Physiology & Behavior 128 (2014) 270–276
Contents lists available at ScienceDirect
Physiology & Behavior journal homepage: www.elsevier.com/locate/phb
Brief, pre-learning stress reduces false memory production and enhances true memory selectively in females Phillip R. Zoladz a,⁎, David M. Peters a, Andrea E. Kalchik a, Mackenzie M. Hoffman a, Rachael L. Aufdenkampe a, Sarah A. Woelke a, Nicholas E. Wolters b, Jeffery N. Talbot b,c a b c
Department of Psychology, Sociology, & Criminal Justice, Ohio Northern University, Ada, OH 45810, USA Department of Pharmaceutical & Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA College of Pharmacy and Program for Novel Therapeutics in Neurological and Psychiatric Disorders, Roseman University of Health Sciences, Henderson, NV, USA
H I G H L I G H T S • Brief, pre-learning stress reduces false memory recall in males and females. • Stress enhances true memory in females, but not males. • Temporal effects of stress on false memory depend on sex.
a r t i c l e
i n f o
Article history: Received 27 August 2013 Received in revised form 16 December 2013 Accepted 4 February 2014 Available online 21 February 2014 Keywords: Amygdala Cortisol False memory Hippocampus Stress
a b s t r a c t Some of the previous research on stress–memory interactions has suggested that stress increases the production of false memories. However, as accumulating work has shown that the effects of stress on learning and memory depend critically on the timing of the stressor, we hypothesized that brief stress administered immediately before learning would reduce, rather than increase, false memory production. In the present study, participants submerged their dominant hand in a bath of ice cold water (stress) or sat quietly (no stress) for 3 min. Then, participants completed a short-term memory task, the Deese–Roediger–McDermott paradigm, in which they were presented with 10 different lists of semantically related words (e.g., candy, sour, sugar) and, after each list, were tested for their memory of presented words (e.g., candy), non-presented unrelated “distractor” words (e.g., hat), and non-presented semantically related “critical lure” words (e.g., sweet). Stress, overall, significantly reduced the number of critical lures recalled (i.e., false memory) by participants. In addition, stress enhanced memory for the presented words (i.e., true memory) in female, but not male, participants. These findings reveal that stress does not unequivocally enhance false memory production and that the timing of the stressor is an important variable that could mediate such effects. Such results could have important implications for understanding the dependability of eyewitness accounts of events that are observed following stress. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Stress exerts complex effects on cognition. On one hand, stress can produce powerful memories that last a lifetime, while on the other hand, stress can be distracting and debilitating and cause us to forget important details in our everyday lives. Much of the initial research in the area of stress and cognition reported deleterious effects of stress on learning and memory [1,2]; however, over the past decade, a significant amount of laboratory research has shown that stress can enhance, ⁎ Corresponding author at: Ohio Northern University, Department of Psychology Sociology, & Criminal Justice, 525 S. Main St. Hill 013, Ada, OH 45810, USA. Tel.: +1 419 772 2142; fax: +1 419 772 2746. E-mail address: [email protected] (P.R. Zoladz).
http://dx.doi.org/10.1016/j.physbeh.2014.02.028 0031-9384/© 2014 Elsevier Inc. All rights reserved.
impair or have no effect on such processes, depending on several factors [3,4]. For instance, the stage of learning and memory that is influenced by stress plays a large role in dictating the types of effects that are observed. Post-learning stress often facilitates long-term memory, while pre-learning and pre-retrieval stress effects are more variable and can involve enhancements or impairments of memory [5,6]. Regardless of the direction of effect observed, the influence of stress on learning and memory is largely due to stress-induced amygdala modulation of cognitive brain structures, such as the hippocampus and prefrontal cortex (PFC) [6,7]. Specifically, stress-induced increases in glucocorticoids and norepinephrine fuel the amygdala to either facilitate or impair processing in these brain areas. Learning and memory are dynamic, constructive processes. Therefore, when we acquire or remember information, it is by no means
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
similar to a tape recorder or the playback thereof. This topic has been particularly salient with regard to the accuracy of eyewitness accounts, and with relation to stress, investigators have been interested in how high states of arousal, such as those that occur when witnessing a crime, influence an observer's memory for the event [8]. Laboratory investigations of the effects of stress on eyewitness accounts have frequently revealed that stress can reduce memory accuracy and impair one's ability to identify the correct suspect for a crime [9]. In addition, more basic research examining the effects of stress on false memory (e.g., memory for words not presented in a word list) production has sometimes indicated that stress increases false recollections. In these studies, investigators have often used what is known as the Deese–Roediger–McDermott (DRM) paradigm to assess false memory [10,11]. This paradigm involves exposing participants to lists of semantically-related words (e.g., bed, rest, awake, tired) that are all associated with a non-presented “critical lure” word (e.g., sleep). Following word list exposure, participants often falsely recall or recognize the non-presented critical lure as being a part of the word list that was originally observed, effects that are presumed to occur as a result of failed source monitoring. Although the DRM paradigm does not involve an event that is witnessed and then recalled by participants, it still allows investigators to gain insight into the mechanisms underlying false memory production and the factors that could influence it. Such examinations could shed light on why eyewitnesses of a crime falsely remember details that were never actually observed. Indeed, some research has reported a positive relationship between false memory in the DRM paradigm and errors of commission on misleading questions and distortions in autobiographical memory [12,13]. Studies examining stress effects on DRM paradigm performance, however, have reported mixed results. For instance, Payne and colleagues were the first to report that stress increased participants' false recognition of the critical lures in the DRM paradigm [14]. However, three subsequent studies found that stress had no effect on false recall or recognition in the DRM paradigm [15–17], and one study reported a reduction of false memories when cortisol was administered prior to retrieval (note, however, that this study also reported a deleterious effect of cortisol on true memory) [18]. Thus, it is unclear as to what factors might mediate the differential effects of stress on false memory in a laboratory setting. Recent work on stress and memory has fostered an appreciation for the influence that the timing of the stress relative to learning can have on memory formation. For instance, Diamond and colleagues contended that stress rapidly activates the amygdala, which results in enhanced hippocampal neuroplasticity and improved learning and memory; however, as time passes, the stressor causes hippocampal function to enter a refractory period, during which synaptic plasticity and learning are impaired [4]. This “temporal dynamics model” was based largely on research showing that glucocorticoids, as well as electrical stimulation of the amygdala, could exert immediate excitatory, but delayed inhibitory, effects on hippocampal synaptic plasticity [19–23]. Indeed, a general consensus has begun to emerge suggesting that if a brief stressor is administered in close proximity to learning, then long-term memory should be enhanced. This line of reasoning has stemmed from a plethora of studies reporting rapid, excitatory non-genomic effects of glucocorticoids on hippocampal function [24]. Thus, we speculated that if a brief stressor was administered immediately before the DRM paradigm, memory accuracy might be increased. The purpose of the present study was to examine the influence of brief stress that was administered immediately prior to learning on false recall and recognition of critical lures from the DRM paradigm. Participants were exposed to stress or a control manipulation and then learned several word lists from the DRM paradigm, one at a time. Following the presentation of each word list, participants' short-term memory for presented and non-presented (i.e., critical lures) words was tested. Based on the ideas discussed above, we hypothesized that true memory (i.e., memory for the presented words) would be
271
enhanced by stress, while false memory (i.e., memory for the critical lures) would be reduced. 2. Material and methods 2.1. Participants Sixty students (30 males, 30 females; mean age = 19.18 years) from Ohio Northern University participated in the present study. Individuals were excluded from participating if they met any of the following conditions: diagnosis of Raynaud's disease or peripheral vascular disease; presence of skin diseases, such as severe psoriasis, eczema, or scleroderma; history of syncope or vasovagal response to stress; history of severe head injury; current treatment with psychotropic medications, narcotics, beta-blockers, steroids, or any other medication that was deemed to significantly affect central nervous or endocrine system function; mental or substance use disorder; regular nightshift work. Individuals who smoked were allowed to participate in the study; information regarding individuals' smoking habits was collected prior to the experiments via a short demographic survey. There were only 2 participants who reported smoking on a regular basis, and inclusion of the data from these participants in the statistical analyses did not alter the results. Females who took birth control on a regular basis were also allowed to participate in the study; prior to participation, we asked female participants if they took birth control via the short demographic survey. Females who reportedly took birth control were not significantly different from naturally cycling females on any physiological or behavioral measure, nor did stress significantly interact with birth control in these analyses. Therefore, we treated all females as a single group in the statistical analyses for this study. Participants were asked to refrain from using recreational drugs (e.g., marijuana) for three days prior to the experimental sessions; to refrain from drinking alcohol or engaging in strenuous exercise for 24 h prior to the experimental sessions; and to refrain from eating or drinking anything but water for 2 h prior to the experimental sessions. Participants were awarded class credit upon completion of the study. All of the methods for the experiment were approved by the Institutional Review Board at Ohio Northern University. 2.2. Experimental procedures The experimental timeline for the present experiment is presented in Fig. 1. To control for diurnal variations in cortisol levels, all testing was carried out between 1100 and 1800 h. 2.2.1. Cold pressor test (CPT) Participants were randomly assigned to a stress or no stress condition. Participants who were randomly assigned to the stress condition (N = 30, 15 males, 15 females) submerged their dominant hand, up to and including the wrist, in a bath of ice cold (0–2 °C) water for 3 min. The water was maintained at the appropriate temperature by a VWR 1160S circulating water bath. To maximize the stress response, participants were encouraged to keep their hand in the water bath for the entire 3-min period. However, if a participant found the water bath to be too painful, he or she was allowed to remove his or her hand from the water and continue with the experiment. Only 2 participants removed their hand from the water prior to 3 min elapsing (mean water time = 172.20 s). Participants who were randomly assigned to the no stress condition sat quietly for the same amount of time. 2.2.2. Subjective stress rating Following the CPT or control condition, participants were asked to rate the stressfulness of the task on an 11-point scale ranging from 0 to 10, with 0 indicating a complete lack of stress and 10 indicating unbearable stress.
