by Andersson and Hockey (1977). They used words presented in different locations on a computer screen. Nicotine (which generally improves memory) impaired recall of word locations (incidental memory).

12

E. Callaway et al. / Cholinergic actiuity and information

processing

If scopolamine impairs recall by releasing constraints on the encoding of associations, then the effect of the drug should be lessened by using other means to force the encoding of associations to target items. Grober et al. (1990) presented four words on a card. The subject was then given a class (fruit) and told to find and point to the word belonging to that class (grape). After identifying all four words, the card was removed and the class cues were read to the subject who was to give the word again (cued recall). This was repeated until immediate cued recall was perfect and then another card was given. Then, after the subject had performed an interference task for a time, cued recall was tested again. Doses of scopolamine that induced delirium in some patients (1 mg IM) produced no deficits in delayed cued recall. In summary, the effects of anticholinergic agents on memory seem not to involve encoding, very short-term memory, decay of memory or retrieval. Rather, they seem to result in a less focused processing of data into long-term memory, with the result being a less adequate network of associations for retrieving target items from semantic memory.

5. Sensitivity

to noxious

stimuli

Responses to noxious stimuli are reduced by cholinergic agonists. Interpreting such studies in information processing terms is difficult because factors such as stimulus intensity, attention, response control and motivation are hard to disentangle. Nevertheless, this reduced responsiveness suggests some sort of processing constraint. Reduced pain sensitivity has been produced by nicotine (Pomerleau, Turk, & Fertig, 1984) and with physostigmine (Gillin et al., 1978). Saran, an irreversible anticholinesterase, reduced subjects’ responses to a noxious stimulus in a study reported by Callaway and Dembo (19.571. Their subjects were instructed not to respond to sudden loud (110 dB) sounds and the electromyographic responses to those sounds were recorded. Exposure to the anticholinesterase reduced the amplitude of the electromyographic responses.

6. Problem solving Acetylcholine also appears to control constraints on the selection and processing of problem solving strategies, just as it appears to control constraints on the selection of environmental aspects in a vigilance task and the associations that are encoded in a memory task. This has been demonstrated by studies using the Lukins water jug (Einstellung) test (Levitt, 1956). In this test, the subject must figure out how to obtain a specified volume of water

E. Callaway et al. / Cholinergic acticity and information processing

13

using jugs of three different volumes. The test consists of ten problems. The first four can be solved only one way. The next four can be solved the first way or an easier way. The last two can only be solved the easier way, so the subject must abandon the initial strategy in order to succeed. The score is the time taken from commencement of problem 5 (the first that can be solved with the new method) until the subject adopts the new method (or ends the task). Callaway and Band (1958) compared performances of subjects given atropine with those given a placebo. Subjects given atropine had significantly better scores (changed strategy more quickly) than placebo-treated subjects. Warburton and Wesnes (1985) found that nicotine had the opposite effect and tended to delay adoption of the easier (new> strategy. This suggests that the antagonist (atropine) reduces constraints and facilitates the adoption of a new strategy while the agonist (nicotine) increases constraints and delays novel trials.

7. Response

processing

7.1. Experimental evidence Response conflict is measured by the Stroop effect, which is the slowing of response that occurs when one tries to name the color of ink used to print the name of another color. For example, with the word “RED” printed in green ink, the subject is supposed to say “green”. It takes longer to name a color used to print a conflicting color-word than to name the color of a spot. That slowing is due to response conflict, and so an increase in that slowing is an indication of reduced constraint on response selection. Evidence that the Stroop effect is changed by changing cholinergic activity will be presented below after giving the evidence for the Stroop effect being the result of response conflict, and not of stimulus interference. The Stroop test makes use of three stimulus sets: (1) a list made up color names (red, blue, green, yellow) printed in black ink, (2) a series of colored patches using the same four colors and (3) the same color names, but printed in conflicting colors (e.g. the word RED printed in green ink). The subject is given four tasks: (1) reading the words in black ink, (2) naming the color patches, (3) reading the words in colored ink and (4) naming the colors of the ink used to print the conflicting color name. Task (4) takes considerably longer than do any of the other tasks. The slowing produced by naming colors used to print conflicting color-names has come to be called the Stroop effect. As noted above, P300 latency of the ERP reflects time taken in stimulus evaluation, but is not slowed by slowed response processing. Duncan-Johnson

