Does Scopolamine Directly Impair Memory?

Ellen Gmber, Rosanne M. Leipzig, Richard B. Upton, Wendy Wisniewski, Mary Schroeder, Peter Davies, Wdter Ritter and Herman Buschke Albert Einstein College of Medicine

Montefiore Medical Center Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021

Introduction are ameliorated by cued recall or recognition (Ghoneim & Mewaldt 1977; Caine, Weingartner, Ludlow, Cudahy, An important goal in the investigation of human mem- & Wehry 1981). Inconsistency in free recall provides fur- ory is to elucidate the role of the cholinergic system. ther evidence of a retrieval deficit; words retrieved on Evidence from three areas of research suggests a ma- one trial may not be retrieved on the next (Caine et al. jor role for the cholinergic system in human memory: 1981). (1) pharmacological studies demonstrate that cholinergic Besides disrupting free recall, scopolamine also dis- blockade disrupts free recall in young normal subjects, rupts attention. Specifically, scopolamine has been (2) post-mortem studies demonstrate cholinergic deple- shown to reduce the level of active attentional con- tion in patients with Alzheimer’s disease (AD) and other trol that subjects can exert when processing information dementias, and (3) clinical studies demonstrate that choli- (Dunne & Hartley 1985,1986). The subject’s attention is nomimetric drugs improve memory in patients with AD. diffused or unfocused. In dichotic listening tasks, this is These studies are reviewed elsewhere (Kopelman 1986). suggested by decreased recall of words from the attended The purpose of the present study is to re-evaluate the channel and increased recall of words from the unat- claim that cholinergic blockade produces direct memory tended channel (Dunne & Hartley 1985). In visual infor- impairment. Previous studies show that scopolamine, an mation processing, unfocused attention following scopol- anticholinergic drug, disrupts free recall using a variety of amine intoxication is shown by increased detection of doses and routes of administration (Drachman & Leavitt targets in low probability locations as well as decreased 1974; Beatty, Butters, & Janowsky, 1986; Nissen, bop- detection of briefly presented target letters in high proba- man, & Schacter 1987; Kopelman & Corn 1988). The bility locations (Dunne & Hartley 1986). Sensitivity decre- free recall deficit is presumed to involve both encoding ments in vigilance tasks during scopolamine intoxication and retrieval mechanisms. Encoding mechanisms have also suggest an inability to maintain voluntary control of been implicated because the deficit does not occur if ini- attention over extended periods (Wesnes & Warburton tial learning takes place before the drug is administered 1983, 1984; Broks, Preston, Traub, Poppleton, Ward, & (Ghoneim & Mewaldt 1975; Peterson 1977); words en- Stahl 1988; Wesnes, Simpson, & Kidd 1988). coded into memory prior to scopolamine administration Scopolamine also may serve to reduce the already lim- can be retrieved during intoxication. Retrieval mecha- ited processing resources available in working memory nisms have been implicated because free recall deficits (Baddeley 1986). Based on the marked impairments

Grok et al. 327

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 that intoxicated subjects displayed on a range of de- must be supplemented by effective cued recall to obtain manding information processing tasks, Wesnes et al. maximum retrieval. The sum of free and cued recall is (1988) suggested that scopolamine reduces the amount termed “total recall.” Total recall provides the best esti- of processing resources available to evaluate incoming mate of the amount of information a subject can encode information. While they did not directly test whether and retrieve. scopolamine-induced processing deficits produce mem- Enhanced cued recall demonstrates memory capabili- ory impairment, they suggested the possibility. If scopol- ties which may not be revealed unless deficits in attention amine disrupts the control of attentional resources and/or and other cognitive processes are circumvented. For ex- reduces the amount of processing resources, the effect ample, nondemented elderly subjects who show deficits