272
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
Stress / No Stress
Short-Term Memory Task (DRM Paradigm)
monitor (Mark of Fitness WS-820 Automatic Wrist Blood Pressure Monitor) placed on the wrist of each participant's non-dominant hand. 2.4. Cortisol analysis
-5
0 S C
5
C
10
15
20
25
C
30
S C
S = saliva sample C = cardiovascular measurement Fig. 1. Experimental timeline and procedures for the present study. Participants were randomly assigned to a stress (cold pressor test; CPT) or no stress (sat quietly) condition. Five minutes following onset of the stress or no stress manipulation, participants were exposed to 10 word lists from the Deese–Roediger–McDermott paradigm (DRM paradigm). Following each word list, participants completed free recall and recognition assessments. Throughout the study, saliva samples (S in the figure) and cardiovascular measurements (C in the figure) were collected to verify the induction of a stress response.
Saliva samples were collected from participants immediately before the stress/no stress manipulation (baseline) and at the end of the session to analyze salivary cortisol concentrations. The samples were collected in a Salivette saliva collection device (Sarstedt, Inc., Newton, NC). Participants were asked to place a synthetic swab in their mouths and chew on it so that it would easily absorb their saliva. Following 1 min of chewing, the synthetic swab was collected and placed in the Salivette conical tube and kept at room temperature until the experimental session was completed. The samples were subsequently stored at −20 °C until assayed for cortisol. Saliva samples were thawed and extracted by low-speed centrifugation. Salivary cortisol levels were determined by enzyme immuno assay (Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's protocol. The minimum detectable concentration of cortisol was approximately 8 pg/ml, and the average inter- and intra-assay percent coefficients of variation were less than 6.9% and 6.8%, respectively. 2.5. Statistical analyses
2.2.3. Word presentation and memory testing Immediately following the CPT or control condition, participants were introduced to word lists with semantically related words (e.g., candy, sour, sugar, chocolate, cake), as per the DRM paradigm [10,11]. The words in each list were also semantically related to a particular “critical lure” word (e.g., sweet). Participants were presented with 10 such word lists (15 words per list) on a projector screen via Microsoft PowerPoint at a rate of one word every 1.5 s. Participants were instructed to do their best to learn the words that they saw because their memory for the words would be tested following list presentation. After the presentation of the each word list, participants were given a memory test during which their recall and recognition were assessed for presented words (e.g., candy), non-presented unrelated “distractor” words (e.g., hat), and non-presented critical lure words (e.g., sweet). Specifically, participants were given 2 min to recall as many of the words that they could. Following the recall assessment, participants completed a brief recognition test for the word list, which contained one “old” (i.e., presented) word and three “new” words (two were distractor words, and one was the critical lure) [see [14] for similar methodology]. Participants underwent the same exact procedure until all 10 word lists had been completed. We employed ten word lists in order to provide enough critical lure data to detect any effects of stress on false memory. As it seemed unreasonable to test participants' memory for all ten word lists after a considerable delay and since we wanted to examine free, rather than cued, recall, we chose to test participants' memory immediately following the presentation of each word list. This also hypothetically allowed us to avoid a floor effect that may be observed with a longer interval between encoding and retrieval.
Initial statistical analyses were performed after combining participants' memory performance across all ten word lists. Percent recall scores were calculated for critical lure words [number of critical lure words recalled divided by 10 (1 word per list times 10 lists) multiplied by 100] to obtain “false recall” performance and for presented words [number of presented words recalled divided by 150 (15 presented words per list times 10 lists) multiplied by 100] to obtain “true recall” performance. A percent recognition score was calculated for critical lures (number of critical lures identified as “old” divided by 10 multiplied by 100) to obtain “false recognition” performance. To assess participants' “true recognition” performance, we calculated a sensitivity index (d′ = z[p(hit)] − z[p(false alarm)]) to be used for statistical analysis. Two-way between-subjects (stress rating, memory performance) or mixed-model (physiological measures) ANOVAs were used to analyze all data. In the analyses, condition (stress, no stress) and sex served as the between-subjects factors, while time served as the within-subjects factor (for analysis of physiological measures only). Since the stressor was temporally closer to some of the studied word lists, we also conducted additional exploratory analyses aimed at examining the effects of stress on memory for the first 5 word lists studied versus its effects on memory for the second 5 word lists studied. This type of analysis allowed us to examine more effectively the importance of the temporal proximity of the stressor relative to learning in any observed effects. Mixed-model ANOVAs were used to analyze the data in this fashion, with condition and sex serving as the between-subjects factors and time (first half, second half) serving as the within-subjects factor. Alpha was set at 0.05 for all analyses, and Bonferroni-corrected post hoc tests were employed when necessary. Outlier data points that were at least 3 standard deviation units beyond the exclusive group means were eliminated from the analyses; less than 1% of all data were outliers. SPSS (version 20.0; SPSS Inc.) was used to perform all statistical analyses.
2.3. Cardiovascular analysis
3. Results
Heart rate (HR) and blood pressure (BP) measurements were taken immediately before the stress/no stress manipulation (baseline), halfway into the manipulation, immediately after the manipulation, and once more at the end of the session (approximately 28 min after baseline). Cardiovascular activity was measured with a vital signs
3.1. Physiological responses Although, in general, participants' HR decreased over time, stress exerted no significant effect on HR activity (significant effect of time: F(3,111) = 6.47, p b 0.001, η2 = 0.15; no significant effect of condition:
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
η2 = 0.08; see Fig. 2). Males also exhibited greater salivary cortisol levels than females (significant effect of sex: F(1,44) = 4.54, p b 0.05, η2 = 0.09). No other significant main effects or interactions were observed.
Table 1 Cardiovascular activity before, during and after the water bath manipulation. DV/condition
Before
Heart rate (bpm) Stress Male Female No stress Male Female
During
Post 1
Post 2
75.67 (2.70) 80.38 (3.93)
70.60 (4.56) 78.17 (5.06)
65.33 (2.61) 71.31 (4.28)
69.85 (3.91) 69.25 (3.10)
64.86 (5.65) 79.43 (2.90)
65.36 (2.98) 73.07 (2.36)
67.57 (3.27) 76.71 (2.67)
63.50 (3.93) 72.18 (2.14)
163.00 (4.96)⁎ 139.33 (3.34)⁎
144.93 (7.00)⁎ 124.15 (4.76)⁎
129.85 (3.86) 117.00 (5.79)
117.14 (8.44) 119.21 (4.08)
124.71 (3.04) 114.50 (1.61)
115.70 (11.35) 116.27 (2.45)
Systolic blood pressure (mm Hg) Stress Male 139.73 (3.59) Female 120.92 (3.35) No stress Male 122.14 (8.41) Female 121.71 (1.73)
3.2. Subjective stress ratings As expected, stressed participants (M = 6.29, SEM = 0.33) reported greater subjective stress ratings than non-stressed participants (M = 0.36, SEM = 0.33) (significant effect of condition: F(1,43) = 160.66, p b 0.001, η2 = 0.79). No other significant main effects or interactions were observed. 3.3. Memory testing
Diastolic blood pressure (mm Hg) Stress Male 86.47 (2.58) 107.93 (4.60)⁎ Female 78.69 (3.06) 94.08 (3.39)⁎ No stress Male 78.76 (2.04) 74.71 (2.28) Female 77.93 (1.36) 73.71 (2.41)
92.07 (5.42)⁎ 80.92 (3.52)⁎
82.77 (3.19) 77.88 (4.72)
73.71 (2.78) 71.57 (1.77)
77.00 (2.26) 75.91 (1.82)
Data are presented as means ± SEM. ⁎ p b 0.05 relative to the no stress group.
