Everyday Memory: Porous in Aging, Distorted in Disease

Home , Memory and aging, Verbal memory, Wechsler Memory Scale

Ulm University Department of Psychiatry and Psychotherapy II Head: Professor Dr. med. Thomas Becker

Everyday memory: Porous in aging, distorted in disease

Dissertation submitted to obtain the doctoral degree of Human Biology of the Medical Faculty of Ulm University

Karolina Sejunaite Vilnius, Lithuania

2019

Acting Dean: Prof. Dr. Thomas Wirth 1st Reviewer: Prof. Dr. Matthias Riepe 2nd Reviewer: Prof. Dr. Georg Grön

Day of the Doctorate: 18.06.2020

„Memory is one of Nature’s most jealously guarded secrets. “ Endel Tulving, Organization of Memory: Quo vadis?, 1985

TABLE OF CONTENTS

LIST OF ABBREVIATIONS IV

1 INTRODUCTION 1

2 METHODS 5

2.1 PARTICIPANTS ...... 5

2.1 MATERIALS ...... 5

2.1 STATISTICS ...... 8

3 PUBLICATION 1 – EVERYDAY MEMORY IN HEALTHY AGING: POROUS BUT NOT DISTORTED 9

3.1 RESULTS ...... 9

3.2 DISCUSSION...... 12

4 PUBLICATION 2 – EVERYDAY FALSE MEMORIES IN OLDER PERSONS WITH DEPRESSIVE

DISORDER 14

4.1 RESULTS ...... 14

4.2 DISCUSSION...... 16

5 PUBLICATION 3 – EVERYDAY MEMORY IN PATIENTS WITH ALZHEIMER’S DISEASE:

FRAGMENTARY AND DISTORTED 18

5.1 RESULTS ...... 18

5.2 DISCUSSION...... 20

6 GENERAL DISCUSSION AND CONCLUSION 22

7 SUMMARY 25

8 REFERENCES 27

9 PUBLICATIONS 38

ACKNOWLEDGEMENTS 84

III

LIST OF ABBREVIATIONS

AD Alzheimer´s disease AUC Area under the curve BKH Bezirkskrankenhaus Günzburg; Hospital for Psychiatry, Psychotherapy, and Psychosomatics CNS Central nervous system CSF Cerebrospinal fluid CVLT California Verbal Learning Test DD Depressive disorder DRM Deese-Roediger-McDermott DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th Edition FA False alarms GDS Geriatric Depression Scale MADRS Montgomery and Asberg Depression-Rating- Scale MMSE Mini Mental Status Examination OA Older adults PET Positron Emission Tomography RWT Regensburger Wortflüssigkeitstest (Verbal Fluency Test) SD Standard deviation SDT Signal detection theory TMT Trail Making Test WMS-IV Wechsler Memory Scale – Fourth Edition WMS-R Wechsler Memory Scale – Revised WST Wortschatztest (Vocabulary Test) YA Young adults

1 INTRODUCTION

Memory problems are by default associated with absence of content that needs to be retrieved, which can be broadly called forgetting. However, cognitive sciences have increasingly brought to light another type of memory fallacy – memory distortions (Schacter, 1999), or false memories. Research into false memories spans from spontaneously reported complex memory distortions, known as confabulations (Johnson & Raye, 1998), to falsely recognized items from a list, often referred to as false alarms (Stanislaw & Todorov, 1999). Whereas confabulations mostly occur in individuals with Korsakoff syndrome (Budson & Price, 2001), false alarms occur to different extents in other disorders (Bhatt, Laws, & McKenna, 2010; Budson, Wolk, Chong, & Waring, 2006; Flanagan et al., 2016) as well as a part of normal memory functioning in healthy individuals (Fraundorf, Hourihan, Peters, & Benjamin, 2019; Graves et al., 2017; Murre, Janssen, Rouw, & Meeter, 2013). Numerous theoretical frameworks try to explain the mechanisms behind the formation of false memories. The fuzzy-trace theory proposes the existence of two memory traces – verbatim trace (i.e. item specific information) and gist trace (i.e. general contextual information). It is suggested that gist traces are more robust and can lead to the formation of false memories (Brainerd, Reyna, & Ceci, 2008; Kim & Cabeza, 2007). The source monitoring framework posits that false memories are brought about by the misattribution of external information to the experienced event (Johnson, Hashtroudi, & Lindsay, 1993; Mitchell & Johnson, 2009). According to this theory, along with a specific memory trace a wider network of contextually similar memory traces is activated and the executive system fails to discriminate between the two (McDonough & Gallo, 2008). Associative Deficit hypothesis (Chalfonte & Johnson, 1996; Naveh-Benjamin, 2000; Old & Naveh-Benjamin, 2008) postulates that impairment in the ability to bind features together into a single memory trace might lead to wrong or novel features being incorporated instead. Inhibitory deficit hypothesis (Hasher & Zacks, 1988; Healey & Kahana, 2016) argues that increases in false memory might be more frequent in individuals with decreased ability to inhibit irrelevant information. This hypothesis incorporates some other theories such as effects of interference (Hamm & Hasher, 1992; May & Hasher, 1998) and priming (Ikier, Yang, & Hasher, 2008). Lastly, increase in false memories can in some cases reflect a normal aging process, which brings about a slowing of most cognitive abilities (Salthouse, 1996a, 1996b). Controlling for speed in explained up to 70% of variance in memory tasks among older adults (Aminoff et al., 2012). Generally, activity of prefrontal cortex and medial temporal lobes is linked to the formation of false memories (Butler, McDaniel, Dornburg, Price, & Roediger, 2004; Chadwick et al., 2016; Hedden & Gabrieli, 2004; Kim & Cabeza, 2007; Meade, Geraci, & Roediger, 2012; Raz et al., 2005). It is argued that in order to compensate for the loss of functionality, older adults demonstrate a greater activation in other cortical areas (Cabeza, Anderson, Locantore, & McIntosh, 2002; Persson et al., 2006). Diseases further undermine a normal functioning in these regions causing even bigger memory deficits (Buckner, 2004; Budson et al., 2002). Further support for the relationship between decreased frontal and medial temporal activity comes from studies that investigated neuropsychological correlates of memory

1 performance. Better performance in tasks with high medial temporal involvement such as free and cued recall tasks was associated with better memory binding and increased rate of hits (Henkel, Johnson, & Leonardis, 1998; McCabe, Roediger, McDaniel, & Balota, 2009). Higher scores in frontal measures such as verbal fluency, working memory, abstract reasoning and problem solving were associated with fewer false alarms (McCabe et al., 2009; Roediger & Geraci, 2007). Despite numerous theoretical frameworks in false memory research, Deese-Roediger- McDermott (DRM) (Roediger & McDermott, 1995) procedure accounts for nearly a half of the paradigms used in false memory research (Pezdek & Lam, 2007). DRM presents participants with a list of words to be memorised (e.g. bed, tired, night, pillow), which are related to a single critical lure (e.g. sleep). In the subsequent recall or recognition task participants falsely claim that the critical lure was present in the list. While classical DRM paradigm and other laboratory tasks (Meade et al., 2012; Mitchell & Johnson, 2009; Paige, Cassidy, Schacter, & Gutchess, 2016; Rosa, Deason, Budson, & Gutchess, 2015) are undoubtedly useful to test theoretical models, it was questioned, if they can fully account for the memory processes that take place on a daily basis (Chaytor & Schmitter-Edgecombe, 2003; Patihis et al., 2013). Everyday life presents one with an abundance of information. Due to information interaction memory distortions are almost inevitable (Kopelman, 1999) and were found in memory for domestic catastrophes (Budson et al., 2004), political news (Frenda, Knowles, Saletan, & Loftus, 2013), and even autobiographical events (Devitt, Monk-Fromont, Schacter, & Addis, 2016; Fernandes, Ross, Wiegand, & Schryer, 2008; McDonough & Gallo, 2008). In order to bridge the gap between laboratory tasks and real-life memory processes, one needs to create paradigms with verisimilitude approach in mind. Standardised instruments resembling everyday cognitive tasks have already been developed for attention (Robertson, Ward, Ridgeway, & Nimmo-Smith, 1996), executive function (Wilson, Alderman, Burgess, Emslie, & Evans, 1996) and memory (Wilson, 2005, 2008). Similar experimental memory tasks were able to demonstrate the importance of emotionally meaningful content (Fung & Carstensen, 2003) and feature binding (Mazurek, Bhoopathy, Read, Gallagher, & Smulders, 2015) in formation of false memories. Challenges, which one’s memory faces on a daily basis to store and retrieve information accurately, get even greater in the presence of cognitive decline and pathological development. Unspecified age-associated cognitive decline affects different aspects of cognitive performance such as visual-constructive abilities, processing speed and memory (Ardila, 2007; Di Carlo et al., 2000; MacDonald, Dixon, Cohen, & Hazlitt, 2004; Royall, Palmer, Chiodo, & Polk, 2005). Age-associated memory decline is not homogenous across its types and processes (Brickman & Stern, 2008). It was demonstrated that episodic memory is subject to the most pronounced deficits (Nilsson, 2003; Salthouse, 2016). Similarly, within memory processes the greatest decline occurs in recall and recognition (Kramer, Yaffe, Lengenfelder, Delis, 2003; Ratcliff, Thapar, & McKoon, 2004; Salthouse, 2016; van Ocker, Light, Olfman, & Rivera, 2017). A recent meta-analysis of recognition studies reported that younger adults generally outperform older adults, who display a liberal answering tendency resulting in an elevated rate of false alarms (Fraundorf et al., 2019). This effect persisted