14

E. C&way

et al. / Cholinergic actit,ity and information

processing

and Kopel (1981) showed that the P300 latency is the same when one names the color of a conflicting color-name stimulus as when one reads the color-name, even though saying the name of the conflicting color takes much more time than reading out loud the printed color-name. Thus, the Stroop effect seems not to be due to slowing of stimulus processing (which would have slowed P300 latency) and so is probably due to response conflict. Callaway and Band (1958) found that atropine had a tendency to increase the Stroop effect. Ostfeld and Aruguette (1962) found that scopolamine increased it significantly, but Kopelman and Corn (1988) found no significant effect. Warburton and Revel (1984) found that nicotine reduced it. The most likely explanation for the actions of cholinergic agonists and antagonists on the Stroop effect is that cholinergic activity constrains response selection and so reduces the response competition that underlies the Stroop effect. 7.2. Clinical eL)idence With the exception of the Stroop studies cited above, we know of no other studies addressing the question of how changes in cholinergic activity affect response processing. There are some clinical observations and some generalizations drawn from animal studies that all support the plausibility of the hypothesis that cholinergic activity modulates the constraints on response processing just as it does for stimulus processing. These arguments for plausibility are not, however, presented as substitutes for controlled studies. One set of clinical observations has to do with the well-known reciprocal effects of dopamine and acetylcholine in both nigrostriatal and mesolimbic systems. Thus, anticholinergics are used to treat Parkinson’s disease (dopamine deficiency), the chorea of Huntington’s disease has been linked to loss of cholinergic neurons (Cote & Crutcher, 1985), and physostigmine has been used to treat familial ataxias (Kark, Blass, & Spence, 1977). Both the rigidity of the patients with Parkinson’s disease as well as their difficulty in initiating voluntary action can be interpreted as excessive response constraint. Their fine tremors may be similar to the oscillations in servo-systems with excessive gain in the negative feedback loop. The uncoordinated but almost purposeful movements of chorea and ataxia suggest inadequately constrained response execution. In other words, it seems plausible that anticholinergics relax constraints on response execution to relieve Parkinson’s disease, and that physostigmine increases constraints on response execution and so diminishes ataxia. The other set of clinical observations has to do with psychiatric syndromes. Based on a variety of neurochemical and pharmacological arguments, increased cholinergic activity has been associated with states characterized by overly constrained responsiveness. Thus, it has been related to depression (Janowsky, El-Yousef, & Davis, 1972), to the negative symptoms of

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schizophrenia (Tandon & Greden, 1989) and to “reduced drive-reduction behavior” (Dilsaver, 1986; Dilsaver & Coffman, 1989). Hypocholinergic states (with their associated loosened constraints on perceptual, cognitive and motor processes) have been related to mania, delirium and the positive symptoms of schizophrenia (Singh, Kay, & Opler, 1987). Anticholinergics can of course produce hallucinations in normal subjects. In summarizing a large number of animal studies, Karczmar (1981) coined the term “cholinergic alert nonmobile behavior ” or CANB, to deal with the changes in motor activity produced by drugs acting on cholinergic systems. Vanderwolf (1988) has hypothesized two sorts of arousal. One sort (type 1) is associated with exploratory behavior. The other (type 2) depends on cholinergic input to the cortex, and is associated with feeding and grooming. Type 2 behavior suggests a narrower focus of attention and a more constrained behavioral repertory. Such conservative (non-exploratory) arousal would be adaptive not only during normal self-care, but also as a response to injury, illness and certain other stresses. That would be consistent with the role assigned to acetylcholine in mediating stress responses (Dilsaver, 1986).

8. Nicotinic

activity

So far, no distinction has been made between muscarinic and nicotinic systems. That has been because most effects of nicotine are reversible by antimuscarinics, and are probably due to release of acetylcholine by nicotine. About 95% of cholinergic receptors are muscarinic, and their slow response is more suited to the modulatory effects detected in information processing studies. However, there are contrasts between the effects of nicotinic activity and those of muscarinic activity that should be noted. Firstly, nicotinic activity seems to enhance dopaminergic activity, to increase self-stimulation, and to improve mood (Warburton, 1990). The reciprocal antagonism between muscarinic activity and dopaminergic activity has already been noted. Thus, muscarinic activity reduces self-stimulation (Stolerman, 1990) and in some circumstances induces dysphoria (Janowsky, Risch, Kennedy, Ziegler, & Huey, 1986). Nicotine also has special effects on motor activity. It tends to relax skeletal muscles, probably by a direct effect on Renshaw cells in the spinal cord (Dominmo & VonBaumgarten, 1969). It also increases tapping speed, and this effect is blocked by the nicotine antagonist, mecamylamine (West & Jarvis, 1986).