F(1,37) = 0.09, p N 0.05, η2 = 0.00; see Table 1). No other significant main effects or interactions were observed. Stressed participants exhibited greater systolic BP than non-stressed participants during and immediately following the CPT (significant effect of time: F(3,111) = 14.63, p b 0.001, η2 = 0.28; significant effect of condition: F(1,37) = 10.62, p b 0.01, η2 = 0.22; significant condition × time interaction: F(3,111) = 16.31, p b 0.001, η2 = 0.31). Also, males exhibited greater systolic BP, overall, than females (significant effect of sex: F(1,37) = 10.97, p b 0.01, η2 = 0.23). No other significant main effects or interactions were observed. Stressed participants also exhibited greater diastolic BP than nonstressed participants during and immediately following the CPT (significant effect of time: F(3,111) = 13.54, p b 0.001, η2 = 0.27; significant effect of condition: F(1,37) = 13.38, p b 0.001, η2 = 0.27; significant condition × time interaction: F(3,111) = 23.52, p b 0.001, η2 = 0.39). No other significant main effects or interactions were observed. Stressed participants exhibited greater salivary cortisol levels than non-stressed participants, particularly following the CPT (significant effect of condition: F(1,44) = 9.55, p b 0.01, η2 = 0.18; time × condition interaction approaching significance: F(1,44) = 3.55, p = 0.066,
The analysis of false recall across all word lists revealed that stressed participants, independent of sex, recalled fewer critical lures than nonstressed participants (significant effect of condition: F(1,53) = 7.12, p b 0.01, η2 = 0.12; see Fig. 3). No other significant main effects or interactions were observed for the analysis across all word lists. When we included time (i.e., first 5 word lists, second 5 word lists) as a repeated measures variable in the analysis of false recall, we found that stressed males recalled fewer critical lures than nonstressed males during the first 5 word lists, while stressed females recalled fewer critical lures than non-stressed females during the second 5 word lists (significant effect of condition: F(1,53) = 7.12, p b 0.01, η2 = 0.12; significant condition × sex × time interaction: F(1,53) = 7.57, p b 0.01, η2 = 0.13; see Fig. 3). No other significant main effects or interactions were observed for the analysis comparing performance on the first 5 versus the second 5 word lists. The analysis of true recall across all word lists revealed that females recalled more presented words than males, and stressed females recalled more presented words than all other groups (significant effect of sex: F(1,54) = 16.62, p b 0.001, η2 = 0.24; significant condition × sex interaction: F(1,54) = 7.99, p b 0.01, η2 = 0.13). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results. The analysis of false recognition performance revealed that stress had no effect on the percent of critical lures falsely recognized (males — stress: 63.33 ± 8.03%; males — no stress: 66.67 ± 4.44%; females — stress: 49.33 ± 7.40%; females — no stress: 52.67 ± 8.08%) (no significant effect of condition: F(1,56) = 0.22, p N 0.05). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results.
Males
Females
5
5
Stress No Stress
3
2
3
2 Stress / No Stress
Stress / No Stress
1
Stress No Stress
4
Cortisol (nmol/l)
4
Cortisol (nmol/l)
273
1 Short-Term Memory Task
Short-Term Memory Task
0
0 -5
0
5
10
15
Time (min)
20
25
30
-5
0
5
10
15
20
25
30
Time (min)
Fig. 2. Salivary cortisol levels from stressed and non-stressed male (left) and female (right) participants. Stressed participants, overall, exhibited greater salivary cortisol levels than nonstressed participants, particularly following CPT exposure (i.e., second time point). Males also exhibited greater salivary cortisol levels than females.
274
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
False Recall - All Lists Stress No Stress
Critical Lure Recall (% of total)
60 50 40
*
30
*
20 10 0
Males
Females
False Recall - First Five Lists
False Recall - Second Five Lists 60
Stress No Stress
50 40 30
**
20 10 0
Critical Lure Recall (% of total)
Critical Lure Recall (% of total)
60
Stress No Stress
50 40 30
**
20 10 0
Males
Females
Males
Females
Fig. 3. False memory recall across all word lists (top) and for the first 5 word lists versus the second 5 word lists (bottom). Stress, independent of sex, led to reduced recall of critical lures across all word lists (top). Interestingly, when analyzing the data from the first 5 word lists versus the second 5 word lists, the results indicated that stressed males recalled fewer critical lures from the first 5 word lists, while stressed females recalled fewer critical lures from the second 5 word lists (bottom). * = significant main effect of stress relative to no stress; p b 0.01; ** = p b 0.01 relative to the no stress group.
The analysis of true recognition performance revealed that stress enhanced the recognition of presented words in females, while having no effect in males (significant condition × sex interaction: F(1,54) = 5.50, p b 0.05; see Fig. 4). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results. 4. Discussion We have shown that brief stress, when administered immediately prior to learning, reduces false memory production in human participants. This effect was observed for free recall, but not for recognition. Importantly, the rates of free recall and recognition produced by the DRM paradigm in our study are comparable to those reported in similar previous studies [e.g., [15,17]]. We also found that stress enhanced true memory recall and recognition in females, while having no significant effect on true memory in males. This suggests that memory accuracy, overall, was more enhanced by stress in females than in males. Collectively, our findings suggest that the timing of a stressor, in addition to the sex of an organism, can significantly influence the types of effects that stress exerts on false memory production, which may provide important insight into the accuracy of eyewitness accounts of events that are observed following stress. To our knowledge, this is the first study to show that acute stress can reduce false memory production. As mentioned above, previous work has typically reported either an increase of false memories following stress or no effects at all. We would contend that our results differ
from those of other investigators for at least two reasons. First, we specifically employed a brief stressor in the present study and stressed participants immediately prior to learning because it was our hypothesis, according to the temporal dynamics model [4], that such stress would put cognitive brain structures, such as the hippocampus, in a primed state during which the acquisition of new information would be enhanced. Theoretically, the PFC might also exhibit enhanced processing, which would potentially facilitate memory accuracy, shortly after stress; however, studies examining the temporal dynamics of stress effects on PFC processing have been limited [24]. Other investigations of stress effects on false memory have frequently employed much longer, strictly psychological stressors (e.g., Trier Social Stress Test; TSST), compared to the CPT, and those stressors have usually been temporally separated from the learning experience [14,15,17]. We would contend that the relatively prolonged (i.e., N 15 min) nature of the stressor in these studies, alone, would potentially push the hippocampus into a refractory phase, during which memory accuracy would be hindered [4,24]. Second, in the present study, we examined within-day memory. Thus, stress exposure could have influenced not just learning, but retrieval processes as well. While this is similar to some of the previous work on stress (or corticosteroids) and false memories [15,17,18], it is not consistent with the study conducted by Smeets and colleagues [16], in which participants were tested for their memory 24 h after learning. Similar to our study, however, Smeets et al. [16] exposed participants to the CPT almost immediately prior to the DRM paradigm; yet, they found no effects of stress on false memory recall. We would contend that the differences between our study and that of Smeets et al.
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
Present Words Recall (% of total)
True Recall - All Lists 70
Stress No Stress
*
60
50
0
Males
Females
Discrimination Index (d')
True Recognition - All Lists 3.0
Stress No Stress
**
2.5
2.0
0.0
Males
Females
Fig. 4. True memory (recall — top; recognition — bottom) in stressed and non-stressed male and female participants. Stress enhanced true memory recall and recognition in males, but not females. However, stress enhanced true recognition in females, but not males. * = p b 0.01 relative to all other groups; ** = p b 0.05 relative to the nonstressed female group.
[16] may be attributable to testing memory at different time points or the fact that Smeets et al. [16] employed cued recall rather than free recall during memory testing. As we indicated above, testing participants' memory for numerous word lists 24 h after encoding would likely result in significant interference among the information and hinder accurate recall. Moreover, Smeets et al. [16] had participants study words that varied in emotional arousal (i.e., emotional vs. neutral), a factor that was not manipulated in the present study (but one that would certainly be important with regard to one's memory for a witnessed crime). In previous work, the effects of stress on false memory have predominantly been assessed by using either cued recall [16] or recognition [14,17]. Only one study of which we are aware has assessed the influence of stress on free recall [15], and these investigators reported that stress had no effect on false memory. The investigators in that study used a timeline of memory testing that is comparable to the one employed here. The major difference is that such investigators employed the TSST, a significantly longer and strictly psychological stressor, relative to the CPT. Our finding that false recall, but not false recognition, was affected by stress is important because it suggests that stress could particularly facilitate the open-ended, narrative component of memory, at least when the stress is administered close in time to the learning situation. This finding is relatively similar to what has been reported in eyewitness research, and although the DRM paradigm does not involve an event that is witnessed and then recalled by participants, it still allows investigators to better understand the factors that can influence false memory generation, which can be applied to understanding the accuracy of eyewitness accounts of events that were
275