of such disruptions on free recall needs to be tested di- in free recall display intact total recall when enhanced Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 rectly. cued recall is used (Grober & Buschke 1987; Grober, The free recall deficit induced by scopolamine has Buschke, Crystal, Bang, & Dresner 1988a). In contrast, been used to support the claim that cholinergic block- patients with dementia or amnesia display deficits in both ade disrupts encoding and retrieval mechanisms. In this free and total recall; their retrieval deficit cannot be over- study, we consider an alternative interpretation based on come by the addition of cued recall. We have suggested the fact that free recall depends on other cognitive fac- previously that free recall deficits which are completely tors such as attention and processing resources as well eliminated by enhanced cued recall may be due to indi- as specific memory mechanisms. Reduction in the abil- rect effects of impairment of other cognitive processes. In ity to direct attention and focus on each word as it is our view, only deficits in free recall which cannot be elim- presented for learning could impair free recall in the fol- inated by enhanced cued recall or similar procedures can, lowing way. Before the to-be-remembered words can be with relative confidence, be considered genuine mem- encoded into memory, each word must be attended to, ory deficits. Here, direct impairment of memory mech- decoded, and related to existing knowledge; only then anisms is shown by diminished cued recall in spite of can the resulting representation be stored. If an adequate adequate attention and cognitive processing and coor- representation is not formed, recall failure could occur. dination of encoding and retrieval (Buschke & Grober Impaired free recall may also occur because of an inabil- 1986; Grober, Buschke, & Bang 1988a). To analyze the ity to use appropriate retrieval strategies. For example, effects of scopolamine on memory, it is important to dis- reductions in the distribution or amount of attentional tinguish between direct effects due to impairment of spe- resources could interfere with the identification or ex- cific memory mechanisms such as encoding or retrieval ecution of effective strategies which permit subjects to and indirect effects due to impairment of other cogni- fully demonstrate their capacity for retrieval. Thus, free tive processes which are necessary but not sufficient for recall deficits may result from impairment of the sup memory and learning. However, this is not to deny that porting cognitive operations essential to normal memory in real life many older people have memory problems; functioning as well as to dysfunction of memory mech- rather, it emphasizes that their memory problems may anisms themselves (Buschke 1987; Grober & Buschke be secondary to impairment of other cognitive processes 1987). which may require different treatment. Since scopolamine disrupts attention and information Two experiments were conducted to determine wheth- processing, impaired free recall following scopolamine er or not scopolamine produces such genuine memory intoxication may reflect indirect effects on attention and impairment. If scopolamine disrupts memory mecha- other cognitive processes rather than direct drug effects nisms directly, deficits in total recall as well as free recall on memory mechanisms. To distinguish between these should occur, consistent with previous findings of gen- two possibilities, we used the procedure of enhanced uine memory impairment in demented and amnestic sub- cued recall to control attention and cognitive process- jects (Grober et al. 1988a). If instead, enhanced cued re- ing (Buschke 1984). Enhanced cued recall begins with call eliminates the retrieval deficit as shown by intact total a search phase in which subjects search for and identify recall when free recall is impaired, then scopolamine may items (e.g., onion) in response to category cues (e.g., veg- not produce genuine memory deficits. In the first experi- etable). The search is intended to optimize encoding by ment, we compared performance on a 16-item enhanced circumventing inattention and inducing appropriate se- cued recall test after administration of 0.7 or 0.8 mg of mantic processing; it also demonstrates that the specified scopolamine to a baseline condition. Because total recall operations have been executed. The search also pro- was unaffected, we conducted the second experiment in motes optimal retrieval because the same cues are used which subjects performed a 32-item enhanced cued re- for encoding and retrieval to assure encoding specificity call test after administration of either active placebo, 0.5, (Thomson & Tulving 1970; Tulving & Thomson 1973; or 1.0 mg of scopolamine. Robust total recall persisted Tulving 1979; Schacter & Tulving 1982). Because free despite high doses of scopolamine and clinical delirium, recall does not result in the retrieval of all items avail- consistent with the hypothesis that cholinergic blockade able in memory (Tulving & Pearlstone 1966), free recall does not produce genuine memory impairment.