9. Conclusions The hypothesis that increasing cholinergic activity increases constraints on information processing in its strong form will be rejected if changing cholin-

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ergic activity can be shown to cause some other unrelated change in information processing. One important alternative hypothesis states that cholinergic activity results in “selective inhibition of non-reinforced behavior” (Carlton, 1963). It was derived from animal studies in the behavioral tradition. In most of the human cognitive studies reviewed here, constraints seem to operate along a dimension of probable relevance. One can argue that probable relevance and past reinforcement may be referring to the same thing, and are in any case closely related. Further, past reinforcement is easier to define operationally in animal studies, while in human work “probable relevance” easily becomes circular (e.g. probable relevance is evidenced by selection when constraints are increased). Warburton (1977) has argued that Carlton’s data only support that hypothesis in respect to stimulus selection, and not in respect to response selection. If one accepts the clinical evidence from movement disorders, the more constrained response execution seen when physostigmine reduces the intrusive movements in ataxia argues against the idea of past reinforcement being crucial. It remains to be seen whether a more specific experimental test can be designed for use with normal subjects. The second and perhaps most interesting alternative hypothesis is that cholinergic activity enhances automatic processing (Naylor, Callaway, & Halliday, in press). In humans, information seems to be processed both serially and in parallel, with serial (controlled) processing requiring more effort and demanding more constrained operations. When tasks are easy or practiced, then more than one operation can be done at the same time (in parallel). When tasks are novel or difficult, then operations tend to be done in a more controlled and serial fashion. Often, serial and parallel processes take place at the same time. The “constraints on information processing” theory suggests that anticholinergics should favor parallel operations, which are tolerant of more unconstrained processing, and should interfere with the efficiency of serial operations. This contrary alternative that cholinergic activity enhances parallel processing gets support from two sources. Based on the work of Triesman and Gelade (19801, one can argue that the easy target in the SERS task can be detected by parallel and automatic search, while the hard stimuli must be searched in a more controlled fashion. On that basis, one would explain scopolamine’s slowing of target selection for easy stimuli more than for hard ones by saying that decreased cholinergic activity slowed automatic parallel processing more than controlled serial search. The second line of support comes from the work of Vanderwolf (1988) that shows cholinergic arousal associated more with automatic activity than with operant activity. There is one potentially relevant study by Broks et al. (1988). Using a Posner-type cued visual reaction time task (Posner, Walker, Friedrich, & Rafal, 19841, they found scopolamine produced the greatest slowing when location cues were valid and the cue-target delay was long. Delayed valid

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cues allow controlled processing; thus automatic processing seems less vulnerable to the drug. The two alternatives concerning visual search need to be explicitly tested, and a possible paradigm for such a test is being studied at present. The final information processing concept to be considered is decision bias. In mania, judgements tend to be more liberal or optimistic, while in depression the opposite tendency is seen. Thus on a word-recognition task the more optimistic manics make false positive errors while depressives make relatively more errors of omission (Corwin, Peslow, Feenan, Rotrosen, & Fieve, 1990). That is to say, manics are more likely to think a decoy (new) word is one that had been seen before (word from the learned list). Corwin et al. also found that propranolol makes subjects more conservative, and that finding is supported by observations reported by Cailaway, Halliday, Perez-Stable, Coates and Hauck (1991). It is hard to invoke the concept of attention to deal with a change in bias. However, a liberal bias could be thought of as representing a loosening of constraint on what will be accepted as a recognized old word, and as a lessened “avoidance of unreinforced behavior”. If bias and constraints are related as suggested, then scopolamine should produce a liberalizing change in bias. There is some evidence to suggest just that sort of effect (Wesnes & Warburton, 1983; Zec, 1988). However, on the basis of data from a continuous performance task, Newhouse, Corwin, and Lewis (1990) have claimed the opposite: that scopolamine produces a more conservative bias. The hypothesis that increasing cholinergic activity increases constraints on information processing is consistent with a large variety of observations. It is also testable, and hence serves to bring alternative hypotheses into focus. In that way it contributes to the evolution of human psychopharmacology from its primitive data-driven tradition towards a more theory-driven science. In the long run, it seems unlikely that manipulating cholinergic activity will be found to alter only constraints on information processing. Testing this hypothesis, however, will help identify and define any other effects of cholinergic manipulations that there may be.

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