Drug-Induced Amnesia Hurts Recognition, but Only for Memories That Can Be Unitized

P S Y C H O L O G I C A L S C I E N C E
Research Report
Drug-Induced Amnesia Hurts
Recognition, but Only for
Memories That Can Be Unitized
Lynne M. Reder,1 Joyce M. Oates,1 Edward R. Thornton,1 Joseph J. Quinlan,2 Abigail Kaufer,3 and
Jennifer Sauer3
1Psychology Department, Carnegie Mellon University; 2Department of Anesthesia, University of Pittsburgh; and
3Nurse Anesthesia Program, University of Pittsburgh
ABSTRACT—Midazolam is a drug that creates temporary
thorn, Arndt, & Passannante, 2002; Mintzer, 2003). When
anterograde amnesia. In a within-subjects, double-blind
stimuli that have a high degree of preexperimental familiarity
experiment, participants studied a list of stimuli after re-
are not included among the experimental stimuli, amnesic pa-
ceiving an injection of midazolam in one session and after
tients are able to discriminate recently experienced (studied)
receiving saline in another session. The lists consisted of
words and pictures from foils (words and pictures that were not
three types of stimuli: words, photographs, and abstract
studied in the experiment; Huppert & Piercy, 1976). However,
pictures. Recognition memory was tested at the end of each
these patients cannot determine whether the words and pictures
session. Memory was reliably poorer in the midazolam
were just studied or studied a day earlier. This suggests that the
condition than the saline condition, but this amnesic effect
temporal (contextual) information was not associated with the
was significantly smaller for pictorial stimuli than for
stimuli and that the judgments are based only on familiarity
words and almost nonexistent for abstract pictures. We
(Balota, Burgess, Cortese, & Adams, 2002; Balota & Ferraro,
argue that the less familiar the stimulus, the less likely it is
1996; Reder et al., 2000, 2002). Likewise, Hirshman et al.
to be associated with an experimental context. These data
(2002) found that subjects under the influence of midazolam, a
bolster our claim that unitization increases the chances of
benzodiazepine that causes transient anterograde amnesia,
episodic binding and that drug-induced amnesia prevents
produce more hits and false alarms to high-frequency items than
episodic binding regardless of unitization.
to low-frequency items; this result is consistent with the view
that the drug blocks the formation of an episodic trace.
Recently Musen, Szerlip, and Szerlip (1999) found evidence
There is evidence that recognition can be based on either the
of priming in color naming when words studied earlier with the
retrieval of episodic information or the backup process of fa-
colors were reinstated. Nonwords and random shapes did not
miliarity (Diana, Reder, Arndt, & Park, 2006; Jacoby, 1991;
provide an analogous facilitation. The authors concluded that
Jacoby & Dallas, 1981; Joordens & Hockley, 2000; Mandler,
only words could be associated with the colors. We believe that
1980; Reder, Angstadt, Cary, Erickson, & Ayers, 2002; Reder et
just as people are unable to associate very unfamiliar stimuli
al., 2000; Yonelinas, 1994, 1999). Research with amnesic pa-
with colors, they are unable to bind unfamiliar stimuli to con-
tients (Huppert & Piercy, 1976, 1978; Piercy & Huppert, 1972)
texts (i.e., to form episodic links). This impairment in the
and with normal subjects under the influence of a drug that
process of binding stimuli to contexts has implications for rec-
produces temporary amnesia suggests that the recollective
ollection (see Reder et al., 2002). Therefore, we hypothesize that
process but not the familiarity-based process is specifically
unfamiliar stimuli are also at a disadvantage when it comes to
vulnerable to anterograde amnesia (Hirshman, Fisher, Hen-
recollection.