328 Journal of Cognitive Neuroscience Viutne 1, Number 4

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 Table 1

FREERECALL* TOTALRECALL*

Amount of DN8cme> Basehe Treatment Baseline Treatment 12 3 12 3 12 3 123

1 30 .7t 14 15 16 35 5 16 16 16 16 16 15 Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 2 27 .7 16 16$ 16$ 10 9 10 16 16$ 16$ 16 16 16 3 22 .7 13 15 15 67 7 16 16 16 15 15 16 4 35 .8t 12 14 16 13 7 16 16 16 11 14 16

Free Recall and Total Recall for Individual Subjects in Study 1. * Maximal response is 16 items per trial. t Subjects with scopolamine-induced delirium. 4 Estimated recall based on perfect free recall on Trial 1.

firmed by separate analyses of variance (ANOVAs) per- Results and Discussion formed on free and total recall with repeated measures on condition (baseline versus treatment) and trials. As study1 expected, scopolamine interfered with free recall as sub- Free recall and total recall on each trial are presented jects retrieved more words by free recall during baseline in Table 1 for individual subjects during baseline and (mean = 14.8, sd = 1.3) than treatment (mean = 6.1, sd treatment. The data are summarized in Figure 1, which = 2.8; F(1,6) = 69.63). Neither the main effect of trials presents the mean number of items in free recall and total (F(1,6) = 3.64, p > .lo) nor its interaction with condi- recall summed across subjects and trials during baseline tion (F < 1) reached significance, due in part to ceiling and treatment. effects in free recall during baseline. Although scopol- Subjects showed striking free recall deficits one hour amine interfered with free recall, it did not interfere with after receiving scopolamine. Free recall was lowest for cued recall by any subject (Table 1). The ANOVA con- two subjects who became delirious following drug ad- firmed that there was no significant difference in number ministration. Free recall grossly underestimated the to- of items retrieved in total recall during baseline (mean tal number of items subjects encoded and retained. In - 16.0, sd = 0.0) and treatment (mean = 15.2, sd - 1.5; fact, subjects retrieved by cued recall as many items as F(1,6) = 2.59, p = .20). No learning was observed be- they had recalled at baseline. These results were con- cause performance was at ceiling (F < 1). While these results are consistent with the hypothesis that scopolamine does not produce genuine memory deficits, they might not have been found because the enhanced cued recall procedure used was not challenging enough or because subjects were not given a large enough dose of scopolamine. These possibilities were evaluated in the second study.

s-2 ** In this study, 12 subjects were randomized to one of L three treatment arms using a double-blind randomized a6 7 design. The treatment arms included an active placebo L at the dose needed to produce peripheral anticholin- 2 ergic effects (glycoperrolate 0.3 mg), lowdose scopolamine (0.5 mg), and high-dose scopolamine (1.0 mg). 0 The high dose, which was used by Drachman and Leav- Free Recall Total Recall I itt (1974), was included to determine if larger doses of scopolamine would produce genuine memory deficits. Figure1.MeanfnerecaUandtdaliccrrllduringbnsellne The low dose was included to show the dosedependent (open bar) and trerrtnrent (stippled bar) in study 1. effect of scopolamine on free recall. Enhanced cued re-

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 Table 2

FREE RECALL.* TOTALRECALL*

Amount of ID Age Drug(W Baseline Treatment Baseline Treatment 1 2 3, 123 123 123

1 23 Placebo 3 19 16 14 14 21 29 31 31 31 32 32 2 35 Placebo 2 19 18 11 15 21 29 32 32 31 32 32 Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 3 25 Placebo 14 18 28 17 20 23 31 31 32 32 32 32 4 35 Placebo 17 26 29 26 31 32 32 31 31 32 32 32 5 24 .5 14 20 26 13 12 15 32 32 32 32 32 32 6 31 .5 18 26 31 10 14 16 31 32 32 31 32 32 7 22 .5 23 27 25 11 20 22 32 32 32 31 32 32 8 31 .5 11 17 22 5 10 17 28 31 32 24 30 32 9 25 1.o 20 25 31 11 14 15 28 32 32 32 32 32 10 24t 1.o 11 20 25 755 32 32 32 29 31 32 11 22t 1.o 16 29 31 448 30 32 32 22 27 29 12 24t 1.o 15 23 23 453 32 31 32 30 28 32