observed following stress. Eyewitness research has shown that stress impacts interrogative recall (i.e., question and answer, cued recall) more negatively than narrative/free recall in eyewitnesses [9]. More interestingly, the influence of stress on narrative/free recall in this metaanalysis of eyewitness memory was found to be statistically unreliable. Thus, the findings presented here support this idea and suggest that eyewitnesses should not be questioned in a leading way about what they have observed or be exposed to other witnesses' accounts, which is consistent with the extensive amount of work conducted by Elizabeth Loftus indicating that eyewitness memory is extremely prone to incorporation of misinformation [8]. Our findings are consistent with recent work indicating that when a brief stressor is presented in close proximity to a learning experience, subsequent memory for the information will be enhanced [4,25]. More importantly, this is the first study to extend the temporal dynamics model to an assessment of false memory generation. The idea behind the temporal dynamics model of emotional memory processing is that stress rapidly induces neuroplasticity in the amygdala, which exerts biphasic effects on hippocampal function [4,19,20,26]. Following the onset of stressor, there is an immediate excitatory phase, during which learning and memory are enhanced, followed later by a refractory phase, during which learning and memory are impaired. The immediate excitatory phase is believed to be related to rapid, stress-induced increases in excitatory neurotransmitter activity (e.g., norepinephrine, glutamate), coupled with non-genomic actions of corticosteroids, while the delayed inhibitory phase is believed to be related to the deleterious effects of genomic corticosteroid activity and excessive calcium influx and NMDA receptor desensitization [6,22–24,27]. Although it was not our goal in the present study to manipulate the timing of the stressor and test the temporal dynamics model to the fullest extent, we did run exploratory analyses to examine how stress differentially influenced participants' memory for the first 5 word lists (which were more proximal to the stressor) versus the second 5 word lists (which were more distal from the stressor). Interestingly, we found an interaction between sex and timing for false recall indicating that stress reduced false recall of critical lures from the first 5 word lists in males while reducing false recall of critical lures from the second 5 word lists in females. Though exploratory and preliminary, these findings suggest that the temporal dynamics of the stress response and its influence on learning and memory may differ between the sexes. This speculation relates well to our previous work, in which we found that when a brief stressor was temporally separated from the learning experience, stressed males, but not females, exhibited impaired long-term memory [28]. Therefore, the excitatory and inhibitory phases of hippocampal neuroplasticity that follow stress onset may be delayed in females, relative to males. Of course, much more work will need to be conducted in this area to explore such a possibility. In addition to false memory, we also observed sex differences in the effects of stress on memory for the presented words. Specifically, stress exposure enhanced true memory recall and recognition in females, while it had no effect on such memory in males. This finding is consistent with our previous work, in which we have observed differential effects of pre-learning stress on memory in males and females [28]. It is also consistent with the work of other investigators who have shown that females are more susceptible to the enhancement of memory following stress [29,30], which may be related to their increased risk for post-traumatic stress disorder [29]. It is likely that ovarian hormones are involved in the differential effects of stress on males versus females, as previous work has shown that depending on stage of the menstrual cycle, females are more or less susceptible to the effects of stress [31–34]. In addition, females tend to show greater activation of the left amygdala during stress, while males tend to show greater activation of the right amygdala [35–38]. As the right amygdala appears to be associated with gist memory and the left amygdala appears to be associated with detail memory [39,40], this finding has been associated with males and females under emotional stress exhibiting greater memory
276
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
for the gist and details of a scene, respectively [41]. These findings may relate to the present study in that females may have exhibited better memory accuracy (i.e., enhanced true memory and reduced false memory) because of a greater attention to detail. The results of the present study should be interpreted with the following caveats in mind. First, since the stress, learning and testing all occurred within the same day, we are unable to ascertain what specific stage of learning and memory (i.e., encoding, consolidation, retrieval) was affected by the stress manipulation. Moreover, our findings are most likely more applicable for understanding how stress affects short-term, rather than long-term, memory. Nevertheless, in the present study, it was our goal to examine specifically whether or not a brief stressor administered immediately before learning would enhance memory, in general, rather than dissect the specific stage of learning and memory that was affected. Second, the control condition that was utilized here may be viewed as subpar. However, we employed this control condition because the data presented here were part of a larger data set with other conditions. We have previously shown that the control condition in which participants place their hand in lukewarm water produces no significant change in cardiovascular activity or stress hormone level [25,28], albeit this does not eliminate the possibility that the control condition in the present study inflated the difference between the stress and control groups. Finally, we did not control for the menstrual stage of females; thus, we are unaware of the influence that ovarian hormones may have had in the observed sex differences. 5. Conclusion In conclusion, we have provided the first evidence for a stressinduced reduction of false memories. Specifically, stress administered immediately before learning reduced false memory recall, but not recognition, in male and female participants. In contrast, females, but not males, exhibited enhanced true recall and recognition memory. Our findings once again suggest that the timing of a stressor, in conjunction with the sex of an organism, plays a critical role in the types of effects that stress exerts on learning and memory processes. Role of the funding source The present study was funded by a research advisor grant from Psi Chi to PRZ. The funding source had no role in the study design, data collection or interpretation of the findings. References [1] Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002;3:453–62. [2] Lupien SJ, Lepage M. Stress, memory, and the hippocampus: can't live with it, can't live without it. Behav Brain Res 2001;127:137–58. [3] Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ. Learning under stress: how does it work? Trends Cogn Sci 2006;10:152–8. [4] Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR. The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes–Dodson law. Neural Plast 2007;2007:60803. [5] Schwabe L, Joels M, Roozendaal B, Wolf OT, Oitzl MS. Stress effects on memory: an update and integration. Neurosci Biobehav Rev 2012;36:1740–9. [6] Joels M, Fernandez G, Roozendaal B. Stress and emotional memory: a matter of timing. Trends Cogn Sci 2011;15:280–8. [7] Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci 2009;10:423–33. [8] Schacter DL, Loftus EF. Memory and law: what can cognitive neuroscience contribute? Nat Neurosci 2013;16:119–23. [9] Deffenbacher KA, Bornstein BH, Penrod SD, McGorty EK. A meta-analytic review of the effects of high stress on eyewitness memory. Law Hum Behav 2004;28:687–706.
[10] Roediger HL, McDermott K. Creating false memories: remembering words not presented on lists. J Exp Psychol Learn Mem Cogn 1995;21:803–14. [11] Deese J. On the prediction of occurrence of particular verbal intrusions in immediate recall. J Exp Psychol 1959;58:17–22. [12] Eisen ML, Lorber W, Kistorian R, Morgan D, Yu S, Tirtabudi P, et al. Individual differences in college students susceptibility to misleading information. Boulder, CO: Soc Appl Res Mem Cogn; 1999. [13] Platt RD, Lacey SC, Iobst AD, Finkelman D. Absorption, dissociation, and fantasyproneness as predictors of memory distortion in autobiographical and laboratorygenerated memories. Appl Cogn Psychol 1998;12:77–89. [14] Payne JD, Nadel L, Allen JJ, Thomas KG, Jacobs WJ. The effects of experimentally induced stress on false recognition. Memory 2002;10:1–6. [15] Smeets T, Jelicic M, Merckelbach H. Stress-induced cortisol responses, sex differences, and false recollections in a DRM paradigm. Biol Psychol 2006;72:164–72. [16] Smeets T, Otgaar H, Candel I, Wolf OT. True or false? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval. Psychoneuroendocrinology 2008;33:1378–86. [17] Beato MS, Cadavid S, Pulido RF, Pinho MS. No effect of stress on false recognition. Psicothema 2013;25:25–30. [18] Diekelmann S, Wilhelm I, Wagner U, Born J. Elevated cortisol at retrieval suppresses false memories in parallel with correct memories. J Cogn Neurosci 2010;23:772–81. [19] Akirav I, Richter-Levin G. Mechanisms of amygdala modulation of hippocampal plasticity. J Neurosci 2002;22:9912–21. [20] Akirav I, Richter-Levin G. Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat. J Neurosci 1999;19:10530–5. [21] Frey S, Bergado-Rosado J, Seidenbecher T, Pape HC, Frey JU. Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amygdala: heterosynaptic induction mechanisms of late-LTP. J Neurosci 2001;21: 3697–703. [22] Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A 2005;102:19204–7. [23] Wiegert O, Joels M, Krugers H. Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn Mem 2006;13:110–3. [24] Groeneweg FL, Karst H, de Kloet ER, Joels M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 2011;209:153–67. [25] Zoladz PR, Clark B, Warnecke A, Smith L, Tabar J, Talbot JN. Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience. Physiol Behav 2011;103:467–76. [26] Richter-Levin G, Akirav I. Emotional tagging of memory formation—in the search for neural mechanisms. Brain Res Brain Res Rev 2003;43:247–56. [27] Joels M, Velzing E, Nair S, Verkuyl JM, Karst H. Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression. Eur J Neurosci 2003;18:1315–24. [28] Zoladz PR, Warnecke AJ, Woelke SA, Burke HM, Frigo RM, Pisansky JM, et al. Prelearning stress that is temporally removed from acquisition exerts sex-specific effects on long-term memory. Neurobiol Learn Mem 2013;100:77–87. [29] Felmingham KL, Tran TP, Fong WC, Bryant RA. Sex differences in emotional memory consolidation: the effect of stress-induced salivary alpha-amylase and cortisol. Biol Psychol 2012;89:539–44. [30] Payne JD, Jackson ED, Ryan L, Hoscheidt S, Jacobs JW, Nadel L. The impact of stress on neutral and emotional aspects of episodic memory. Memory 2006;14:1–16. [31] Ertman N, Andreano JM, Cahill L. Progesterone at encoding predicts subsequent emotional memory. Learn Mem 2011;18:759–63. [32] Andreano JM, Cahill L. Menstrual cycle modulation of medial temporal activity evoked by negative emotion. Neuroimage 2010;53:1286–93. [33] Rohleder N, Wolf JM, Kirschbaum C, Wolf OT. Effects of cortisol on emotional but not on neutral memory are correlated with peripheral glucocorticoid sensitivity of inflammatory cytokine production. Int J Psychophysiol 2009;72:74–80. [34] Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med 2001;63:966–72. [35] Cahill L, Uncapher M, Kilpatrick L, Alkire MT, Turner J. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an FMRI investigation. Learn Mem 2004;11:261–6. [36] Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, et al. Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem 2001;75:1–9. [37] Canli T, Desmond JE, Zhao Z, Gabrieli JD. Sex differences in the neural basis of emotional memories. Proc Natl Acad Sci U S A 2002;99:10789–94. [38] Mackiewicz KL, Sarinopoulos I, Cleven KL, Nitschke JB. The effect of anticipation and the specificity of sex differences for amygdala and hippocampus function in emotional memory. Proc Natl Acad Sci U S A 2006;103:14200–5. [39] Fink GR, Marshall JC, Halligan PW, Dolan RJ. Hemispheric asymmetries in global/local processing are modulated by perceptual salience. Neuropsychologia 1999;37:31–40. [40] Fink GR, Halligan PW, Marshall JC, Frith CD, Frackowiak RS, Dolan RJ. Where in the brain does visual attention select the forest and the trees? Nature 1996;382:626–8. [41] Cahill L, van Stegeren A. Sex-related impairment of memory for emotional events with beta-adrenergic blockade. Neurobiol Learn Mem 2003;79:81–8.