Although Reder et al. (2000, 2002) suggested that recognition
judgments can be based on retrieval of episodic traces or on
Address correspondence to Lynne M. Reder, Psychology Department,
familiarity, they also claimed that stimuli with greater preex-
Carnegie Mellon University, 5000 Forbes Ave., Pittsburgh, PA 15213,
e-mail: reder@cmu.edu.
perimental familiarity are more vulnerable to spurious ‘‘old’’
562
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L.M. Reder et al.
judgments arising from the familiarity process. The amnesiacs
than the entire face or scene. When a face (e.g., Marilyn Mon-
in Huppert and Piercy’s (1976, 1978) experiments were suc-
roe), scene (e.g., the Eiffel Tower), or abstract picture (e.g.,
cessful in recognition because the stimuli were not high in
painting by Jackson Pollock or Mark Rothko) has been experi-
preexperimental familiarity and therefore not vulnerable to
enced many times, it becomes unitized, and then that entire
spurious recognition. Although the patients could recognize
chunk is bound to an episode in which it is experienced, but we
low-frequency words and pictures on the basis of the familiarity
did not use identifiable faces, scenes, or abstract pictures.
process, they could not discriminate whether those stimuli were
In summary, we predicted that memory for abstract pictures
seen the day before or 10 min before the test.
would be least vulnerable to the effects of the amnestic drug
We propose that the less familiar a stimulus is, the more dif-
because there would be no preexisting chunks to bind to context
ficult it is to encode and, as a consequence, the more difficult it is
and binding resources would be consumed processing the pic-
to bind to an episodic trace or to another stimulus. Conversely,
tures. Memory for photographs of faces and outdoor scenes
the more familiar a stimulus, the easier it is to encode. For ex-
would be intermediately affected because sometimes the entire
ample, lexical decision and word naming are faster for high-
photograph or enough lower-level chunks would be bound to the
frequency than low-frequency words (Balota & Chumbley,
context to facilitate later recognition. We also expected the
1984). We believe that ease of encoding affects ease of binding.
photographs to be most vulnerable to foils because the features
Previous research using midazolam has supported the results
of these photographs were shared by many of the stimuli.
found with amnesic patients: Familiarity judgments are unaf-
Memory for words was expected to be most affected by the drug
fected by amnesia, but ability to form new associations is im-
because, under saline, words are the most easily bound to
paired whether or not the amnesia is drug induced (Hirshman et
context, and they therefore should show the greatest decrement
al., 2002; Huppert & Piercy, 1976, 1978). Therefore, we expect
when the recollection process is impaired.
that to the degree that stimuli are too difficult to bind to an
episodic node and are recognized on the basis of familiarity,
recognition performance will be unaffected by a psychophar-
METHOD
macological intervention that produces temporary amnesia.
The present experiment was designed to investigate whether
Participants
stimuli that are especially unfamiliar would show a reduced
Twenty-five participants with a mean age of 22 received $120
effect from a drug that creates temporary amnesia. To the degree
upon completion of the experiment.
that a subject cannot create a binding to a stimulus under normal
circumstances, the impact of midazolam should be minimized.
Musen et al. (1999) used words, nonwords, and random shapes
Design and Materials
in their priming task. We chose to use abstract drawings, pho-
The study employed a 3 (stimulus type: abstract pictures vs.
tographs of faces and outdoor scenes, and words.
photographs vs. words) Â 2 (drug condition: midazolam vs. sa-
We predicted that memory for words would be hurt most by the
line) within-subjects design, with the saline and midazolam
drug because normally they can be easily bound to context. In
sessions 1 week apart. Assignment of drug condition to session
contrast, unfamiliar abstract pictures are difficult to encode,
was counterbalanced and double-blind.
having no stored memory representation. The attention required
From the MRC psycholinguistics on-line database, we se-
to parse such stimuli consumes the resources that otherwise
lected nouns that are four to nine letters long, have a con-
would bind a stimulus to context. The more familiar a stimulus,
creteness rating between 300 and 700, and have a mean Kucera
the more likely that it will be unitized, or transformed into a
and Francis frequency of 15.1 Examples of the pictorial stimuli
single chunk (Charness, 1976; Chase & Simon, 1973; Simon,
are shown in Figure 1. The color photographs of unfamiliar
1974). Once unitized, a chunk can be bound to an episodic trace.