Free Recall and Total Recall for Individual Subjects in Study 2. * Maximal response is 32 items per trial. t Subjects with scopolamine-induced delirium.

call was made more challenging by increasing the num- level of free recall did not differ among the subjects in the ber of items to be learned from 16 to 32. This change three treatment conditions (F(2,9) = 1.57). As in Study 1, was expected to eliminate the ceiling effects found for free recall was significantly lower during treatment (mean free recall during baseline in the first study. = 13.8; sd = 7.5) than baseline (mean = 21.5; sd = 6.0; The performance of young normal subjects who re- F(1,9) = 68.191, showing that scopolamine interfered ceived 1.0 mg of scopolamine provides the strongest test with free recall. This discrepancy between baseline and of the hypothesis that scopolamine produces genuine treatment was greater at higher doses (F(2,9) = 29.701, memory deficits. Preservation of total recall would sug- replicating the dose-dependent effect of scopolamine on gest that scopolamine has little direct effect on encoding free recall found in other studies (Crow & Grove-White and retrieval mechanisms when other cognitive process- 1973; Drachman & Leavitt 1974; Peterson 1977; Caine et ing is controlled. al. 1981; Nissen, Knopman, & Schacter 1987; Kopelman Free recall and total recall for each trial during baseline & Corn 1988; Broks et al. 1988). There was a signifi- and treatment is shown in Table 2 for individual subjects. cant increase in free recall over trials (F(2,18) = 82.221, A summary of the free recall data is presented in the left which was more marked during baseline than treatment half of Figure 2, which shows the mean number of items (F(2,18) = 5.64). Thus, according to free recall mea- retrieved by free recall for subjects in each condition dur- sures, subjects given scopolamine learned less. When ing baseline and treatment. Subjects who received 1.0 mg cued recall was added to free recall to obtain total recall, of scopolamine showed the greatest difference between total recall remained high despite high doses of scopol- baseline and treatment; subjects who received placebo amine. Unlike free recall, total recall was not impaired. showed no difference, while subjects who received 0.5 Total recall did not differ among the subjects in the three mg of scopolamine showed an intermediate difference. treatment conditions (F(2,9) = 1.57). In contrast to free As in the first study, the three delirious subjects had the recall, the number of items retrieved in total recall re- lowest free recall. The right half of Figure 2 presents the mained uniformly high during treatment as well baseline average number of items in total recall in each condition (30.8 versus 31.4; F(1,9) = 1.08). This was true at each during baseline and treatment. Scopolamine had no ef- treatment level (F(2,9) = 2.261, indicating that subjects fect on total recall even at the 1.0 mg dose. This can be given 1.0 mg of scopolamine learned the same number seen for individual subjects in Table 2. of items as they did at baseline. Total recall increased sig- The differential effect of scopolamine on free recall nificantly over trials (F(2,18) = 6.99) from 30.1 on Trial 1 and total recall was confirmed by statistical tests. Overall to 31.8 on Trial 3.

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12 Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021

0 P1 acebo .5 mg 1.0 mg P1acebo .5 mg 1.0 mg

Free Recall Total Recall

Figure 2. Mean &ee recall and total recall during baseline (open bar) and treatment (stippled bar) in Study 2.