Contents lists available at ScienceDirect
Physiology & Behavior journal homepage: www.elsevier.com/locate/phb
Brief, pre-learning stress reduces false memory production and enhances true memory selectively in females Phillip R. Zoladz a,⁎, David M. Peters a, Andrea E. Kalchik a, Mackenzie M. Hoffman a, Rachael L. Aufdenkampe a, Sarah A. Woelke a, Nicholas E. Wolters b, Jeffery N. Talbot b,c a b c
Department of Psychology, Sociology, & Criminal Justice, Ohio Northern University, Ada, OH 45810, USA Department of Pharmaceutical & Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, OH 45810, USA College of Pharmacy and Program for Novel Therapeutics in Neurological and Psychiatric Disorders, Roseman University of Health Sciences, Henderson, NV, USA
H I G H L I G H T S • Brief, pre-learning stress reduces false memory recall in males and females. • Stress enhances true memory in females, but not males. • Temporal effects of stress on false memory depend on sex.
a r t i c l e
i n f o
Article history: Received 27 August 2013 Received in revised form 16 December 2013 Accepted 4 February 2014 Available online 21 February 2014 Keywords: Amygdala Cortisol False memory Hippocampus Stress
a b s t r a c t Some of the previous research on stress–memory interactions has suggested that stress increases the production of false memories. However, as accumulating work has shown that the effects of stress on learning and memory depend critically on the timing of the stressor, we hypothesized that brief stress administered immediately before learning would reduce, rather than increase, false memory production. In the present study, participants submerged their dominant hand in a bath of ice cold water (stress) or sat quietly (no stress) for 3 min. Then, participants completed a short-term memory task, the Deese–Roediger–McDermott paradigm, in which they were presented with 10 different lists of semantically related words (e.g., candy, sour, sugar) and, after each list, were tested for their memory of presented words (e.g., candy), non-presented unrelated “distractor” words (e.g., hat), and non-presented semantically related “critical lure” words (e.g., sweet). Stress, overall, significantly reduced the number of critical lures recalled (i.e., false memory) by participants. In addition, stress enhanced memory for the presented words (i.e., true memory) in female, but not male, participants. These findings reveal that stress does not unequivocally enhance false memory production and that the timing of the stressor is an important variable that could mediate such effects. Such results could have important implications for understanding the dependability of eyewitness accounts of events that are observed following stress. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Stress exerts complex effects on cognition. On one hand, stress can produce powerful memories that last a lifetime, while on the other hand, stress can be distracting and debilitating and cause us to forget important details in our everyday lives. Much of the initial research in the area of stress and cognition reported deleterious effects of stress on learning and memory [1,2]; however, over the past decade, a significant amount of laboratory research has shown that stress can enhance, ⁎ Corresponding author at: Ohio Northern University, Department of Psychology Sociology, & Criminal Justice, 525 S. Main St. Hill 013, Ada, OH 45810, USA. Tel.: +1 419 772 2142; fax: +1 419 772 2746. E-mail address: [email protected] (P.R. Zoladz).
http://dx.doi.org/10.1016/j.physbeh.2014.02.028 0031-9384/© 2014 Elsevier Inc. All rights reserved.
impair or have no effect on such processes, depending on several factors [3,4]. For instance, the stage of learning and memory that is influenced by stress plays a large role in dictating the types of effects that are observed. Post-learning stress often facilitates long-term memory, while pre-learning and pre-retrieval stress effects are more variable and can involve enhancements or impairments of memory [5,6]. Regardless of the direction of effect observed, the influence of stress on learning and memory is largely due to stress-induced amygdala modulation of cognitive brain structures, such as the hippocampus and prefrontal cortex (PFC) [6,7]. Specifically, stress-induced increases in glucocorticoids and norepinephrine fuel the amygdala to either facilitate or impair processing in these brain areas. Learning and memory are dynamic, constructive processes. Therefore, when we acquire or remember information, it is by no means
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
similar to a tape recorder or the playback thereof. This topic has been particularly salient with regard to the accuracy of eyewitness accounts, and with relation to stress, investigators have been interested in how high states of arousal, such as those that occur when witnessing a crime, influence an observer's memory for the event [8]. Laboratory investigations of the effects of stress on eyewitness accounts have frequently revealed that stress can reduce memory accuracy and impair one's ability to identify the correct suspect for a crime [9]. In addition, more basic research examining the effects of stress on false memory (e.g., memory for words not presented in a word list) production has sometimes indicated that stress increases false recollections. In these studies, investigators have often used what is known as the Deese–Roediger–McDermott (DRM) paradigm to assess false memory [10,11]. This paradigm involves exposing participants to lists of semantically-related words (e.g., bed, rest, awake, tired) that are all associated with a non-presented “critical lure” word (e.g., sleep). Following word list exposure, participants often falsely recall or recognize the non-presented critical lure as being a part of the word list that was originally observed, effects that are presumed to occur as a result of failed source monitoring. Although the DRM paradigm does not involve an event that is witnessed and then recalled by participants, it still allows investigators to gain insight into the mechanisms underlying false memory production and the factors that could influence it. Such examinations could shed light on why eyewitnesses of a crime falsely remember details that were never actually observed. Indeed, some research has reported a positive relationship between false memory in the DRM paradigm and errors of commission on misleading questions and distortions in autobiographical memory [12,13]. Studies examining stress effects on DRM paradigm performance, however, have reported mixed results. For instance, Payne and colleagues were the first to report that stress increased participants' false recognition of the critical lures in the DRM paradigm [14]. However, three subsequent studies found that stress had no effect on false recall or recognition in the DRM paradigm [15–17], and one study reported a reduction of false memories when cortisol was administered prior to retrieval (note, however, that this study also reported a deleterious effect of cortisol on true memory) [18]. Thus, it is unclear as to what factors might mediate the differential effects of stress on false memory in a laboratory setting. Recent work on stress and memory has fostered an appreciation for the influence that the timing of the stress relative to learning can have on memory formation. For instance, Diamond and colleagues contended that stress rapidly activates the amygdala, which results in enhanced hippocampal neuroplasticity and improved learning and memory; however, as time passes, the stressor causes hippocampal function to enter a refractory period, during which synaptic plasticity and learning are impaired [4]. This “temporal dynamics model” was based largely on research showing that glucocorticoids, as well as electrical stimulation of the amygdala, could exert immediate excitatory, but delayed inhibitory, effects on hippocampal synaptic plasticity [19–23]. Indeed, a general consensus has begun to emerge suggesting that if a brief stressor is administered in close proximity to learning, then long-term memory should be enhanced. This line of reasoning has stemmed from a plethora of studies reporting rapid, excitatory non-genomic effects of glucocorticoids on hippocampal function [24]. Thus, we speculated that if a brief stressor was administered immediately before the DRM paradigm, memory accuracy might be increased. The purpose of the present study was to examine the influence of brief stress that was administered immediately prior to learning on false recall and recognition of critical lures from the DRM paradigm. Participants were exposed to stress or a control manipulation and then learned several word lists from the DRM paradigm, one at a time. Following the presentation of each word list, participants' short-term memory for presented and non-presented (i.e., critical lures) words was tested. Based on the ideas discussed above, we hypothesized that true memory (i.e., memory for the presented words) would be
271
enhanced by stress, while false memory (i.e., memory for the critical lures) would be reduced. 2. Material and methods 2.1. Participants Sixty students (30 males, 30 females; mean age = 19.18 years) from Ohio Northern University participated in the present study. Individuals were excluded from participating if they met any of the following conditions: diagnosis of Raynaud's disease or peripheral vascular disease; presence of skin diseases, such as severe psoriasis, eczema, or scleroderma; history of syncope or vasovagal response to stress; history of severe head injury; current treatment with psychotropic medications, narcotics, beta-blockers, steroids, or any other medication that was deemed to significantly affect central nervous or endocrine system function; mental or substance use disorder; regular nightshift work. Individuals who smoked were allowed to participate in the study; information regarding individuals' smoking habits was collected prior to the experiments via a short demographic survey. There were only 2 participants who reported smoking on a regular basis, and inclusion of the data from these participants in the statistical analyses did not alter the results. Females who took birth control on a regular basis were also allowed to participate in the study; prior to participation, we asked female participants if they took birth control via the short demographic survey. Females who reportedly took birth control were not significantly different from naturally cycling females on any physiological or behavioral measure, nor did stress significantly interact with birth control in these analyses. Therefore, we treated all females as a single group in the statistical analyses for this study. Participants were asked to refrain from using recreational drugs (e.g., marijuana) for three days prior to the experimental sessions; to refrain from drinking alcohol or engaging in strenuous exercise for 24 h prior to the experimental sessions; and to refrain from eating or drinking anything but water for 2 h prior to the experimental sessions. Participants were awarded class credit upon completion of the study. All of the methods for the experiment were approved by the Institutional Review Board at Ohio Northern University. 2.2. Experimental procedures The experimental timeline for the present experiment is presented in Fig. 1. To control for diurnal variations in cortisol levels, all testing was carried out between 1100 and 1800 h. 2.2.1. Cold pressor test (CPT) Participants were randomly assigned to a stress or no stress condition. Participants who were randomly assigned to the stress condition (N = 30, 15 males, 15 females) submerged their dominant hand, up to and including the wrist, in a bath of ice cold (0–2 °C) water for 3 min. The water was maintained at the appropriate temperature by a VWR 1160S circulating water bath. To maximize the stress response, participants were encouraged to keep their hand in the water bath for the entire 3-min period. However, if a participant found the water bath to be too painful, he or she was allowed to remove his or her hand from the water and continue with the experiment. Only 2 participants removed their hand from the water prior to 3 min elapsing (mean water time = 172.20 s). Participants who were randomly assigned to the no stress condition sat quietly for the same amount of time. 2.2.2. Subjective stress rating Following the CPT or control condition, participants were asked to rate the stressfulness of the task on an 11-point scale ranging from 0 to 10, with 0 indicating a complete lack of stress and 10 indicating unbearable stress.