landscapes and cityscapes were collected from the Internet. The
Therefore, we expected the drug intervention to have less effect
black-and-white photographs of unfamiliar faces came from the
on memory for the abstract pictures, which are not easily per-
Facial Recognition Technology (FERET) Database (2001). The
ceived as a unit.
abstract color pictures included stimuli developed by Koutstaal
We included another category of pictures that we expected to
et al. (2003), created in our lab using Adobe Photoshop, and
be more easily parsed than the abstract pictures, specifically,
found on the Internet. We discarded any abstract stimuli that
photographs of faces and outdoor scenes. Although not unusual
were readily judged as meaningful or given an interpretation.
in appearance, they were not easily labeled in a way that would
enable them to be discriminated from other items on the test list
1We selected words of both low frequency (M 5 1 per million occurrences of
(i.e., generic labels such as ‘‘male face’’ or ‘‘mountain scene’’
words) and high frequency (M 5 29 per million occurrences of words). The word-
would be of little help). We suspect that often features or sets of
frequency effects were not of interest because they served only to replicate the
findings of Hirshman et al. (2002), but we varied word frequency to ensure that
features from a nonfamiliar face or scene are perceived as lower-
the expected pattern would emerge, and it did. To save space, we do not report the
level chunks and that these will be bound to the context, rather
statistics here.
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Midazolam Hurts Unitized Memories
Fig. 1. Examples of the photographs and abstract pictures used in the experiment;
faces were shown in black and white, and the rest of the stimuli in color.
Procedure
receiving little or no sleep the previous night and thus were
Prospective participants were carefully screened and signed an
particularly vulnerable to the sedation. A multifactor analysis of
informed-consent form prior to the medical procedure. At each
variance (ANOVA) was conducted on d0 scores, hit rates, and
session, they received a single intravenous injection of either
false alarm rates. We report prep values, which represent the
0.03 mg/kg (to a maximum of 2.5 mg) of midazolam or a matching
probability of replicating an experimental effect (Killeen, 2005).
volume of saline. The effects of midazolam are almost immedi-
Figure 2 presents the mean d0 scores as a function of stimulus
ate, but dissipate and are typically gone within 60 min.
type and drug condition. For d0, there was a main effect of drug
Prior to the midazolam or saline injection, all participants
condition, F(1, 22) 5 66.2, p
2
rep > .999, Zp
¼ :75, such that
were told that they would view a series of items on a laptop
memory was better under saline than under midazolam. There
computer and rate how pleasant each was, using a 4-point Likert
was also a main effect of stimulus type, F(2, 44) 5 33.3, prep >
scale from very much to not at all. They were also told to expect a
.999, Z 2
p
¼ :60, reflecting the fact that words were recognized
recognition test on the stimuli at the end of the session. Ap-
better than other stimuli.
proximately 2 min after receiving the injection, participants
Of greater interest was how midazolam differentially affected
viewed the three types of stimuli, presented in a random order.
memory for the stimulus classes.2 Memory for both words and
Each item remained on the screen for 1 s, after which the par-
photographs differed by drug condition, F(1, 22) 5 79.8, prep >
ticipant rated its pleasantness by clicking on the scale, using the
.999, Z 2
2
p
¼ :78, and F(1, 22) 5 37.0, prep > .999, Zp ¼ :63,
built-in mouse pad on the computer. Time to rate each stimulus
respectively, but memory for abstract pictures was not affected,
was self-paced, and the study phase lasted for approximately
F < 1. There was an interaction between drug condition and
12 to 15 min.
stimulus type, F(2, 44) 5 22.1, p
2
rep > .999, Zp
¼ :50, such that
Participants were then given the Modified Digit Span task
midazolam did not have an equal effect on all stimulus types,
(MODS; Lovett, Reder, & Lebiere, 1997), which lasted ap-
F(1, 22) 5 28.9, p
2
rep > .999, Zp
¼ :57. In particular, the dif-
proximately 20 min and tested each participant’s working
ference in d0 between the midazolam and saline conditions was
memory. Immediately after the working memory task, partici-
smaller for abstract pictures than for photographs, F(1, 22) 5
pants were given a recognition test on the items judged earlier.