Free recall remains poor because scopolamine has disrupted other cognitive processes required for free recall. These studies tested the claim that cholinergic blockade One possibility is that scopolamine depletes processing disrupts encoding and retrieval mechanisms, using en- resources needed for the temporary storage and manip hanced cued recall to test memory when attention and ulation of information in working memory (Baddeley cognitive processing are controlled. Enhanced cued re- 1986). Successful performance on standard tests of free call facilitates encoding by circumventing inattention and recall requires grouping of single items into larger units inducing appropriate semantic processing. It facilitates (Tulving 1962; Buschke 19761, which in turn requires suf- retrieval by providing for effective cued recall, which is ficient processing resources. Since items are presented needed because free recall does not result in the retrieval one at a time, processing resources are needed to main- of all items available in memory (Tulving & Pearlstone tain a representation of each item in working memory un- 1966). Since scopolamine can disrupt attention and cog- til the grouping is complete. Additionally, processing re- nitive processing, direct effects on encoding and retrieval sources are needed to identlfy and execute the cognitive must be differentiated from indirect effects due to im- operations involved in grouping. After the administration pairment of other cognitive processes. The procedure of of scopolamine, the combined resources needed for stor- enhanced cued recall was used to identify such genuine age and processing in working memory may exceed the memory impairment. If scopolamine disrupted encod- available resources which are normally limited in sup ing or retrieval, then it should not have been possible ply (Kahneman 1973). In this view, the dose-dependent to overcome the free recall deficit which is the hallmark decrement in free recall reflects an increasing depletion of scopolamine amnesia. We found that while there was of working memory resources at higher doses of scopol- a dose-dependent decrement in free recall, total recall, amine. Such a free recall deficit is not considered a gen- obtained by the addition of cued recall to free recall, was uine memory impairment because it is due to disruption the same with and without scopolamine. Furthermore, of processing resources rather than to direct impairment five clinically delirious subjects maintained nearly perfect of memory mechanisms such as encoding or retrieval. levels of total recall despite decreased free recall. Before discussing other interpretations, we want to Enhanced cued recall shows that when processing is point out three limitations of this study. First, only 12 properly controlled, encoding and storage mechanisms subjects were given scopolamine in the present study. necessary for learning may still operate effectively. Pre- Though each of them displayed intact total recall, the sumably, encoding succeeds because the search phase findings should be confumed in a larger sample. Sec- minimizes the deficits in attention and cognitive process- ond, it could be argued that scopolamine might disrupt ing induced by scopolamine so that adequate mental rep- memory mechanisms if given in higher doses. At higher resentations are formed and stored. Effective cued recall doses, however, the results might be difficult to interpret also shows that retrieval is unimpaired when encoding if subjects became so delirious that they could not be and retrieval are coordinated. tested.

Grober et al. 331

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 Third, the claim that scopolamine does not produce present study cannot reasonably be attributed to implicit genuine memory impairment is limited by ceiling effects memory. in total recall. Because total recall was nearly perfect A final possibility is that despite the preservation of in the first study, a true difference in total recall due to total recall, scopolamine may limit the amount of infor- drug intoxication might have been missed. Therefore, mation encoded in memory traces. Less information may we increased the number of items to be learned to 32 have been stored in each trace than at baseline, perhaps but ceiling effects persisted. In our other studies of ef- because scopolamine reduces available processing ca- fective cued recall, ceiling effects persist even when the pacity so that fewer semantic features can be processed. number is increased to 64. In fact, it may not be possi- Retrieval of a less elaborated memory trace may not be