2 across varying learning material, emotional valence and retrieval interval. Interestingly, older adults performed worse in easier tasks and in tasks requiring source monitoring. Alzheimer’s disease (AD) is one of the most common pathologies affecting memory performance (Ritchie & Lovestone, 2002). Memory loss in AD qualitatively differs from that in aging and impairs episodic memory in particular (Budson & Price, 2005; Tromp, Dufour, Lithfous, Pebayle, & Despres, 2015). Whereas most research on memory in AD focused on forgetting, memory distortions recently came into focus as well. It was demonstrated that AD patients have elevated level of false alarms (MacDuffie, Atkins, Flegal, Clark, & Reuter-Lorenz, 2012; Pillon, Deweer, Agid, & Dubois, 1993) and a liberal response bias (Budson et al., 2006). The tendency to falsely recognize novel items as previously studied, was shown to persist among AD patients even when other factors contributing to false alarms were matched to those of control group (Budson et al., 2006). In contrast to healthy controls AD patients had more false alarms for low-frequency words (Balota, Burgess, Cortese, & Adams, 2002) and after repeated exposure to the material (Balota et al., 1999; Budson, Daffner, Desikan, & Schacter, 2000). This was interpreted as an increased reliance on gist among patients with AD. Among older adults, depression is second psychiatric disorder in its incidence after dementia (Alexopoulos, 2005). Real and perceived cognitive deficits in patients with depressive disorder often resemble an early stage of dementia (Nussbaum, 1994; Zapotoczky, 1998). Studies on memory function among patients with clinical depression focused primarily on omitted memory content (Elderkin-Thompson et al., 2003). Few studies have investigated false alarms among patients with depressive disorder. These studies mostly used laboratory stimuli such as word lists (Howe & Malone, 2011) or photographs (Toffalini, Mirandola, Drabik, Melinder, & Cornoldi, 2014). An increase in false memory content seems to be a part of a broader memory decline. Since most studies used artificially created material, inferences about memory processes in real life settings remain questionable. In order to predict cognitive performance outside of laboratory or clinical setting, ecologically valid paradigms are of great importance. Understanding the exact mechanism behind false memories in daily life also offers a chance to adapt therapy of cognitive function to situations of everyday relevance and to diminish the likelihood of false alarms through psychoeducation. This series of studies developed a memory task using ecologically valid material to investigate false memory content in healthy older adults as well as patients with AD and depressive disorder. Given a broad topic of false memories and often overlapping nomenclature, it is important to point out that this work will further focus solely on recognition memory and use terminology as it is used within a framework of Signal Detection Theory (SDT; Stanislaw & Todorov, 1999). Three separate manuscripts aimed to answer the following questions: 1. What insights can be made into healthy aging memory by using a recognition task with daily relevance? We hypothesized that younger adults will outperform older adults and that age differences will be explained by decline in frontal functioning.

2. What is the mechanism of false alarms for ecologically valid tasks in patients with depressive disorder? We predicted an elevated rate of false alarms, which will be explained by typically impaired executive functioning in these patients. 3. Do patients with very mild AD show an elevated rate of false alarms using an ecologically valid task? What cognitive variables and physiological markers are associated with false alarms? We hypothesized that compared to healthy controls patients with AD have significantly less hits and more false alarms and these are mainly related to the decreased performance in verbal and visual memory as well as to a lesser extent executive function.

2 METHODS

The study was designed as an open-label, non-randomized experiment, which received an approval of the ethics committee of Ulm University (233/15). It was implemented in accordance with the ethical standards of Ulm University and the guidelines of the Declaration of Helsinki. All participants were volunteers and signed an informed consent to participate in the study. Young and older healthy adults were recruited from personal contacts and by advertising the study at educational events for general public. Patients were recruited in the outpatient clinic and geriatric wards of the Department of Psychiatry, Psychotherapy, and Psychosomatics of Ulm University at the Bezirkskrankenhaus Günzburg. The data collection including the pilot study took place between December 2015 and January 2017.

2.1 Participants The study comprised four groups – healthy young adults (YA), healthy old adults (OA), patients with Alzheimer’s Disease (AD) and patients with Depressive disorder (DD). Mental retardation, addictive behaviour, disorders of the central nervous system other than Alzheimer’s disease in the AD group, and the affective disorders other than major depressive disorder in the DD group were ruled out for the total sample by taking medical history. Furthermore, participants with a Mini-Mental State Examination (MMSE) score below 25, or digit span below 5 were excluded from the study. A total of 104 participants were screened to take part in the study. Out of the total sample 11 participants did not fulfil the inclusion criteria, three participants discontinued the study and another two were excluded due to incomplete data. The final sample of the study comprised 88 participants. Full demographic information is presented in Table 1. To accommodate suggestions made during the review process, the number of OA in Publication 3 was reduced to 21. Alzheimer’s disease was diagnosed according to ICD-10 criteria. Information to support the diagnosis came from clinical examination, neuropsychological examination and lumbar puncture or positron emission tomography (PET), in cases where lumbar puncture was contraindicated due to treatment with anticoagulants or refusal of the patient. Depressive disorder (DD) was diagnosed using symptoms suggested by ICD-10 criteria but considering the frequency of comorbid conditions in old age so that no organic exclusions or diagnostic hierarchy rules were applied (Kessler et al., 2010). Prior to diagnosis patients received a comprehensive analysis of psychiatric and neurological findings as well as laboratory parameters.

2.1 Materials All participants were administered two short screening tests: Mini Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975) for cognitive status and Montgomery and Asberg Depression-Rating- Scale (MADRS) (Montgomery & Asberg, 1989) for affective symptoms. To assess the familiarity of the experimental memory tasks all participants were asked whether they watch news and commercials on a daily basis.

Moreover, participants were examined with a comprehensive neuropsychological test battery that comprised the California Verbal Learning Test (CVLT; Niemann, Sturm, Thöne- Otto, & Willmes, 2008), Digit and Visual Span (Wechsler Memory Scale Revised, WMS- R; Härting et al., 2000), Symbol Span (Wechsler Memory Scale – Fourth Edition, WMS-IV; Wechsler, Petermann, & Lepach, 2012), Trail Making Tests A & B (TMT-A & TMT-B; Reitan & Wolfston, 1985), semantic and phonemic verbal fluency tasks (Regensburger Wortflüssigkeitstest; RWT; Aschenbrenner, Tucha, & Lange, 2000), and the Vocabulary Test (Wortschatztest; WST; Schmidt & Metzler, 1992). Comprehensive description of the tests can be found in the original publications.

Table 1. Demographic variables of study participants. Data collected between December 2015 and January 2017 at the Department of Psychiatry and Psychotherapy II of Ulm University, Bezirkskrankenhaus Günzburg. YA OA AD DD

N 21 23 20 24 Gender (male/female) 8/13 11/12 9/11 12/12 Age (years; M ± SD) 26.90 ± 3.55 69.74 ± 6.46 72.20 ± 5.87 69.33 ± 5.75 Highest degree (n): Secondary school 1 16 16 18 High school 13 2 3 4 University 7 5 1 2 Watch news on a daily basis 67% 87% 80% 83% Watch commercials on a daily 33% 26% 20% 17% basis Legend: AD = Alzheimer’s disease; DD = depressive disorder; OA = older adults; YA = young adults.