272
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
Stress / No Stress
Short-Term Memory Task (DRM Paradigm)
monitor (Mark of Fitness WS-820 Automatic Wrist Blood Pressure Monitor) placed on the wrist of each participant's non-dominant hand. 2.4. Cortisol analysis
-5
0 S C
5
C
10
15
20
25
C
30
S C
S = saliva sample C = cardiovascular measurement Fig. 1. Experimental timeline and procedures for the present study. Participants were randomly assigned to a stress (cold pressor test; CPT) or no stress (sat quietly) condition. Five minutes following onset of the stress or no stress manipulation, participants were exposed to 10 word lists from the Deese–Roediger–McDermott paradigm (DRM paradigm). Following each word list, participants completed free recall and recognition assessments. Throughout the study, saliva samples (S in the figure) and cardiovascular measurements (C in the figure) were collected to verify the induction of a stress response.
Saliva samples were collected from participants immediately before the stress/no stress manipulation (baseline) and at the end of the session to analyze salivary cortisol concentrations. The samples were collected in a Salivette saliva collection device (Sarstedt, Inc., Newton, NC). Participants were asked to place a synthetic swab in their mouths and chew on it so that it would easily absorb their saliva. Following 1 min of chewing, the synthetic swab was collected and placed in the Salivette conical tube and kept at room temperature until the experimental session was completed. The samples were subsequently stored at −20 °C until assayed for cortisol. Saliva samples were thawed and extracted by low-speed centrifugation. Salivary cortisol levels were determined by enzyme immuno assay (Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's protocol. The minimum detectable concentration of cortisol was approximately 8 pg/ml, and the average inter- and intra-assay percent coefficients of variation were less than 6.9% and 6.8%, respectively. 2.5. Statistical analyses
2.2.3. Word presentation and memory testing Immediately following the CPT or control condition, participants were introduced to word lists with semantically related words (e.g., candy, sour, sugar, chocolate, cake), as per the DRM paradigm [10,11]. The words in each list were also semantically related to a particular “critical lure” word (e.g., sweet). Participants were presented with 10 such word lists (15 words per list) on a projector screen via Microsoft PowerPoint at a rate of one word every 1.5 s. Participants were instructed to do their best to learn the words that they saw because their memory for the words would be tested following list presentation. After the presentation of the each word list, participants were given a memory test during which their recall and recognition were assessed for presented words (e.g., candy), non-presented unrelated “distractor” words (e.g., hat), and non-presented critical lure words (e.g., sweet). Specifically, participants were given 2 min to recall as many of the words that they could. Following the recall assessment, participants completed a brief recognition test for the word list, which contained one “old” (i.e., presented) word and three “new” words (two were distractor words, and one was the critical lure) [see [14] for similar methodology]. Participants underwent the same exact procedure until all 10 word lists had been completed. We employed ten word lists in order to provide enough critical lure data to detect any effects of stress on false memory. As it seemed unreasonable to test participants' memory for all ten word lists after a considerable delay and since we wanted to examine free, rather than cued, recall, we chose to test participants' memory immediately following the presentation of each word list. This also hypothetically allowed us to avoid a floor effect that may be observed with a longer interval between encoding and retrieval.
Initial statistical analyses were performed after combining participants' memory performance across all ten word lists. Percent recall scores were calculated for critical lure words [number of critical lure words recalled divided by 10 (1 word per list times 10 lists) multiplied by 100] to obtain “false recall” performance and for presented words [number of presented words recalled divided by 150 (15 presented words per list times 10 lists) multiplied by 100] to obtain “true recall” performance. A percent recognition score was calculated for critical lures (number of critical lures identified as “old” divided by 10 multiplied by 100) to obtain “false recognition” performance. To assess participants' “true recognition” performance, we calculated a sensitivity index (d′ = z[p(hit)] − z[p(false alarm)]) to be used for statistical analysis. Two-way between-subjects (stress rating, memory performance) or mixed-model (physiological measures) ANOVAs were used to analyze all data. In the analyses, condition (stress, no stress) and sex served as the between-subjects factors, while time served as the within-subjects factor (for analysis of physiological measures only). Since the stressor was temporally closer to some of the studied word lists, we also conducted additional exploratory analyses aimed at examining the effects of stress on memory for the first 5 word lists studied versus its effects on memory for the second 5 word lists studied. This type of analysis allowed us to examine more effectively the importance of the temporal proximity of the stressor relative to learning in any observed effects. Mixed-model ANOVAs were used to analyze the data in this fashion, with condition and sex serving as the between-subjects factors and time (first half, second half) serving as the within-subjects factor. Alpha was set at 0.05 for all analyses, and Bonferroni-corrected post hoc tests were employed when necessary. Outlier data points that were at least 3 standard deviation units beyond the exclusive group means were eliminated from the analyses; less than 1% of all data were outliers. SPSS (version 20.0; SPSS Inc.) was used to perform all statistical analyses.
2.3. Cardiovascular analysis
3. Results
Heart rate (HR) and blood pressure (BP) measurements were taken immediately before the stress/no stress manipulation (baseline), halfway into the manipulation, immediately after the manipulation, and once more at the end of the session (approximately 28 min after baseline). Cardiovascular activity was measured with a vital signs
3.1. Physiological responses Although, in general, participants' HR decreased over time, stress exerted no significant effect on HR activity (significant effect of time: F(3,111) = 6.47, p b 0.001, η2 = 0.15; no significant effect of condition:
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
η2 = 0.08; see Fig. 2). Males also exhibited greater salivary cortisol levels than females (significant effect of sex: F(1,44) = 4.54, p b 0.05, η2 = 0.09). No other significant main effects or interactions were observed.
Table 1 Cardiovascular activity before, during and after the water bath manipulation. DV/condition
Before
Heart rate (bpm) Stress Male Female No stress Male Female
During
Post 1
Post 2
75.67 (2.70) 80.38 (3.93)
70.60 (4.56) 78.17 (5.06)
65.33 (2.61) 71.31 (4.28)
69.85 (3.91) 69.25 (3.10)
64.86 (5.65) 79.43 (2.90)
65.36 (2.98) 73.07 (2.36)
67.57 (3.27) 76.71 (2.67)
63.50 (3.93) 72.18 (2.14)
163.00 (4.96)⁎ 139.33 (3.34)⁎
144.93 (7.00)⁎ 124.15 (4.76)⁎
129.85 (3.86) 117.00 (5.79)
117.14 (8.44) 119.21 (4.08)
124.71 (3.04) 114.50 (1.61)
115.70 (11.35) 116.27 (2.45)
Systolic blood pressure (mm Hg) Stress Male 139.73 (3.59) Female 120.92 (3.35) No stress Male 122.14 (8.41) Female 121.71 (1.73)
3.2. Subjective stress ratings As expected, stressed participants (M = 6.29, SEM = 0.33) reported greater subjective stress ratings than non-stressed participants (M = 0.36, SEM = 0.33) (significant effect of condition: F(1,43) = 160.66, p b 0.001, η2 = 0.79). No other significant main effects or interactions were observed. 3.3. Memory testing
Diastolic blood pressure (mm Hg) Stress Male 86.47 (2.58) 107.93 (4.60)⁎ Female 78.69 (3.06) 94.08 (3.39)⁎ No stress Male 78.76 (2.04) 74.71 (2.28) Female 77.93 (1.36) 73.71 (2.41)
92.07 (5.42)⁎ 80.92 (3.52)⁎
82.77 (3.19) 77.88 (4.72)
73.71 (2.78) 71.57 (1.77)
77.00 (2.26) 75.91 (1.82)
Data are presented as means ± SEM. ⁎ p b 0.05 relative to the no stress group.
F(1,37) = 0.09, p N 0.05, η2 = 0.00; see Table 1). No other significant main effects or interactions were observed. Stressed participants exhibited greater systolic BP than non-stressed participants during and immediately following the CPT (significant effect of time: F(3,111) = 14.63, p b 0.001, η2 = 0.28; significant effect of condition: F(1,37) = 10.62, p b 0.01, η2 = 0.22; significant condition × time interaction: F(3,111) = 16.31, p b 0.001, η2 = 0.31). Also, males exhibited greater systolic BP, overall, than females (significant effect of sex: F(1,37) = 10.97, p b 0.01, η2 = 0.23). No other significant main effects or interactions were observed. Stressed participants also exhibited greater diastolic BP than nonstressed participants during and immediately following the CPT (significant effect of time: F(3,111) = 13.54, p b 0.001, η2 = 0.27; significant effect of condition: F(1,37) = 13.38, p b 0.001, η2 = 0.27; significant condition × time interaction: F(3,111) = 23.52, p b 0.001, η2 = 0.39). No other significant main effects or interactions were observed. Stressed participants exhibited greater salivary cortisol levels than non-stressed participants, particularly following the CPT (significant effect of condition: F(1,44) = 9.55, p b 0.01, η2 = 0.18; time × condition interaction approaching significance: F(1,44) = 3.55, p = 0.066,
The analysis of false recall across all word lists revealed that stressed participants, independent of sex, recalled fewer critical lures than nonstressed participants (significant effect of condition: F(1,53) = 7.12, p b 0.01, η2 = 0.12; see Fig. 3). No other significant main effects or interactions were observed for the analysis across all word lists. When we included time (i.e., first 5 word lists, second 5 word lists) as a repeated measures variable in the analysis of false recall, we found that stressed males recalled fewer critical lures than nonstressed males during the first 5 word lists, while stressed females recalled fewer critical lures than non-stressed females during the second 5 word lists (significant effect of condition: F(1,53) = 7.12, p b 0.01, η2 = 0.12; significant condition × sex × time interaction: F(1,53) = 7.57, p b 0.01, η2 = 0.13; see Fig. 3). No other significant main effects or interactions were observed for the analysis comparing performance on the first 5 versus the second 5 word lists. The analysis of true recall across all word lists revealed that females recalled more presented words than males, and stressed females recalled more presented words than all other groups (significant effect of sex: F(1,54) = 16.62, p b 0.001, η2 = 0.24; significant condition × sex interaction: F(1,54) = 7.99, p b 0.01, η2 = 0.13). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results. The analysis of false recognition performance revealed that stress had no effect on the percent of critical lures falsely recognized (males — stress: 63.33 ± 8.03%; males — no stress: 66.67 ± 4.44%; females — stress: 49.33 ± 7.40%; females — no stress: 52.67 ± 8.08%) (no significant effect of condition: F(1,56) = 0.22, p N 0.05). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results.