ble to eliminate ceiling effects in cued recall when each possible by free recall, although cued recall would re- Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 item is associated with a unique cue. Mantyla (1986) main unimpaired. Further study is needed to determine showed that subjects were able to recall almost 500 to if scopolamine limits the amount of information encoded 600 words using their own cues generated during study. in memory traces. Ceiling effects in cued recall may be unavoidable as long The failure of scopolamine to produce genuine mem- as the study phase ensures adequate cognitive process- ory deficits provides another challenge to the choliner- ing of each item with its cue. Although the present re- gic hypothesis of Alzheimer’s Disease. According to this sults do not rule out the possibility that under different hypothesis, the loss of cholinergic cells is the primary conditions, scopolamine might produce genuine mem- neurochemical deficit of the disease and is responsible ory impairment, intact cued recall challenges the notion for the memory impairment that is its most ubiquitous that scopolamine directly disrupts encoding or retrieval symptom (Bartus, Dean, Beer, & Lipp 1982; Coyle, Price, mechanisms. & DeLong 1983). The cholinergic hypothesis of AD has Another possible interpretation of robust cued recall is been challenged by other studies in which scopolamine that it is due to implicit memory, a phenomenon known intoxication provided an inadequate model for specific to occur in patients ‘with amnesia (Graf & Schacter 1985; disruptions of attention, memory, language, and praxis Schacter & Graf 1986; Schacter 1987; Nissen & Bullemer displayed by patients with AD (Beatty et al. 1986; Mohs, 1987) rather than to explicit memory. A growing num- Johns, Dunn, Sherman, Rosen, & Davis 1986; Broks et al. ber of studies have shown that amnestic patients, unable 1988; Kopelman & Corn 1988; Wesnes & Simpson 1988). to ‘consciouslyrecollect recent events, nonetheless show The finding of intact cued recall with scopolamine is in- evidence of learning when it can be expressed without consistent with the impairment of cued recall shown by awareness or deliberate recollection. Improved perfor- demented patients. In fact, the identification of such gen- mance attributable to information acquired during pre- uine memory impairment is a highly sensitive and specific vious study is referred to as priming and is presumed way to screen elderly persons for dementia (Grober et al. to reflect implicit memory. Intact priming in amnestic 1988a). patients appears to occur when the priming stimulus is There are several possible reasons why scopolamine part of a pre-existing unit in semantic memory (Schacter does not produce the genuine memory deficits seen in 1987). Since the category-item pairs used in enhanced patients with AD. Although there is very good evidence cued recall constitute pre-existing units, it is possible for cholinergic dysfunction in these patients (Davies & that robust total recall reflects implicit rather than explicit Maloney 1976; Coyle et al. 19831, a number of other neu- memory. rochemical abnormalities have been reported. The most However, the results of an unpublished study (Grober, consistent of these involve serotonin, somatostatin, and Buschke, & Bang 1988b) indicate that enhanced cued corticotrophin releasing factor (Davies, Katzman, & Terry recall produces high levels of explicit learning in the el- 1980; Bissette, Reynolds, Kilts, Widerlov, & Nemeroff derly. Enhanced cued recall was administered to 36 non- 1985; DeSouza, Whitehouse, Kuhar, Price, & Vale 1986). demented and 18 demented elderly subjects followed 90 It is possible that one or more of these other deficits, per- minutes later by a word association test to measure prim- haps interacting with the cholinergic system dysfunction, ing and a final trial of cued recall to measure deliberate re- is necessary for genuine memory impairment (Kopelman call. Category cues from the memory test were included 1986). Another reason for the failure of scopolamine to among the stimulus terms in the word association task. mimic the memory dysfunction of AD concerns its speci- By comparing the number of memory words retrieved by ficity for muscarinic acetylcholine receptors. Presumably, association without awareness to the number retrieved the cholinergic deficiency in AD produces denervation by deliberate recollection, it was possible to estimate the of both muscarinic and nicotinic receptors, while scopol- amount of learning due to priming of pre-existing units amine antagonizes the effects of acetylcholine at only and the amount due to explicit learning. Many more the muscarinic receptor Whitehouse, Struble, Hedreen, memory words were retrieved by deliberate recollection Clark, & Price 1984). Further, nicotinic rec@tor density (explicit memory) than by priming without awareness is decreased approximately 50% in the temporal cortex of (implicit memory) by both demented and nondemented AD patients (Davies 1985). Finally, the structural pathol- elderly. Therefore, the robust total recall observed in the ogy and cell loss in the hippocampus and neocortex may