Experimental paradigm News and commercials were used as a memory task representing the daily memory processes. Participants were told they would be shown a selection of six old news and six old commercials, each lasting for an average of 30 s. Neither of the selected commercial videos were aired recently. Likewise, the topics in the news were not discussed in the past years. Participants were instructed to watch the videos attentively and told that each video will be followed by a memory task. Immediately after each clip they were asked to evaluate twelve statements about the video they had just seen based on their truthfulness and to select one of the three possible answer choices (see section Questionnaires). The answer choices were repeated for each participant after each video. News: Six news videos were shown to the participants with each video lasting between 27 and 39 s. All videos were selected from the same German news agency (ARD) and were originally broadcasted between the 1980s and early 1990s. The news topics pertained to domestic affairs (increase of radio/TV licence fee, political discussions on skateboard ban, river pollution, merging of state-run train services, ferryboat incident in the Baltic sea,

6 shortage of apprenticeship training positions for the youth). All six videos had the same format with a speaker (three female and three male speakers) in the foreground and extra information such as a photo or a map being shown in the background. Commercials: Six commercials were shown to the participants with each video being between 25 and 34 s. All clips were selected from the internet and were originally broadcasted between the 1990s and early 2000s. The content of the commercials pertained to groceries of famous brands that are still on the market today (beer, flour, rice, chocolate, detergent, grocery retailer). Questionnaires: A questionnaire with twelve questions was designed for each video to assess the amount of correctly retrieved facts from the respective video. Six out of twelve questions could be answered from the information presented in the video, whereas the remaining six questions asked about details that were made up by the investigators to assess the number of erroneous memory items. All questions were in a form of a statement and needed to be answered by giving one of three possible answer choices: “Yes” (the statement is true), “No” (the statement is false), and “Unknown” (the information was not addressed or shown in the video). The total number of correct “Yes” and “No” responses was counted to give the total score of hits. Questions for which the correct answer would have been “Unknown” but for which the participant answered with “Yes” or “No” were counted as the total score of false alarms. Scoring matrix with sample statements is presented in Table 2.

Table 2 Scoring matrix for hits and false alarms.

Answer choices Item Statement in Scene in film Yes No Unknown type questionnaire The older The older woman1 Original woman1 offers Correct Incorrect Incorrect offers rice2 to her signal rice2 to her (hit) (miss) (miss) granddaughter3. granddaughter3. Skateboards1 are Skateboards1 are Reversed Incorrect Correct Incorrect popular2 in unpopular2* in signal (miss) (hit) (miss) Germany3. Germany3. The woman1 Correct wears a blue Incorrect Incorrect Noise Not applicable (correct dress2 while (false alarm) (false alarm) rejection) baking3. Legend: 123 = separate features of a recognition statement; * = reversed feature; bold statements mark correct responses.

At the end of the experimental part participants were asked to evaluate subjective feeling of difficulty of the questions on a 5-point Likert scale with “1” being very easy and “5” being very difficult. After being debriefed about the number of answerable and misleading questions, participants were asked to give a subjective estimate of the correctly answered questions (out of max 72) and correctly identified misleading questions (out of max 36) for news and for commercials. 7

2.1 Statistics Statistical analyses were carried out using statistics software SPSS (SPSS 21.0 for Windows, Armonk, NY, 2012). The normality of distribution was tested with Kolmogorov- Smirnov Test for each group separately. Group comparisons were calculated using t-test, correlations using Pearson’s correlation coefficient. In the Publication 1 raw scores were used to calculate discriminability (d’) and bias (C) according to SDT (Stanislaw & Todorov, 1999). To investigate underlying mechanisms of false memories a stepwise regression analysis was performed in Publications 2 and 3. Additionally Publication 2 evaluated the diagnostic value of false memories using ROC analysis.

3 PUBLICATION 1 – EVERYDAY MEMORY IN HEALTHY AGING: POROUS BUT NOT DISTORTED

3.1 Results Compared to YA, OA had significantly lower scores in the MMSE and WST and significantly higher scores in the MADRS. None of the scores of these screening scales were indicative of clinical pathology. OA also performed worse in most neuropsychological measures. No differences were observed in the digit span and in the semantic and phonemic verbal fluency (Table 3). Before calculating the group differences in the experimental recognition paradigm, we compared the frequency of news and commercial watching habits. The results showed that OA watch news significantly more often than YA (χ2 (1) = 8.039, p = 0.005) and subjectively perceived questions to the news material as significantly easier (YA = 3.48 ± 0.81, OA = 2.84 ± 0.90; t (38) = 2.343, p = 0.024). There were no group differences in the commercials watching frequency (χ2 (1) = 0.053, p = 0.819); however, OA perceived the recognition task for commercials as significantly harder (YA = 2.71 ± 0.72, OA = 3.26 ± 0.87; t (38) = - 2.183, p = 0.035). An overview of subjective and objective hits, false alarms and a subjective estimate of task difficulty is presented in Table 4. YA and OA did not differ in the subjective estimate of their performance. Furthermore, the two groups had a comparable number of false alarms, however the number of hits was significantly lower in OA in both news and commercials task. SDT analysis showed a significant difference in discriminability variable d’ between the groups in news (YA = 1.26 ± 0.46, OA = 0.89 ± 0.55; t (39) = 2.339, p = 0.025) and in commercials (YA = 1.49 ± 0.46, OA = 1.08 ± 0.48; t (39) = 2.821, p = 0.007). Both YA and OA displayed a liberal answering strategy with mean C values being below zero for news (YA - 0.19 ± 0.21; OA – 0.20 ± 0.30) and commercials (YA – 0.19 ± 0.26; OA – 0.07 ± 0.21) and did not differ in respect to this variable (news: t (39) = 0.086, p = 0.932; commercials: t (39) = - 1.505, p = 0.140). In line with the pre-existing literature (Fraundorf et al., 2019) OA had significantly fewer hits than YA. However, contrary to our hypothesis, the two age groups did not differ in terms of the number of false alarms. Considering this unexpected finding, we have re- scored hits and false alarms using a different schema.

Table 3. Performance in standard neuropsychological tests between YA and OA.

YA (n = 21) OA (n = 20) M ± SD M ± SD t p Age 26.90 ± 3.55 69.80 ± 5.85 -28.235 <0.001 MADRS 0.71 ± 1.35 2.55 ± 2.72 -2.715 0.011 MMSE 30 ± 0.00 29.65 ± 0.67 2.333 0.031 WST 35.10 ± 2.51 32.80 ± 3.55 2.401 0.021 DS forward 9.62 ± 1.53 8.70 ± 1.69 1.826 0.075 DS backward 8.43 ± 2.01 7.00 ± 2.45 2.044 0.048 VS forward 10.14 ± 2.24 7.00 ± 1.69 5.053 <0.001 VS backward 9.38 ± 1.75 6.40 ± 1.98 5.114 <0.001 Symbol test 27.95 ± 9.43 17.95 ± 8.36 3.586 0.001 TMT A 19.86 ± 5.57 41.55 ± 11.56 -7.594 <0.001 TMT B 47.57 ± 15.33 93.45 ± 30.36 -6.152 <0.001 TMT (B – A) 27.71 ± 13.56 51.90 ± 27.34 -3.616 <0.001 Semantic fluency 23.43 ± 4.90 24.50 ± 5.74 -0.644 0.523 Phonemic fluency ‘P’ 12.43 ± 4.35 11.30 ± 3.39 0.923 0.362 Phonemic fluency ‘S’ 16.05 ± 4.31 14.45 ± 3.76 1.262 0.214 CVLT 1 7.38 ± 1.69 5.10 ± 2.05 3.899 <0.001 CVLT 5 14.95 ± 1.43 12.70 ± 2.20 3.902 <0.001 CVLT 1-5 60.62 ± 8.75 47.35 ± 8.88 4.819 <0.001 CVLT long delay 14.14 ± 1.93 10.80 ± 2.84 4.387 <0.001 CVLT hits 15.90 ± 0.30 15.55 ± 0.76 1.949 0.063 CVLT FA 0.10 ± 0.44 0.70 ± 1.49 -1.745 0.095 Legend: CVLT = California Verbal Learning Test; DS = Digit Span; FA = false alarms; MADRS = Montgomery-Asberg-Depression-Rating-Scale; MMSE = Mini Mental State Examination; OA = older adults; TMT = Trail Making Test; VS = Visual Span; WST = vocabulary test (ger. Wortschatztest); YA = young adults.

Table 4. Performance in recognition task for news and commercial videos between YA and OA.

YA (n = 21) OA (n = 20) M ± SD M ± SD t p News Hits 28.38 ± 2.27 26.40 ± 3.07 2.359 0.023 FA 12.33 ± 4.45 14.55 ± 6.22 -1.317 0.195 Subjective difficulty 3.48 ± 0.81 2.84 ± 0.90 2.343 0.024 Subjective hits 43.71 ± 11.80 43.56 ± 13.47 0.035 0.972 Subjective FA 20.29 ± 8.09 19.17± 6.99 0.419 0.678 Commercials Hits 29.33 ± 2.82 26.10 ± 3.24 3.413 0.002 FA 10.76 ± 4.88 11.85 ± 4.64 -0.731 0.469 Subjective difficulty 2.71 ± 0.72 3.26 ± 0.87 -2.183 0.035 Subjective hits 48.50 ± 10.43 39.61 ± 18.05 1.748 0.091 Subjective FA 21.14 ± 8.38 18.17 ± 8.32 1.001 0.325

Legend: FA = false alarms; OA = older adults; YA = young adults.