Males
Females
5
5
Stress No Stress
3
2
3
2 Stress / No Stress
Stress / No Stress
1
Stress No Stress
4
Cortisol (nmol/l)
4
Cortisol (nmol/l)
273
1 Short-Term Memory Task
Short-Term Memory Task
0
0 -5
0
5
10
15
Time (min)
20
25
30
-5
0
5
10
15
20
25
30
Time (min)
Fig. 2. Salivary cortisol levels from stressed and non-stressed male (left) and female (right) participants. Stressed participants, overall, exhibited greater salivary cortisol levels than nonstressed participants, particularly following CPT exposure (i.e., second time point). Males also exhibited greater salivary cortisol levels than females.
274
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
False Recall - All Lists Stress No Stress
Critical Lure Recall (% of total)
60 50 40
*
30
*
20 10 0
Males
Females
False Recall - First Five Lists
False Recall - Second Five Lists 60
Stress No Stress
50 40 30
**
20 10 0
Critical Lure Recall (% of total)
Critical Lure Recall (% of total)
60
Stress No Stress
50 40 30
**
20 10 0
Males
Females
Males
Females
Fig. 3. False memory recall across all word lists (top) and for the first 5 word lists versus the second 5 word lists (bottom). Stress, independent of sex, led to reduced recall of critical lures across all word lists (top). Interestingly, when analyzing the data from the first 5 word lists versus the second 5 word lists, the results indicated that stressed males recalled fewer critical lures from the first 5 word lists, while stressed females recalled fewer critical lures from the second 5 word lists (bottom). * = significant main effect of stress relative to no stress; p b 0.01; ** = p b 0.01 relative to the no stress group.
The analysis of true recognition performance revealed that stress enhanced the recognition of presented words in females, while having no effect in males (significant condition × sex interaction: F(1,54) = 5.50, p b 0.05; see Fig. 4). No other significant main effects or interactions were observed for the analysis across all word lists, and the inclusion of time as a variable in this analysis did not alter the results. 4. Discussion We have shown that brief stress, when administered immediately prior to learning, reduces false memory production in human participants. This effect was observed for free recall, but not for recognition. Importantly, the rates of free recall and recognition produced by the DRM paradigm in our study are comparable to those reported in similar previous studies [e.g., [15,17]]. We also found that stress enhanced true memory recall and recognition in females, while having no significant effect on true memory in males. This suggests that memory accuracy, overall, was more enhanced by stress in females than in males. Collectively, our findings suggest that the timing of a stressor, in addition to the sex of an organism, can significantly influence the types of effects that stress exerts on false memory production, which may provide important insight into the accuracy of eyewitness accounts of events that are observed following stress. To our knowledge, this is the first study to show that acute stress can reduce false memory production. As mentioned above, previous work has typically reported either an increase of false memories following stress or no effects at all. We would contend that our results differ
from those of other investigators for at least two reasons. First, we specifically employed a brief stressor in the present study and stressed participants immediately prior to learning because it was our hypothesis, according to the temporal dynamics model [4], that such stress would put cognitive brain structures, such as the hippocampus, in a primed state during which the acquisition of new information would be enhanced. Theoretically, the PFC might also exhibit enhanced processing, which would potentially facilitate memory accuracy, shortly after stress; however, studies examining the temporal dynamics of stress effects on PFC processing have been limited [24]. Other investigations of stress effects on false memory have frequently employed much longer, strictly psychological stressors (e.g., Trier Social Stress Test; TSST), compared to the CPT, and those stressors have usually been temporally separated from the learning experience [14,15,17]. We would contend that the relatively prolonged (i.e., N 15 min) nature of the stressor in these studies, alone, would potentially push the hippocampus into a refractory phase, during which memory accuracy would be hindered [4,24]. Second, in the present study, we examined within-day memory. Thus, stress exposure could have influenced not just learning, but retrieval processes as well. While this is similar to some of the previous work on stress (or corticosteroids) and false memories [15,17,18], it is not consistent with the study conducted by Smeets and colleagues [16], in which participants were tested for their memory 24 h after learning. Similar to our study, however, Smeets et al. [16] exposed participants to the CPT almost immediately prior to the DRM paradigm; yet, they found no effects of stress on false memory recall. We would contend that the differences between our study and that of Smeets et al.
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
Present Words Recall (% of total)
True Recall - All Lists 70
Stress No Stress
*
60
50
0
Males
Females
Discrimination Index (d')
True Recognition - All Lists 3.0
Stress No Stress
**
2.5
2.0
0.0
Males
Females
Fig. 4. True memory (recall — top; recognition — bottom) in stressed and non-stressed male and female participants. Stress enhanced true memory recall and recognition in males, but not females. However, stress enhanced true recognition in females, but not males. * = p b 0.01 relative to all other groups; ** = p b 0.05 relative to the nonstressed female group.
[16] may be attributable to testing memory at different time points or the fact that Smeets et al. [16] employed cued recall rather than free recall during memory testing. As we indicated above, testing participants' memory for numerous word lists 24 h after encoding would likely result in significant interference among the information and hinder accurate recall. Moreover, Smeets et al. [16] had participants study words that varied in emotional arousal (i.e., emotional vs. neutral), a factor that was not manipulated in the present study (but one that would certainly be important with regard to one's memory for a witnessed crime). In previous work, the effects of stress on false memory have predominantly been assessed by using either cued recall [16] or recognition [14,17]. Only one study of which we are aware has assessed the influence of stress on free recall [15], and these investigators reported that stress had no effect on false memory. The investigators in that study used a timeline of memory testing that is comparable to the one employed here. The major difference is that such investigators employed the TSST, a significantly longer and strictly psychological stressor, relative to the CPT. Our finding that false recall, but not false recognition, was affected by stress is important because it suggests that stress could particularly facilitate the open-ended, narrative component of memory, at least when the stress is administered close in time to the learning situation. This finding is relatively similar to what has been reported in eyewitness research, and although the DRM paradigm does not involve an event that is witnessed and then recalled by participants, it still allows investigators to better understand the factors that can influence false memory generation, which can be applied to understanding the accuracy of eyewitness accounts of events that were
275
observed following stress. Eyewitness research has shown that stress impacts interrogative recall (i.e., question and answer, cued recall) more negatively than narrative/free recall in eyewitnesses [9]. More interestingly, the influence of stress on narrative/free recall in this metaanalysis of eyewitness memory was found to be statistically unreliable. Thus, the findings presented here support this idea and suggest that eyewitnesses should not be questioned in a leading way about what they have observed or be exposed to other witnesses' accounts, which is consistent with the extensive amount of work conducted by Elizabeth Loftus indicating that eyewitness memory is extremely prone to incorporation of misinformation [8]. Our findings are consistent with recent work indicating that when a brief stressor is presented in close proximity to a learning experience, subsequent memory for the information will be enhanced [4,25]. More importantly, this is the first study to extend the temporal dynamics model to an assessment of false memory generation. The idea behind the temporal dynamics model of emotional memory processing is that stress rapidly induces neuroplasticity in the amygdala, which exerts biphasic effects on hippocampal function [4,19,20,26]. Following the onset of stressor, there is an immediate excitatory phase, during which learning and memory are enhanced, followed later by a refractory phase, during which learning and memory are impaired. The immediate excitatory phase is believed to be related to rapid, stress-induced increases in excitatory neurotransmitter activity (e.g., norepinephrine, glutamate), coupled with non-genomic actions of corticosteroids, while the delayed inhibitory phase is believed to be related to the deleterious effects of genomic corticosteroid activity and excessive calcium influx and NMDA receptor desensitization [6,22–24,27]. Although it was not our goal in the present study to manipulate the timing of the stressor and test the temporal dynamics model to the fullest extent, we did run exploratory analyses to examine how stress differentially influenced participants' memory for the first 5 word lists (which were more proximal to the stressor) versus the second 5 word lists (which were more distal from the stressor). Interestingly, we found an interaction between sex and timing for false recall indicating that stress reduced false recall of critical lures from the first 5 word lists in males while reducing false recall of critical lures from the second 5 word lists in females. Though exploratory and preliminary, these findings suggest that the temporal dynamics of the stress response and its influence on learning and memory may differ between the sexes. This speculation