20.8, p
2
rep 5 .99, Zp
¼ :49, and was smaller for photographs
They responded to each item by pressing one of two keys on the
than for words, F(1, 22) 5 48.6, p
2
rep > .999, Zp
¼ :69.
keyboard: ‘‘yes’’ if they had seen the item before and ‘‘No’’ if they
Figure 3 presents mean hit and false alarm rates for each
had not seen it before. Each test item remained on screen until a
stimulus type for the two drug conditions. These data help to
response was made. Each session, regardless of drug condition,
illuminate the cause of the different d0 patterns. First, consider
took approximately 1 hr to complete.
the hit rate data, shown in the top portion of the figure. There
were significantly more hits in the saline than in the midazolam
RESULTS
2The effect of drug on d0 was approximately the same for both levels of word
Two participants’ data were excluded from the analyses because
frequency, F < 1. Faces and scenes produced virtually identical patterns of
they fell asleep during the testing. Both participants reported
performance and were affected in the same way by the drug manipulation, F < 1.
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L.M. Reder et al.
Z 2
p
¼ :71. The effect of the drug was smaller for abstract pic-
tures than for words, F(1, 22) 5 20.7, p
2
rep 5 .99, Zp
¼ :48, and
was smaller for abstract pictures than for photographs, F(1, 22)
5 5.3, p
2
rep 5 .91, Zp
¼ :49.
The false alarm data are displayed in the bottom half of Figure
3. False alarms differed by stimulus type, F(2, 44) 5 11.3, prep >
.99, Z 2
p
¼ :34, reflecting the fact that abstract pictures pro-
duced significantly fewer false alarms than photographs, F(1,
22) 5 8.5, p
2
rep 5 .96, Zp
¼ :28. There was also a reliable in-
teraction of drug condition and stimulus type, F(2, 44) 5 4.8,
p
2
rep 5 .94, Zp
¼ :18. Abstract pictures did not produce more
false alarms under midazolam than under saline, F(1, 22) 5 1.0,
p
2
rep 5 .62, Zp
¼ :04, and in fact produced slightly fewer false
alarms under midazolam than under saline, a pattern opposite
that found in the other conditions. When abstract stimuli were
excluded from analysis, there were more false alarms under
Fig. 2. Mean d0 as a function of stimulus type and drug condition.
midazolam than under saline, F(1, 22) 5 5.2, prep 5 .90,
Z 2
p
¼ :18, and drug condition did not interact with stimulus
type, F(1, 22) 5 1.2, p
2
rep 5 .65, Zp
¼ :05.
condition, F(1, 22) 5 35.9, p
2
rep > .999, Zp
¼ :62. There was
also a reliable interaction of drug condition and stimulus type,
F(2, 44) 5 10.3, p
2
DISCUSSION
rep 5 .99, Zp
¼ :32. Inspection of the figure
shows that the hit rate did not differ among the three stimulus
types under midazolam, F(2, 44) 5 1.3, p
2
This study demonstrates that the effect of midazolam, a drug
rep 5 .65, Zp
¼ :06.
However, in the saline condition, abstract stimuli produced
used commonly in medical procedures to produce temporary
significantly fewer hits than did photographs, F(1, 22) 5 6.4,
amnesia, is differentially expressed across various types of
p
2
stimuli. In particular, the study illustrates the important role of
rep 5 .93, Zp
¼ :22, and these two stimulus types produced
significantly fewer hits than words, F(1, 22) 5 53.9, p
experience in the two processes underlying recognition, recol-
rep > .999,
lection and familiarity (Diana et al., 2006; Reder et al., 2000,
2002). Midazolam hurt performance for words and, to a lesser
degree, for photographs, and effectively did not hurt perfor-
mance at all for abstract pictures. Previous research has sug-
gested that midazolam prevents binding in memory (e.g.,
Ghoneim, 2004; Park, Quinlan, Thornton, & Reder, 2004),
creating temporary amnesia by blocking the formation of new
episodic traces. Our results with these stimulus types provide
more evidence for the notion that recognition can be based on
familiarity or recollection and that it is only the latter process
that is selectively vulnerable to midazolam. Midazolam prevents
the binding of the representation of a stimulus to an experi-
mental context, a key prerequisite for a recollection response.