To rule out gist influence on the results we have implemented a procedure described by (Koutstaal & Schacter, 1997; Koutstaal, Schacter, Galluccio, & Stofer, 1999), in which in addition to classical signal detection theory (signal items vs noise items) noise items are compared to items strongly related to original signal items. The procedure aims to assess false recognition of lure items that are conceptually, perceptually or semantically related to studied items and draws a distinction between baseline false alarms and memory mistakes as a result of gist. According to the procedure we have first calculated discriminability and bias using only original signal items and noise items. This analysis omitted the reversed signal items. There were no significant differences in the number of hits to original item between YA and OA (news: YA 14.52 ± 1.57, OA 13.40 ± 2.46, t (39) = 1.754, p = 0.087; commercials: YA 15.52 ± 1.78, OA 14.35 ± 2.43, t (39) = 1.770, p = 0.085). There was a significant difference in the discriminability for news (YA 1.56 ± 0.57, OA 1.13 ± 0.56, t (39) = 2.465, p = 0.018), but not for commercials (YA 1.75 ± 0.59, OA 1.41 ± 0.74, t (39) = 1.624, p = 0.112). There were no differences in bias (news: YA -0.35 ± 0.29, OA -0.32 ± 0.42, t (39) = 2.465, p = 0.018; commercials: YA -0.31 ± 0.30, OA -0.24 ± 0.28, t (39) = -0.834, p = 0.409). Next, we have calculated discriminability and bias using only reversed signal items and noise items. This analysis omits the original signal items. Yes answers to reversed items were treated here as hits for gist signal. There were no differences in the gist signal between the two groups (news: YA 3.52 ± 1.54, OA 4.35 ± 1.81, t (39) = -1.576, p = 0.123; commercials: 11

YA 2.48 ± 1.44, OA 3.35 ± 1.95, t (39) = -1.637, p = 0.110). There were also no differences between YA and OA in discriminability (news: YA -0.49 ± 0.38, OA -0.47 ± 0.48, t (39) = -0.181, p = 0.858; commercials: YA -0.59 ± 0.65, OA -0.51 ± 0.58, t (39) = -0.427, p = 0.671) or bias (news: YA 0.68 ± 0.31, OA 0.48 ± 0.36, t (39) = 1.896, p = 0.065; commercials: YA 0.86 ± 0.23, OA 0.72 ± 0.30, t (39) = 1.624, p = 0.112) for gist memory.

3.2 Discussion Although it is generally acknowledged that memory performance decreases with age, the current study questions this assumption in regard to daily memory. Contrary to our hypothesis, older adults did not have more false alarms than younger adults, despite their decreased number of hits and inferior performance on most neuropsychological measures. Younger adults had slightly higher discriminability scores, which resulted from their higher hit rate; however, there were no differences in response tendencies – both groups displayed a comparable moderately liberal bias. As our hypothesis of increased false alarms in older adults was rejected, the planned analysis of neuropsychological variables contributing to it was not pursued. The outcomes of the neuropsychological variables themselves are in line with existing literature (Ardila, Ostrosky-Solis, Rosselli, & Gomez, 2000; Lipnicki et al., 2013; Park et al., 2002; Zahodne et al., 2011). We have observed a diminished memory performance in older adults. The deficits were only observed in free recall and not recognition, which most likely represents ceiling effect in sensitivity of the test. Similarly, no age differences were found in performance in verbal fluency tasks. Furthermore, compared to young adults, older adults demonstrated inferior attention, working memory, cognitive processing speed and mental flexibility. Performance of older adults was comparable with normative data for their age group. The unpredicted result of no performance differences in false alarms between young and older adults is explained with the help of associative deficit hypothesis (Naveh-Benjamin, 2000; Old & Naveh-Benjamin, 2008), which offers a surprising advantage for older adults in recognition memory. It was argued that binding features, which belong to the same memory trace, together is a crucial memory factor; hence what we remember is not blue and pen, but a blue pen (Chalfonte & Johnson, 1996). Similarly, the current paradigm offered multi-feature recognition statements (e.g. the older woman offers rice to a girl), which form a single entity and need to be either recognised or rejected in their entirety. Partial recognition of some features (but not a complete item) is not enough for a hit in our paradigm. This is due to an ambiguity created by the presence of reversed statements. Participants need to have encoded and bound all features together. If they were not able to do so due to increased deficits in binding ability, their hit rate dropped. In contrast to this, items that only present noise without any features from the target memory content require a correct response Unknown, with any other response resulting in a false alarm. A complex statement featuring no signal information is easier to reject, as it requires no binding. It is enough to know that the features of the item were not presented. This hints at a paradoxical effect of complex recognition tasks, which are more often encountered in ecologically valid material: while correct recognition is harder due to the binding deficits, correct rejection of false items might be easier, since several false features within a noise item make it more

12 salient and easier to identify such item as noise. Similar results already exist in the literature (Fraundorf et al., 2019). Although they remained unexplained, they seemed to appear in studies employing ecologically valid tasks (LaVoie & Malmstrom, 1998; Matzen & Benjamin, 2013). After separating original and reversed items, no difference in the number of hits to original items was found. It seems that the inferior performance of older adults in the initial analysis combining both original and reversed statements was due to their inferior memory for reversed items only. This was most likely caused by older adults’ reduced ability to process sentential negation (Bartoli et al., 2013; Beltrán, Muñetón-Ayala, & de Vega, 2018; Tettamanti et al., 2008). SDT analysis using only original statements showed differences only in discriminability for news, but not commercials, which might reflect differences in the material on memory and needs to be addressed in future studies. Furthermore, separating gist signal from the original signal items, showed no group differences. Although susceptibility to gist among older adults was frequently documented (Koutstaal et al., 1999; LaVoie & Faulkner, 2000), differing results in our study could be explained through detailed a priori instructions (Carmichael & Gutchess, 2016) or immediate recall task, which did not give time for verbatim traces to fade, hence reducing the reliance on gist traces (Abadie & Camos, 2019). Overall, this study demonstrated that increased rate of false alarms among older adults is not a universal phenomenon and is subject to further influences such as ecological validity of the tasks and complexity of recognition statement items.

4 PUBLICATION 2 – EVERYDAY FALSE MEMORIES IN OLDER PERSONS WITH DEPRESSIVE DISORDER

4.1 Results Prior to the experimental paradigm, participants completed a thorough neuropsychological test battery. Patients with DD scored worse on all cognitive measures except for digit span and immediate recall of supra-span list (Table 5). The analysis of the memory results in the experimental paradigm revealed a performance discrepancy between memory task for news and commercials videos. In the news paradigm the number of hits was the same between DD and OA (t (45) = 1.808, p = 0.077), however in the commercials’ paradigm OA had significantly more hits than DD (t (42) = 2.294, p < 0.027). In both paradigms OA had significantly less false alarms (news t (45) = -4.715, p < 0.000; commercials t (42) = -3.613, p = 0.001; Table 6).

Table 5. Performance in standard neuropsychological tests between OA and DD.

OA (N = 23) DD (N = 24) M ± SD M ± SD t p DS forward 8.70 ± 1.69 8.00 ± 1.82 1.357 0.182 DS backward 7.35 ± 2.57 5.00 ± 1.91 3.543 0.001 VS forward 7.17 ± 1.80 6.13 ± 1.19 2.345 0.024 VS backward 6.52 ± 2.00 5.46 ± 1.44 2.099 0.041 Symbol test 17.95 ± 8.36 12.67 ± 6.63 2.339 0.024 TMT A 39.13 ± 12.78 52.33 ± 18.44 -2.841 0.007 TMT B 91.48 ± 29.25 136.67 ± 57.00 -3.440 0.002 TMT (B – A) 52.35 ± 25.61 84.33 ± 47.22 -2.903 0.006 Semantic fluency 25.00 ± 5.70 19.04 ± 5.06 3.795 <0.001 Phonetic fluency "P" 11.48 ± 3.41 8.38 ± 4.10 2.817 0.007 Phonetic fluency "S" 14.61 ± 3.60 11.04 ± 3.61 3.392 0.001 CVLT 1 5.04 ± 2.18 4.17 ± 1.55 1.592 0.118 CVLT 5 13.13 ± 2.34 10.25 ± 2.79 3.829 <0.001 CVLT 1-5 49.04 ± 9.60 38.75 ± 9.10 3.774 <0.001 CVLT long delay 11.39 ± 3.09 7.63 ± 3.42 3.956 <0.001 CVLT hits 15.61 ± 0.72 14.67 ± 1.05 3.569 0.001 CVLT FA 0.61 ± 1.41 1.88 ± 1.75 -2.725 0.009 Legend: CVLT = California Verbal Learning Test; DD = depressive disorder; DS = digit span; FA = false alarms OA = older adults; TMT = Trail Making Test; VS = visual span.

Table 6. Performance in recognition task for news and commercial videos between OA and DD.

OA (N = 23) DD (N = 24) M ± SD M ± SD t p News Hits 26.61 ± 2.92 24.96 ± 3.32 1.808 0.077 FA 13.39 ± 6.56 23.08 ± 7.48 -4.715 <0.001 subjective difficulty 2.84 ± 0.90 3.00 ± 0.76 -0.611 0.545 Commercials Hits 26.10 ± 3.24 23.63 ± 3.81 2.294 0.027 FA 11.85 ± 4.64 19.21 ± 8.05 -3.786 0.001 subjective difficulty 3.26 ± 0.83 3.05 ± 1.17 0.665 0.510

Legend: DD = depressive disorder; FA = false alarms; OA = older adults.