relates well to our previous work, in which we found that when a brief stressor was temporally separated from the learning experience, stressed males, but not females, exhibited impaired long-term memory [28]. Therefore, the excitatory and inhibitory phases of hippocampal neuroplasticity that follow stress onset may be delayed in females, relative to males. Of course, much more work will need to be conducted in this area to explore such a possibility. In addition to false memory, we also observed sex differences in the effects of stress on memory for the presented words. Specifically, stress exposure enhanced true memory recall and recognition in females, while it had no effect on such memory in males. This finding is consistent with our previous work, in which we have observed differential effects of pre-learning stress on memory in males and females [28]. It is also consistent with the work of other investigators who have shown that females are more susceptible to the enhancement of memory following stress [29,30], which may be related to their increased risk for post-traumatic stress disorder [29]. It is likely that ovarian hormones are involved in the differential effects of stress on males versus females, as previous work has shown that depending on stage of the menstrual cycle, females are more or less susceptible to the effects of stress [31–34]. In addition, females tend to show greater activation of the left amygdala during stress, while males tend to show greater activation of the right amygdala [35–38]. As the right amygdala appears to be associated with gist memory and the left amygdala appears to be associated with detail memory [39,40], this finding has been associated with males and females under emotional stress exhibiting greater memory
276
P.R. Zoladz et al. / Physiology & Behavior 128 (2014) 270–276
for the gist and details of a scene, respectively [41]. These findings may relate to the present study in that females may have exhibited better memory accuracy (i.e., enhanced true memory and reduced false memory) because of a greater attention to detail. The results of the present study should be interpreted with the following caveats in mind. First, since the stress, learning and testing all occurred within the same day, we are unable to ascertain what specific stage of learning and memory (i.e., encoding, consolidation, retrieval) was affected by the stress manipulation. Moreover, our findings are most likely more applicable for understanding how stress affects short-term, rather than long-term, memory. Nevertheless, in the present study, it was our goal to examine specifically whether or not a brief stressor administered immediately before learning would enhance memory, in general, rather than dissect the specific stage of learning and memory that was affected. Second, the control condition that was utilized here may be viewed as subpar. However, we employed this control condition because the data presented here were part of a larger data set with other conditions. We have previously shown that the control condition in which participants place their hand in lukewarm water produces no significant change in cardiovascular activity or stress hormone level [25,28], albeit this does not eliminate the possibility that the control condition in the present study inflated the difference between the stress and control groups. Finally, we did not control for the menstrual stage of females; thus, we are unaware of the influence that ovarian hormones may have had in the observed sex differences. 5. Conclusion In conclusion, we have provided the first evidence for a stressinduced reduction of false memories. Specifically, stress administered immediately before learning reduced false memory recall, but not recognition, in male and female participants. In contrast, females, but not males, exhibited enhanced true recall and recognition memory. Our findings once again suggest that the timing of a stressor, in conjunction with the sex of an organism, plays a critical role in the types of effects that stress exerts on learning and memory processes. Role of the funding source The present study was funded by a research advisor grant from Psi Chi to PRZ. The funding source had no role in the study design, data collection or interpretation of the findings. References [1] Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002;3:453–62. [2] Lupien SJ, Lepage M. Stress, memory, and the hippocampus: can't live with it, can't live without it. Behav Brain Res 2001;127:137–58. [3] Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ. Learning under stress: how does it work? Trends Cogn Sci 2006;10:152–8. [4] Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR. The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes–Dodson law. Neural Plast 2007;2007:60803. [5] Schwabe L, Joels M, Roozendaal B, Wolf OT, Oitzl MS. Stress effects on memory: an update and integration. Neurosci Biobehav Rev 2012;36:1740–9. [6] Joels M, Fernandez G, Roozendaal B. Stress and emotional memory: a matter of timing. Trends Cogn Sci 2011;15:280–8. [7] Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci 2009;10:423–33. [8] Schacter DL, Loftus EF. Memory and law: what can cognitive neuroscience contribute? Nat Neurosci 2013;16:119–23. [9] Deffenbacher KA, Bornstein BH, Penrod SD, McGorty EK. A meta-analytic review of the effects of high stress on eyewitness memory. Law Hum Behav 2004;28:687–706.
[10] Roediger HL, McDermott K. Creating false memories: remembering words not presented on lists. J Exp Psychol Learn Mem Cogn 1995;21:803–14. [11] Deese J. On the prediction of occurrence of particular verbal intrusions in immediate recall. J Exp Psychol 1959;58:17–22. [12] Eisen ML, Lorber W, Kistorian R, Morgan D, Yu S, Tirtabudi P, et al. Individual differences in college students susceptibility to misleading information. Boulder, CO: Soc Appl Res Mem Cogn; 1999. [13] Platt RD, Lacey SC, Iobst AD, Finkelman D. Absorption, dissociation, and fantasyproneness as predictors of memory distortion in autobiographical and laboratorygenerated memories. Appl Cogn Psychol 1998;12:77–89. [14] Payne JD, Nadel L, Allen JJ, Thomas KG, Jacobs WJ. The effects of experimentally induced stress on false recognition. Memory 2002;10:1–6. [15] Smeets T, Jelicic M, Merckelbach H. Stress-induced cortisol responses, sex differences, and false recollections in a DRM paradigm. Biol Psychol 2006;72:164–72. [16] Smeets T, Otgaar H, Candel I, Wolf OT. True or false? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval. Psychoneuroendocrinology 2008;33:1378–86. [17] Beato MS, Cadavid S, Pulido RF, Pinho MS. No effect of stress on false recognition. Psicothema 2013;25:25–30. [18] Diekelmann S, Wilhelm I, Wagner U, Born J. Elevated cortisol at retrieval suppresses false memories in parallel with correct memories. J Cogn Neurosci 2010;23:772–81. [19] Akirav I, Richter-Levin G. Mechanisms of amygdala modulation of hippocampal plasticity. J Neurosci 2002;22:9912–21. [20] Akirav I, Richter-Levin G. Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat. J Neurosci 1999;19:10530–5. [21] Frey S, Bergado-Rosado J, Seidenbecher T, Pape HC, Frey JU. Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amygdala: heterosynaptic induction mechanisms of late-LTP. J Neurosci 2001;21: 3697–703. [22] Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A 2005;102:19204–7. [23] Wiegert O, Joels M, Krugers H. Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn Mem 2006;13:110–3. [24] Groeneweg FL, Karst H, de Kloet ER, Joels M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 2011;209:153–67. [25] Zoladz PR, Clark B, Warnecke A, Smith L, Tabar J, Talbot JN. Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience. Physiol Behav 2011;103:467–76. [26] Richter-Levin G, Akirav I. Emotional tagging of memory formation—in the search for neural mechanisms. Brain Res Brain Res Rev 2003;43:247–56. [27] Joels M, Velzing E, Nair S, Verkuyl JM, Karst H. Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression. Eur J Neurosci 2003;18:1315–24. [28] Zoladz PR, Warnecke AJ, Woelke SA, Burke HM, Frigo RM, Pisansky JM, et al. Prelearning stress that is temporally removed from acquisition exerts sex-specific effects on long-term memory. Neurobiol Learn Mem 2013;100:77–87. [29] Felmingham KL, Tran TP, Fong WC, Bryant RA. Sex differences in emotional memory consolidation: the effect of stress-induced salivary alpha-amylase and cortisol. Biol Psychol 2012;89:539–44. [30] Payne JD, Jackson ED, Ryan L, Hoscheidt S, Jacobs JW, Nadel L. The impact of stress on neutral and emotional aspects of episodic memory. Memory 2006;14:1–16. [31] Ertman N, Andreano JM, Cahill L. Progesterone at encoding predicts subsequent emotional memory. Learn Mem 2011;18:759–63. [32] Andreano JM, Cahill L. Menstrual cycle modulation of medial temporal activity evoked by negative emotion. Neuroimage 2010;53:1286–93. [33] Rohleder N, Wolf JM, Kirschbaum C, Wolf OT. Effects of cortisol on emotional but not on neutral memory are correlated with peripheral glucocorticoid sensitivity of inflammatory cytokine production. Int J Psychophysiol 2009;72:74–80. [34] Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med 2001;63:966–72. [35] Cahill L, Uncapher M, Kilpatrick L, Alkire MT, Turner J. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an FMRI investigation. Learn Mem 2004;11:261–6. [36] Cahill L, Haier RJ, White NS, Fallon J, Kilpatrick L, Lawrence C, et al. Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol Learn Mem 2001;75:1–9. [37] Canli T, Desmond JE, Zhao Z, Gabrieli JD. Sex differences in the neural basis of emotional memories. Proc Natl Acad Sci U S A 2002;99:10789–94. [38] Mackiewicz KL, Sarinopoulos I, Cleven KL, Nitschke JB. The effect of anticipation and the specificity of sex differences for amygdala and hippocampus function in emotional memory. Proc Natl Acad Sci U S A 2006;103:14200–5. [39] Fink GR, Marshall JC, Halligan PW, Dolan RJ. Hemispheric asymmetries in global/local processing are modulated by perceptual salience. Neuropsychologia 1999;37:31–40. [40] Fink GR, Halligan PW, Marshall JC, Frith CD, Frackowiak RS, Dolan RJ. Where in the brain does visual attention select the forest and the trees? Nature 1996;382:626–8. [41] Cahill L, van Stegeren A. Sex-related impairment of memory for emotional events with beta-adrenergic blockade. Neurobiol Learn Mem 2003;79:81–8.