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 contribute to the development of genuine memory im- the test phase. The use of such immediate cued recall is pairment in AD (Hyman, Van Hoesen, Wolozin, Davies, essential to obtain maximum recall from some demented Kromer, & Damasio 1988); isolated cholinergic deficiency patients (Grober & Buschke 1987). may be irrelevant for producing this effect. The search phase was followed by 3 trials of recall, In conclusion, the procedure of enhanced cued recall each preceded by 20 sec of interference in order to obtain circumvents free recall deficits induced by scopolamine recall from secondary memory. Each recall trial consisted just as it circumvents free recall deficits in the aged. Be- of two parts. First, up to two minutes was provided for cause it demonstrates memory function which might oth- free recall. When free recall was exhausted, cued recall erwise be obscured by impairment of other cognitive op- was tested by presenting the category cue for each item

erations, it has been useful in identlfying genuine mem- that was not retrieved by free recall. If the item was not Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 ory deficits in demented and amnestic individuals and retrieved within 10 sec, the subject was reminded of that should prove to be useful in the search for pharmaco- item. Total recall obtained by the addition of cued recall logic agents that can induce or treat genuine memory to free recall is critical because it shows the amount of impairment. information that was encoded and retrieved.

Methods Drug Treatment and Procedure Each subject received either 0.7 or 0.8 mg of intravenous study1 scopolamine hydrobromide (Elkin-Sinn, Cherry Hill, NJ). subjects Enhanced cued recall testing began one hour after drug Four subjects, 3 men and 1 woman, ranging in age from administration. In addition to enhanced cued recall, 22-35 gave informed consent as specified by the Com- serial measures of scopolamine serum levels, evoked mittee on Clinical Investigation of the Albert Einstein Col- potentials, supraspan digits, and behavioral self-ratings lege of Medicine (AECOM). Subjects were paid for their were obtained. This paper is limited to the data obtained participation. During a baseline evaluation, all subjects from enhanced cued recall. passed a medical screen comprised of a medical history, physical examination, SMA 18, CBC, and EKG. In addi- study2 tion, all subjects performed within normal limits on the subjects Benton Visual Retention Test (Benton, Hamsher, Vamey, Subjects were 12 male medical students who gave in- & Spreen 1983) and the Associate Learning and Logical formed consent as specified by the Committee on Clinical Memory Subtests of the Weschler Memory Scale Wech- Investigations at AECOM and were paid for their partici- sler 1945). Depression was excluded by scores below 10 pation. Subjects were randomly assigned to one of three on the Carroll.Rating Scale for Depression (Carroll, Fein- treatment conditions in a double-blind design. There berg, Smouse, Rawson, & Greden 1981). Performance were four subjects in each condition: 1.0 mg scopol- on enhanced cued recall, which was administered during amine, 0.5 mg scopolamine, and 0.3 mg of the active this baseline evaluation, was compared to performance placebo. All subjects passed the medical screen and per- during drug administration. Following drug administra- formed within normal limits at baseline on the neuropsy- tion, two subjects displayed features of delirium.' chological tests described in Study 1. Following drug administration, three subjects developed a subjective feel- EnhnncedCuedRecall ing of chilliness, shivering, and acrocyanosis; one other The 16 items to be learned were presented 4 at a time, subject developed hallucinations. All 3 of the subjects 1 word in each quadrant of an 8 1/2 x 11-inch card. A who became ill were subsequently determined to have card was placed in front of the subject who was asked received 1.0 mg of scopolamine. During their transient to search the card, point to, and name each item (e.g., illness, they displayed features of delirium.2 gupes) when its category cue (e.g., fruit) was given ver- bally. After the search was completed and all four items EnhancedCuedRecall were correctly identified, the card was removed and im- The procedure was identical to Study 1 except that 32 mediate verbal cued recall of just those four items was items were used instead of 16. tested by reading each cue to the subject. If the subject failed to recall an item in response to its cue, the search Drug Treatment and Procedure was performed again, and the subject was given another Each subject received either 0.3 mg glycopyrrolate (Ru- opportunity at immediate cued recall. Once immediate binol, Elkin-Sinn), an active placebo, low-dose scopol- cued recall for a set of 4 items was correct, the procedure amine hydrobromide (0.5 ma, or high-dose scopolamine was repeated for the next set of 4 items, until all 16 items hydrobromide (1 .O mgl intramuscularly in a double-blind were identified and retrieved in immediate cued recall. randomized study design. Glycopyrrolate' is a periph- Successful completion of the search procedure requires erally acting anticholinergic drug which does not enter semantic processing; immediate cued recall confirms cor- the central nervous system. Drug was prepared each rect initial encoding and provides retrieval practice before day by whichever study physician (RBL or RML.) was