Table 7. Linear regression model for false alarms in news and commercials between OA and DD.

News false alarms Regression Standardized Standard R2 Adj. R2 coefficient coefficient t p error B Beta Model* 0.293 0.258 Phon. fluency "S" -0.694 0.275 -0.345 -2.522 0.016 MADRS 0.208 0.086 0.332 2.428 0.020 *Model including CVLT long delay, semantic fluency, phonetic fluency "P", phonetic fluency "S", TMT (B – A), symbol test, MADRS, news hits

Commercials false alarms Regression Standardized Adjusted Standard R2 coefficient coefficient t p R2 error B Beta Model 0.283 0.248 TMT (B – A) 0.066 0.025 0.367 2.682 0.011 MADRS 0.178 0.081 0.302 2.210 0.033 Model including CVLT long delay, semantic fluency, phonetic fluency "P", phonetic fluency "S", TMT (B – A), symbol test, MADRS, commercials hits Legend: CVLT = California Verbal Learning Test, MADRS = Montgomery-Asberg-Depression- Rating-Scale, TMT = Trail Making Test.

A linear regression analysis was performed in the next step to identify the contributing factors to the false alarms formation in the patients with DD. CVLT long delay measure was chosen as a marker of memory consolidation, verbal fluency as an indicator of lexical access speed, discrepancy between TMT-A and TMT-B as a marker of executive functioning, symbol test as a measure of sequential working memory, MADRS score as a measure of the severity of depressive symptom, and a number of hits in news and commercials paradigm (Table 7). The model predicted 29.3% of variance for the false alarms in news and 28.3% in commercials. The number of false alarms increased with higher MADRS score in both conditions and additionally with the smaller score in phonemic fluency for news paradigm and a greater discrepancy between TMT-A and TMT-B for commercials paradigm. To evaluate the diagnostic relevance of everyday false alarms for people with DD, ROC curves were calculated for hits and false alarms for both paradigms. False alarms proved to be a better diagnostic marker to distinguish DD from OA than hits (see Sejunaite, Lanza, & Riepe, 2018, page 461, Figure 1). Comparing the number of hits between two groups, the area under the curve was 0.635 ± 0.084 (M ± SE, p < 0.126; 95% confidence interval 0.470 – 0.801) for news and 0.726 ± 0.080 (M ± SE, p = 0.080; 95% confidence interval 0.569 – 0.883) for commercials. Comparing the number of false alarms between two groups, the area under the curve was 0.817 ± 0.069 (M ± SE, p < 0.001; 95% confidence interval 0.681 – 0.952) for news and 0.786 ± 0.070 (M ± SE, p = 0.001; 95% confidence interval 0.649 – 0.924) for commercials.

4.2 Discussion Performance of patients with DD on standard neuropsychological battery was in good harmony with reports in the existing literature (Gron, Bittner, Schmitz, Wunderlich, & Riepe, 2002; Lim et al., 2013; Papakostas, 2014; Thomas et al., 2009; Xu et al., 2012). In the list learning paradigm patients with DD had significantly more false alarms compared to healthy controls; however, the difference was not clinically significant or indicative of pathology. Since the word list, as per instructions, was presented five times, the repetition effect might have decreased false alarm rate (Budson et al., 2000). In the experimental recognition task patients with DD had significantly more false alarms in both news and commercials and significantly less hits in commercials task. The discrepancy between hits in news and false alarms can be explained by impairment of patients with depression in processing positive stimuli (Lemoult, Yoon, & Joormann, 2012). News presented participants with neutral material without any noteworthy relevance for today’s situation. On the other hand, commercials by nature have positive emotional emphasis, therefore presented an additional challenge for participants with DD in the recognition task. The impact of emotional salience of material on memory intrusions is not yet clearly understood and produced mixed results (Joormann, Teachman, & Gotlib, 2009; Moritz, Glascher, & Brassen, 2005). A regression analysis showed that negative mood and decreased executive function (as measured by phonetic fluency and mental flexibility) contributed to the formation of false alarms. Impaired cognitive function and mood are known to be closely related (Rock, Roiser, Riedel, & Blackwell, 2014) and are both linked to frontal lobe malfunction (Elderkin- Thompson, Moody, Knowlton, Hellemann, & Kumar, 2011). This finding was in good

16 harmony with previous reports on relation between mood, executive function and memory distortions (Butler et al., 2004; Moritz et al., 2005; Yeh & Hua, 2009). The interaction between these two factors is supported by two false memory frameworks. As outlined in the fuzzy trace theory, emotional context impairs encoding of verbatim traces thus promoting false alarms. Simultaneously, impaired executive function is overwhelmed with rich contextual information and further aggravation of memory distortions takes places due to impaired source monitoring (Johnson et al., 1993; McDonough & Gallo, 2008; Straube, 2012). False alarms were previously used to discriminate between healthy controls and patients with neurodegenerative disorder and yielded comparable results to discrimination based on hits (Ally, Gold, & Budson, 2009). The current study shows that for patients with DD false alarms in a complex ecologically valid task might offer a higher diagnostic value, as it is more sensitive to minor impairments of executive functioning, which in turn has influence on memory function.

5 PUBLICATION 3 – EVERYDAY MEMORY IN PATIENTS WITH ALZHEIMER’S DISEASE: FRAGMENTARY AND DISTORTED

5.1 Results There was no significant difference in the news (χ2 (1) = 3.421, p = 0.064) and commercials (χ2 (1) = 0.296, p = 0.587) watching frequency between OA and AD. As expected, the analysis of the neuropsychological variables as assessed by the conventional neuropsychological test battery showed that the AD group scored considerably lower in all of the measures except digit span forward, which was controlled for in the selection criteria (Table 8).

Table 8. Performance in standard neuropsychological tests between OA and AD.

OA (N = 23) AD (N = 20) M ± SD M ± SD t p

MMSE 29.70 ± 0.64 26.85 ± 1.90 6.396 <0.001 WST 32.00 ± 3.56 29.35 ± 5.80 2.294 0.031 DS forward 8.70 ± 1.69 7.60 ± 1.90 2.000 0.052 DS backward 7.35 ± 2.57 4.30 ± 1.59 4.738 <0.001 VS forward 7.17 ± 1.80 5.75 ± 1.52 2.780 0.008 VS backward 6.52 ± 1.99 4.40 ± 2.23 3.289 0.002 Symbol Span 17.95 ± 8.36 8.17 ± 5.18 4.380 <0.001 TMT A 39.13 ± 12.78 80.70 ± 44.91 -4.001 0.001 TMT B 91.48 ± 29.25 210.30 ± 79.72 -6.307 <0.001 TMT (B – A) 52.35 ± 25.61 129.60 ± 59.62 -5.379 <0.001 CVLT 1 5.04 ± 2.18 3.00 ± 1.34 3.750 0.001 CVLT 5 13.13 ± 2.34 6.35 ± 2.50 9.182 <0.001 CVLT 1-5 49.04 ± 9.60 25.25 ± 6.37 9.684 <0.001 CVLT LD free 11.39 ± 3.09 2.75 ± 3.63 8.445 <0.001 CVLT LD cued 13.00 ± 2.30 5.40 ± 3.66 8.012 <0.001 CVLT hits 15.61 ± 0.72 13.70 ± 3.13 2.843 0.007 CVLT FA 0.61 ± 1.41 8.35 ± 8.64 -3.961 0.001 Legend: AD = Alzheimer’s disease; CVLT = California Verbal Leaning Scale; DS = digit span; FA = false alarms; LD = long delay; MMSE = Mini Mental State Examination; OA = older adults; TMT = Trail Making Test; VS = visual span; WST = vocabulary test (Ger. Wortschatztest).

The performance in the recognition task for the material presented in the news and commercial videos followed a similar pattern. As is shown in the Table 9, the AD group had significantly less correct recognitions and significantly more false alarms. To see whether the type of video affected memory performance we calculated a total correct score (i.e. sum of correct recognitions and correct rejections of misleading statements). There was no difference between total correct for news and commercials in the OA group (news (M ± SD) 49.22 ± 7.10, commercials 50.25 ± 5.99; p = 0.117) and in the AD group (news 34.44 ± 9.51, commercials 31.39 ± 8.76; p = 0.064). As shown by the analysis of the subjective performance evaluations, AD patients were just as confident about their performance as was the OA group (Table 9). There were no differences between the two groups in the perceived difficulty of the task as measured by the 5-point Likert scale (news OA 2.84 ± 0.898, AD 3.18 ± 0.883, t (34) = -1.124, p = 0.269; commercials OA 3.26 ± 0.872, AD 3.06 ± 1.144, t (34) = 0.607, p = 0.548).

Table 9. Performance in recognition task for news and commercial videos between OA and AD.