Our data are consistent with the results of Huppert and Piercy
(1976, 1978), who found that patients with anterograde amnesia
can still recognize pictures as long as judgments do not require
list discrimination (i.e., remembering which list a picture came
from). Our results are also consistent with the priming study of
Musen et al. (1999), which showed that it is easier to create an
association to a word than to an unfamiliar stimulus. Our hy-
pothesis that familiarity affects the probability of encoding as
well as the probability of a false alarm can also explain a finding
of Koutstaal et al. (2003): Older adults, compared with younger
adults, showed poorer recognition for all stimulus classes except
Fig. 3. Proportion of hits (top) and false alarms (bottom) as a function of
stimulus type and drug condition.
abstract pictures. Older adults generally have more trouble
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Midazolam Hurts Unitized Memories
recollecting than do young adults and as a result rely more
Ghoneim, M.M. (2004). Drugs and human memory (Part 2): Clinical,
heavily on familiarity (Buchler & Reder, in press). That ten-
theoretical, and methodologic issues. Anesthesiology, 100, 1277–
dency does not affect recognition of abstract pictures, because
1297.
Hirshman, E., Fisher, J., Henthorn, T., Arndt, J., & Passannante, A.
even young adults have trouble building episodic traces for
(2002). Midazolam amnesia and the dual-process models of the
abstract pictures. Furthermore, age does not increase vulnera-
word-frequency mirror effect. Journal of Memory and Language,
bility to commit false alarms to unfamiliar, abstract pictures,
47, 499–516.
because older adults do not have more experience with these
Huppert, F.A., & Piercy, M. (1976). Recognition memory in amnesic
pictures than do younger adults. For unfamiliar, abstract pic-
patients: Effect of temporal context and familiarity of material.
tures, unlike other stimulus classes used by Koutstaal et al.,
Cortex, 12, 3–20.
Huppert, F.A., & Piercy, M. (1978). Normal and abnormal forgetting
false alarm rates did not differ between the two age groups.
in organic amnesia: Effect of locus of lesion. Cortex, 15, 385–
In summary, midazolam introduces a specific dissociation
390.
among stimulus types such that when participants cannot cap-
Jacoby, L.L. (1991). A process dissociation framework: Separating
italize on unitization—a process that results from the lasting
automatic from intentional uses of memory. Journal of Memory and
effects of experience—performance is relatively unaffected by
Language, 30, 513–541.
the drug. Unitization is a prerequisite for building contextual
Jacoby, L.L., & Dallas, M. (1981). On the relationship between auto-
biographical memory and perceptual learning. Journal of Exper-
associations that enable recollection, and midazolam affects
imental Psychology: General, 110, 306–340.
recollection only when these associations could otherwise
Joordens, S., & Hockley, W.E. (2000). Recollection and familiarity
be built.
through the looking glass: When old does not mirror new. Journal
of Experimental Psychology: Learning, Memory, and Cognition,
26, 1534–1555.
Acknowledgments—This work was supported by Grant 2-R01-
Killeen, P.R. (2005). An alternative to null-hypothesis significance
MH52808 from the National Institute of Mental Health. We
tests. Psychological Science, 16, 345–353.
thank John Anderson, Norbou Buchler, and Heekyeong Park for
Koutstaal, W., Reddy, C., Jackson, E.M., Prince, S., Cendan, D.L., &
comments on the manuscript and John O’Donnell, program
Schacter, D.L. (2003). False recognition of abstract versus com-
mon objects in older and younger adults: Testing the semantic
director of the Nurse Anesthesia Program, University of Pitts-
categorization account. Journal of Experimental Psychology:
burgh School of Nursing, for providing nurses.
Learning, Memory, and Cognition, 29, 499–510.
Lovett, M.C., Reder, L.M., & Lebiere, C. (1997). Modeling individual
differences in a digit working memory task. In Proceedings of the
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