Grober et al. 333

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1989.1.4.327 by guest on 25 September 2021 not involved in monitoring the subject during the exper- Buschke, H. (1976). Learning is organized by chunking. Journal iment. Subjects were told that they would receive either of Verbal Learning and Verbal Behavior, 15, 313-324. an active placebo, a low dose of scopolamine, or a high Buschke, H. (1984). Cued recall in amnesia. Journal of Clinical dose. All investigators present during the experiment Neuropsychology, 4, 433440. were blind to the drug and dosage. Buschke, H. (1987). Criteria for the identification of memory Notes deficits: Implications for the design of memory tests. In D. Gor- 1. Five pilot subjects were not included because they either fein, & R. Hoffman, (Eds.), Learning and Memory: The Ebbing- did not have free recall or did not have immediate cued recall huus Centennial Conference, 331-344. Hillsdale, NJ: Lawrence after the search. All subjects displayed intact cued recall except Erlbaum. one who is described below. The results of these subjects plus Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/1/4/327/1755608/jocn.1989.1.4.327.pdf by guest on 18 May 2021 the four from Study 1 have been reported in a previous abstract Buschke, H., & Grober, E. (1986). Genuine memory deficits in (Leipzig, Grober, Lipton, Schroeder, Davies, & Buschke, 1987). age-associated memory impairment. Developmental Neuropsy- 2. A 37-year-old man, tested under different conditions in a ~holOgY,2, 287-307. pilot study, recalled only 20 of 32 items after receiving 0.8 mg of scopolamine intravenously. One difference was the nature Caine, E.D., Weingartner, H., Ludlow, C.L., Cudahy, E.A., & of the search task; he was required to point to a printed word Wehry, S. (1981). Qualitative analysis of scopolamine-induced after hearing it spoken for half of the items. This task induces amnesia. Psychophurmacologiu, 74,7440. shallow lexical processing usually associated with reduced recall relative to tasks which require deeper semantic processing. Carroll, B.J., Feinberg, M., Smouse, P.E., Rawson, S.G., & Gre- It is not clear whether the impairment in total recall in this pilot den, J.F. (1981). The Carroll Rating Scale for depression. I. De- subject reflects this procedural difference or individual differ- velopment, reliability and validation. British Journal of Psychi- ences in scopolamine effects. atry, 138, 194200.

Acknowledgments Coyle, J.T., Price, D.L., & DeLong, M.R. (1983). Alzheimer’s The authors would !ike to thank Dr. Herbert G. Vaughan for Disease: A disorder of cortical cholinergic innervation. Science, his support of this project and for his comments on a previous 219, 11841190. version of this manuscript. This research was supported by PHS Grants AG03949, Craik, F.I.M., & Lockhart, R.S. (1972). Levels of processing: A NS19234, AG04623, HD01799 and a Brookdale Foundation framework for memory research. Journal of Vmbul Learning and Geriatric Fellowship to RML. Verbul Behuvior, 11, 671-684. The work was conducted in the Rose F. Kennedy Center of the Albert Einstein College of Medicine. Crow, T.J. , & Grove-White, I.G. (1973). An analysis of the learn- Reprint requests should be sent to Dr. Ellen Grober, Depart- ing deficit following hyoscine administration to man. British ment of Neurology, Albert Einstein College of Medicine, Van Journal of Pharmacology, 49, 322-327. Etten Hospital, Room 319, 1300 Morris Park Avenue, Bronx, NY 10461. Davies, P. (1985). A critical review of the role of the cholinergic system in human cognition. Annuls of the New York Academy of Sciences, 444,212-217.

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