OA (N = 23) AD (N = 24) M ± SD M ± SD t p News Hits 26.61 ± 2.92 21.00 ± 3.46 5.763 <0.001 FA 13.39 ± 6.56 22.50 ± 9.08 -3.807 <0.001 Subjective hits 43.46 ± 13.47 38.88 ± 11.66 1.094 0.282 Subjective FA 19.17 ± 6.99 15.88 ± 9.64 1.159 0.255 Commercials Hits 26.10 ± 3.24 19.56 ± 4.31 5.319 <0.001 FA 11.85 ± 4.64 24.17 ± 10.16 -4.720 <0.001 Subjective Hits 39.61 ± 18.05 38.06 ± 15.28 0.279 0.782 Subjective FA 18.17 ± 8.32 15.94 ± 9.18 0.761 0.452 Legend: AD = Alzheimer’s disease; FA = false alarms; OA = older adults.

A lineal regression analysis was performed to pinpoint contributing factors to the number of false alarms in both groups for each paradigm. The predictors were chosen in terms of their correlation as well as clinical and theoretical relevance for memory processes in AD. Symbol span was chosen as a marker of visual memory, the difference value between TMT-A and TMT-B as a marker of executive function, CVLT trial 1 as a marker of short- term verbal memory and a number of hits for news and commercials respectively as a marker for encoded information in the presented videos. The model predicted 16.6% of variance for the false alarms in news and 37.6% in commercials. The number of false alarms increased with the larger difference between TMT-A and TMT-B scores in both conditions and additionally with the smaller score in symbol span for the commercials condition (Table 10). 19

Table 10. Linear regression model for false alarms in news and commercials between OA and AD.

News Standardized Adjusted Regression Standard Predictor R² coefficient t p R² coefficient B error Beta Model* 0.166 0.143 TMT (B – A) 0.062 0.023 0.408 2.679 0.011 *Regression model including variables CVLT 1, TMT (B – A), symbol span and news hits. Commercials Standardized Adjusted Regression Standard Predictor R² coefficient t p R² coefficient B error Beta Model** 0.376 0.340 Symbol Span -0.425 0.182 -0.367 -2.323 0.026 TMT (B – A) 0.056 0.027 0.332 2.103 0.043 **Regression model including variables CVLT 1, TMT (B – A), symbol span and commercials hits. Legend: CVLT = California Verbal Learning Test, TMT = Trail Making Test.

To examine a connection between the false memories’ paradigm and the biological markers of AD, a correlational analysis between number of false alarms in each paradigm and the values of Aβ42 and total tau protein was calculated with the available CSF markers data. Due to ethical reasons, neurobiological markers were only assessed in the AD group. Six patients received PET scan and therefore the final sample for the correlational analysis comprised fourteen patients. Due to decreased sample size, a non-parametric Spearman’s rho procedure was employed to calculate correlation. There was a significant negative correlation between the values of Aβ42 and the number of false alarms for both news (r = -0.629, p = 0.016) and commercials (r = -0.636, p = 0.019) (see Sejunaite, Lanza, & Riepe, 2017, page 1495, Figure 1); however, there was no significant correlation between Aβ42 and hits for either news (r = -0.018, p = 0.952) or commercials (r = 0.014, p = 0.964) (see Sejunaite, Lanza, & Riepe, 2017, page 1495, Figure 2). No significant correlation was observed between total tau protein and false alarms or hits in either of the paradigms (FA news: r = -0.320, p = 0.265; FA commercials: r = -0.493, p = 0.087; hits news: r = -0.431, p = 0.124; hits commercials: r = -0.526, p = 0.065).

5.2 Discussion The present study was able to demonstrate significantly higher rate of false alarms in patients with AD compared to healthy controls using tasks with daily relevance. The type of material (news or commercials) did not play a significant role in the recognition outcome. Furthermore, there was no relationship between objective and subjective performance. The 20 number of false alarms increased with decreasing flexibility (measured as the time difference to complete TMT-A and TMT-B) in the news paradigm and with decreasing flexibility and decreasing symbol span in the commercials’ paradigm. Patients with AD tended to respond “Yes” in the recognition task significantly more often and their Aβ42 values correlated significantly with the number of false alarms. Inferior memory performance, biased answering pattern and anosognosia for their own deficits among patients with AD is in good harmony with previous findings (Budson et al., 2004; Budson et al., 2006; Cooper, Shanks, & Venneri, 2006; Gallo, Chen, Wiseman, Schacter, & Budson, 2007; Mimura & Yano, 2006). The current study was able to confirm the same pattern of deficits using an ecologically valid material among patients with very mild AD. Mental flexibility and visual working memory were able to partly explain the rate of false alarms in the recognition task. These two abilities tap into executive function and depend greatly on prefrontal cortex (Yuan & Raz, 2014). Memory, as a higher and more complex function, builds up on such basic cognitive processes. Deficient flexibility and working memory were associated with decreased encoding (Karlsgodt, Shirinyan, van Erp, Cohen, & Cannon, 2005), which in turn impairs formation of detailed verbatim traces. Fuzzy trace framework posits that in absence of robust verbatim traces, memory becomes dependent on gist, which makes it more fallible and the rate of false alarms increases (Anderson et al., 2008; Brainerd et al., 2008). Furthermore, patients with AD showed a greater impairment in all measures of frontal functioning, which makes it likely that not only gist, but also post-retrieval verification and inhibition might be impaired and further increase the rate of false alarms (Budson et al., 2002). Among patients with AD there was a strong negative correlation between Aβ42 values and false alarms, but not between Aβ42 and hits. Lower levels of Aβ42 in the CSF indicate more amyloid depositions in the brain (Beinhoff, Tumani, & Riepe, 2009; Bouwman et al., 2007), resulting in widespread neuronal malfunction, more cognitive deficits and ultimately more false alarms. This could also mean that correctly rejecting a false statement requires a larger neural network than accepting a true statement. Alternatively, correct rejection of false statements might be dependent on brain areas that are affected by amyloid pathology at earlier stages of the disease.

6 GENERAL DISCUSSION AND CONCLUSION

In general, research on memory in aging and age-associated diseases primarily focuses on information obtained in standardized test and demonstrated a link between decrease in memory hits and age. Few studies that used ecologically valid tasks, found no such clear connection. These two approaches were rarely brought together to investigate a second type of error occurring during memorization or retrieval of information – false alarms. These errors often accompany memory omissions in a number of memory tasks. They were reported to occur in healthy younger and older participants in experimental tasks and are often observed in clinical practice, especially among patients with Alzheimer’s disease and depressive disorder. Given a varying degree of memory performance among these populations and different cognitive demands posed by laboratory and ecologically valid tasks, it is unlikely that false alarms follow the same pattern in both types of tasks. The current series of publications investigated the rate of false alarms in healthy aging and in two most common psychiatric diagnoses among geriatric patients – AD and DD. The paradigm employed in these studies used a daily memory activity of watching news and commercials followed by a recognition task. It was demonstrated that although in general false alarms are brought about by similar underlying mechanisms, the susceptibility to them differs not only as a function of group but also as a function of task. Most importantly, it was demonstrated that contrary to results from laboratory studies, the number of false alarms is not higher among older adults in daily memory tasks. This finding has implications not only in understanding the patterns of healthy aging but also in early diagnosis of a pathological one. The best recognition hit scores were displayed by young adults. In comparison there was a homogenous decline in the rate of hits in healthy old controls followed by patients with DD and AD. These results are consistent with the reports in the previous literature, both with studies using laboratory paradigms (Budson et al., 2006; Gallo et al., 2007; Howe & Malone, 2011; Nilsson, 2003; Toffalini et al., 2014) and few ecologically valid paradigms (Budson et al., 2004; LaVoie & Malmstrom, 1998; Matzen & Benjamin, 2013). In contrast, there was no such clear pattern in the rate of false alarms. Patients with AD and DD both had a similar and significantly higher rate of false alarms compared to healthy older controls. Furthermore, there was no difference in false alarms between OA and YA. Whereas results for AD and DD patients are in line with majority of literature (Budson et al., 2006; Gallo et al., 2007; Howe & Malone, 2011), absence of difference between healthy older and younger adults disagrees with prior studies and most likely reflects the nature of the ecologically valid stimuli. Similar results were previously reported in a few of other studies (Kramer et al., 2003; Ratcliff et al., 2004; Salthouse, 2016; van Ocker et al., 2017). In the groups, where a significant difference in the rate of false alarms was observed, it can be partially explained by reduced mental flexibility and lower scores in attention and verbal fluency. All these neuropsychological variables are linked to frontal lobes (Baldo, Shimamura, Delis, Kramer, & Kaplan, 2001; Carter, Botvinick, & Cohen, 1999; Karnath & Wallesch, 1992) and their malfunction can lead to increased rate of false alarms (McCabe et al., 2009; Roediger & Geraci, 2007). Interestingly, false alarms in a list-learning paradigm were linked to free recall, a measure of activity in medial temporal lobes (Kramer et al.,

2005; Straube, 2012). This discrepancy helped to illustrate different demands placed on memory processes in laboratory testing and daily life. List learning paradigms represent a purer measure of memory processes, which offers little context or possibilities to build on existing memory traces. Memory tasks using news and commercials, on the other hand, offer a context-rich platform to aid encoding and retrieval, at the same time placing a greater strain on executive function controlled by the frontal lobes, to filter and correctly attribute familiar and novel content. False memory research is accompanied by propositions of multiple theoretical frameworks to explain the formation of these memory errors. Whereas majority of them work well to explain separate findings, they often fail to account for aggregated findings (Healey & Kahana, 2016). As was shown by regression analyses in our studies, false memories seem to be related to attentional and executive control. These aspects could be incorporated in more than one proposed framework. Whether and to what extent these frameworks overlap still remains to be explored. Furthermore, whether the same frameworks can be applied to different subject groups, or there is a hierarchy of more basic to more specific causes to false memory content needs to be addressed in future studies. Keeping these limitations in mind, it could be speculated that patients with AD and DD are subject to broader deficits, where a decrease in mental flexibility, attention and affective interference impairs memory for exact verbatim traces, making these groups more dependent on gist and thus leading to an increased rate of false alarms. Increased dependence on gist among older adults using an ecologically valid paradigm could not be supported in the current study. Instead, we have concluded that complex recognition statements might facilitate correct rejection among older adults in a context rich environment, which gives additional cues and facilitates the role of executive function in recognition memory. As already mentioned, the performance of OA seems to be at odds with prior research. This discrepancy can be explained by a differing degree of impairment among patients and older controls and by additional cognitive resources available for each of the groups. As was demonstrated by their decreased performance on standard cognitive assessments, patients with AD and DD seem to have greater medial temporal and frontal impairments, which prevent them from using recognition strategies. OA, on the other hand, have fewer general deficits and can use a broader cognitive network to compensate for the deficits (Devitt & Schacter, 2016; Fandakova, Lindenberger, & Shing, 2015). This allows them to correctly reject complex novel statements, if they are sure that at least one of the components was not present during encoding. It seems likely that laboratory experiments using word list paradigms can accurately reflect memory deficit of older adults; however, it fails to capture the presence of additional strategies and resources that older adults use in their daily lives to aid recognition memory. Conventional neuropsychological assessments and laboratory paradigms are unquestionably valuable in assessing impairment and giving insight into the basic mechanisms of memory processes. However, daily life is by no means basic and the cognitive processes that one is faced outside the lab are complex and multifaceted. So, when ecologically valid memory assessments could come in handy? One area that could profit from such paradigms is predicting a level of functioning in domestic or work environment. Despite such tasks being increasingly common in clinical practice, the tools that are available

23 to make such predictions were mostly designed to detect a pathology and have moderate ecological validity at best (Chaytor & Schmitter-Edgecombe, 2003). Ecologically valid memory paradigms could also prove advantageous in the diagnostic process. The valuable knowledge that healthy older adults efficiently use compensatory strategies to avoid extensive false alarms, could help identify individuals, in which such strategies fail, at an earlier stage, where standard neuropsychological tests might not be selective just yet. There is no doubt that such ecological paradigms have still some way to go before they offer diagnostic value; however, the current work has demonstrated a robust link between such paradigms and biological markers of pathology. Other similar assessments are also being developed (Mazurek et al., 2015). When interpreting results of the above studies, some limitations need to be noted. First, the relevance of the information reported in the news clips and the familiarity with the product presented in the commercials was not assessed. Although none of the videos were current, the effects of familiarity or meaningfulness on memory outcomes could not be entirely ruled out. Furthermore, despite the effort to choose neutral videos, the emotional salience was not measured and it is likely that commercials by nature present viewers with more positive content. This limitation is of particular importance when interpreting results of the patients with DD, as their memory performance is a subject to their own mood as well as valence of the material. Moreover, due to ethical considerations biological markers were not available for healthy older controls and neurodegenerative disease was ruled out based on medical history and clinical indicators alone. Finally, the exact frequency with which participants watch news or commercials on a daily basis and exposure time to these videos was not assessed. Personal interest in the task might have increased the level of attention and affected memory processes. To conclude, memory was not designed to exist in a vacuum and should not be assessed in one. Its performance is more complex than can be captured by laboratory tasks and there is a greater variability in false alarms in different age and disease groups than has been previously reported. Despite false alarms in daily memory having common aetiology, the variability in their occurrence makes them a potentially useful diagnostic tool. Future research should tap into the potential of ecologically valid memory tasks in both fundamental and applied research.

7 SUMMARY

Memory errors are most often associated with omission of memory content; however, memory is no less susceptible to distortions and false memories. In the context of recognition tasks, the former are referred to as hits and misses, whereas the latter as correct rejections and false alarms (FA). The current series of publications looks into the frequency of false alarms using ecologically valid stimuli in healthy younger (YA; n = 24, age (M ± SD) 26.58 ± 3.57) and older adults (OA; n = 23, age 69.74 ± 6.46) as well as patients with Alzheimer’s disease (AD; n = 20, age 72.20 ± 5.87) and older patients with depressive disorder (DD; n = 24, age 69.33 ± 5.75). All participants were shown 12 short video clips (six news clips and six commercial clips), which were followed by a recognition task of 12 items after each video. Videos used in the study were originally broadcasted between 1980s and early 2000s. Items in a recognition task comprised a complex statement of several features and fell into one of three categories: original statements, reversed statements, and noise. Participants were asked to answer with “Yes” (the statement is true; original statement), “No” (the statement is false/reversed; reversed statement), and “Unknown” (the information was not addressed or shown in the video; noise). Correct answers to original and reversed statements were regarded as hits; false answers to noise statements were regarded as FA. Additionally, each participant received a comprehensive neuropsychological assessment of attention, memory and executive function. The results showed that compared to YA, OA performed worse on most neuropsychological measures except for digit span and verbal fluency. Subjective estimate of hits and FA was comparable between the two groups. The objective measures revealed a significant difference in hits with YA outperforming OA, but no difference in false alarms. OA demonstrated significantly lower discriminability scores, however no group differences were found in bias, with both YA and OA choosing a liberal answering strategy. The absence of expected difference could not be explained by one group’s greater susceptibility to gist memory and persisted after comparing original and noise statements. The results were explained as a facilitation of correct rejection through complex and context rich recognition statements that are characteristic of ecologically valid tasks. OA outperformed DD on most of neuropsychological measures and had fewer FA in the recognition task for both news and commercials. Although DD had fewer hits in commercials paradigm, there was no difference in the number of hits in the news paradigm. Twenty nine percent of variance in FA in news paradigm was explained by decrease in phonemic fluency and increase in depressive symptoms. Similarly, 28.3% of variance in FA in commercials paradigm was explained by decrease mental flexibility and increase in depressive symptoms. ROC curve analysis showed that FA have a diagnostic advantage over hits in discriminating between patients with DD and OA. It was concluded that memory in patients with DD is marked not only by memory omissions, but additionally and even more profoundly by memory distortions. AD performed significantly worse in all measures of cognitive functioning and had significantly less hits and significantly more FA in both news and commercials. There was no difference in the subjective performance estimate between the two groups. Using a multiple regression analysis with neuropsychological variables as independent variable and

25 the number of FA as dependent variable, it was demonstrated that mental flexibility was able to predict 16.6% of the variance in FA for news. The number of FA increased as the mental flexibility decreased. Similarly, mental flexibility and visual working memory predicted 37.6% of FA in commercials. The number of FA increased as the working memory and mental flexibility decreased. Finally, there was a significant correlation between Aβ42 and FA in news and commercials; however, no correlation between hits and any of the biomarkers of Alzheimer’s disease. The results showed that the patients with very mild AD suffer from considerable number of false alarms in daily tasks and these results can be utilized to improve diagnostic process. Overall, it was demonstrated that ecologically valid tasks produce different results in recognition memory for older adults than was reported by studies using laboratory tasks. Daily complex tasks reduce older adults’ susceptibility to false alarms by allowing a better discrimination between signal and noise items. This ability to compensate for memory deficits is not utilised in conventional memory tests. Furthermore, false alarms were closely linked to pathology biomarkers in AD and were a better diagnostic discriminator in DD than the number of hits. The results of these studies stress the importance of false alarms in daily memory as a sensitive surrogate of pathological memory deficits.

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9 PUBLICATIONS

Sejunaite, K., Lanza, C., & Riepe, M. W. (2019). Everyday memory in healthy aging: porous but not distorted. Frontiers in Aging Neuroscience, 11, 153.

Sejunaite, K., Lanza, C., & Riepe, M. W. (2018). Everyday false memories in older persons with depressive disorder. Psychiatry Research, 261, 456-463.

Sejunaite, K., Lanza, C., & Riepe, M. W. (2017). Everyday Memory in Patients with Alzheimer’s Disease: Fragmentary and Distorted. Journal of Alzheimer's Disease, 60(4), 1489-1498.

Research Article

Original Paper 1: Everyday memory in healthy aging: Porous but not distorted.

Reference: Sejunaite, K., Lanza, C., & Riepe, M.W. (2019). Everyday memory in healthy aging: Porous but not distorted. Frontiers in Aging Neuroscience, 11, 153. https://doi.org/10.3389/fnagi.2019.00153

Permission to reprint: Open access content made available under CC BY 4.0, https://creativecommons.org/licenses/by/4.0/.

Contribution: Development of the study design (hypotheses, methods); data collection, data analysis and interpretation; writing, submitting and revising the manuscript.

ORIGINAL RESEARCH published: 25 June 2019 doi: 10.3389/fnagi.2019.00153

Everyday Memory in Healthy Aging: Porous but Not Distorted

Karolina Sejunaite, Claudia Lanza and Matthias W. Riepe*

Department of Psychiatry and Psychotherapy II, Division of Mental Health & Old Age Psychiatry, University of Ulm, Ulm, Germany

Most studies targeting age-association of memory functions report a decline in recognition hits and an increase in false alarms. The goal of the present study was to assess these findings in tasks with day-to-day relevance. We investigated healthy young (YA; age 26.90 3.55 years) and old (OA; age 69.80 5.85 years) adults. Participants ± ± were asked to watch six news and six commercials and complete a recognition task relating to the information presented in the videos. OA had a lower hit rate in both news and commercials compared to YA. However, the number of false alarms (FA) was the same in both age groups. Applying signal detection theory, we found age differences in discriminability for both news and commercials paradigm. The groups showed no differences in bias and both chose a liberal answering tendency. We interpret our finding as a result of complex recognition items in an ecologically valid task. Multi-feature items offer an advantage in correct rejection—it is enough to know that at least one feature of an item is false. This benefit does not extend to hits, where all features of an item need to be recognized. This indicates that recognition memory of naturalistic stimuli in OA is porous, but not distorted. Edited by: Rommy Von Bernhardi, Keywords: memory, recognition, false alarms, daily life, neuropsychology, healthy aging Pontifical Catholic University of Chile, Chile

Reviewed by: BACKGROUND Jesse Q. Sargent, Francis Marion University, Aging goes along with a decline in various cognitive functions such as visual-constructive abilities, United States processing speed, and memory (Di Carlo et al., 2000; Park et al., 2002; MacDonald et al., 2004; Royall Kristin Flegal, et al., 2005; Ardila, 2007). Changes in memory performance are not homogeneous and different University of Glasgow, aspects of memory change differently. Among memory deficits, episodic memory performance United Kingdom undergoes the most pronounced changes with increasing age (Souchay et al., 2000; Daselaar et al., *Correspondence: 2003; Kramer et al., 2003; Nilsson, 2003; Salthouse, 2016). Concerning memory processes, literature Matthias W. Riepe suggests that the most drastic deterioration occurs in recall (Hultsch, 1969; Petersen et al., 1992; [email protected] Hertzog et al., 2010), whereas recognition is only moderately affected (Jacoby, 1999; Ratcliff et al., 2004; Spaniol et al., 2006; Van Ocker et al., 2017). Received: 28 November 2018 Accepted: 11 June 2019 Recognition errors comprise two kinds of errors, not recognizing studied items (misses), Published: 25 June 2019 and falsely recognizing new unstudied items (false alarms, FA; Stanislaw and Todorov, 1999; Shapiro, 2014). A recent meta-analysis of 232 studies by Fraundorf et al.(2019) has reported that Citation: Sejunaite K, Lanza C and Riepe MW (2019) Everyday Memory in Healthy Abbreviations: CVLT, California Verbal Learning Test; DRM, Deese-Roediger-McDermott procedure; FA, False alarms; Aging: Porous but Not Distorted. MADRS, Montgomery-Asberg-Depression-Rating-Scale; MMSE, Mini Mental State Examination; OA, Older adults; RWT, Front. Aging Neurosci. 11:153. Regensburg Verbal Fluency Test; TMT, Trail Making Test; WMS, Wechsler Memory Scale; WST, Vocabulary test; YA, doi: 10.3389/fnagi.2019.00153 Young adults.

Frontiers in Aging Neuroscience| www.frontiersin.org 1 June 2019 | Volume 11 | Article 153 Sejunaite et al. Everyday Memory in Healthy Aging younger adults generally outperformed older adults (OA) in memory measures, the performance on the new memory task was recognition tasks and that older adults showed a more liberal also predicted by the self-evaluation memory questionnaires. The answering tendency resulting in an increase in false alarms. authors suggested that such ecologically valid task could offer an Interestingly, it was reported that age differences in recognition advantage over conventional scales by picking up on very early accuracy were largest for easy tasks. Furthermore, older adults signs of cognitive decline in older population. memory showed an even greater detriment, when recognition Exposure to material frequently seen on TV, which often task involved new combinations of already familiar items. serves as a most common information acquisition source, has The main effect of age on recognition memory persisted been studied previously. Daily exposure to material such as news across different studies in spite of variability in learning or commercials influences our attitudes, preferences and decision material, emotional valance of the stimuli or retention interval, making (Martin, 2003; Prior, 2003; Weitzer and Kubrin, 2004). suggesting that recognition memory decline involves a general For that reason, it is important to assess memory for this kind process operating across different modalities. An increase of of information presentation across different age groups. Thus erroneous memory content was also previously observed in far, studies using real life paradigms of news or commercials in different paradigms such as a recognition version of the healthy populations focused primarily on brain activity (Frings Deese-Roediger-McDermott (DRM) procedure (Roediger and et al., 2010), emotional salience (Fung and Carstensen, 2003) McDermott, 1995; Seamon et al., 2002), conceptual similarity or pre-existing attitudes (Frenda et al., 2013) rather than false (Paige et al., 2016), self-related information (Rosa et al., alarms. Although recognition memory using such everyday life 2015), misinformation (Meade et al., 2012), and misattribution material has already been investigated in the context of disorders (Mitchell and Johnson, 2009). directly affecting memory performance (Sejunaite et al., 2017, While such paradigms are useful to test theoretical models 2018), the pattern and causes of false alarms with healthy aging and advance understanding of memory construct, it has been in everyday life remains vague. questioned if they can fully account for cognitive processes faced Generally, the age-related decline in hits and the increase in by healthy older and younger persons on a daily basis (Chaytor false alarms are linked to changes in brain activity. Functional and Schmitter-Edgecombe, 2003). A recent study reported that imaging studies reported an increased task-related activity in DRM and other above mentioned tasks do not sufficiently predict the left temporal, frontal, and posterior parietal cortex among memory outcomes and questioned the implications to use these older adults during memory tasks (Frings et al., 2010; Craik paradigms to predict memory distortions in real-life situations and Rose, 2012). This pattern was thought to reflect increased (Patihis et al., 2018). effort and decreased reliance on automatic effortless processing One way to bridge the gap between laboratory and in older subjects compared to young adults. Two brain regions ecologically valid paradigms would be to create assessments that seem to be affected the most by aging were medial temporal using verisimilitude approach, which refers to development and prefrontal cortex (Buckner, 2004; Butler et al., 2004; Hedden of tests that are comprised of everyday cognitive tasks. Such and Gabrieli, 2004; Raz et al., 2005; Meade et al., 2012). They instruments were developed for everyday skills such as attention were associated with increased susceptibility to lure items in (Robertson et al., 1994), executive function (Wilson et al., recognition (Plancher et al., 2009; Fandakova et al., 2013a) as 1996) and some aspects of memory (Wilson et al., 2004, 2008). well as increased misattribution of memory sources (Craik et al., A study of memory for commercials reported that despite 1990; Chan and McDermott, 2007; Fandakova et al., 2013b) having less correct rejections than young adults (YA), older respectively. Aging-related hippocampal volume reduction puts a adults demonstrated better memory for emotionally meaningful strain on effective memory process requiring other cortical areas, content compared to neutral one (Fung and Carstensen, 2003). such as prefrontal cortex, to compensate for the deficits (Cabeza, Another study by Mazurek et al.(2015) required healthy 2002; Cabeza et al., 2002; Persson et al., 2006). In contrast, older younger and older participants to hide objects in a room, adults that were able to maintain memory processing patterns which was later followed by a surprise memory task, where akin to those in young adults were reported to have fewer false participants were asked to freely recall what, where, and when recognitions (Fandakova et al., 2015). they had hidden. Results showed that older adults recalled Further support for the involvement of decreased frontal and significantly less full combinations of object, location and medial temporal functioning in false recognitions comes time, but memory for incomplete combinations (i.e., what- from studies that compared memory performance with where, what-when, and where-when) did not differ between neuropsychological correlates. Better performance in memory the two groups. Furthermore, the ability to bind the three measures such as free and cued recall was shown to contribute to features together varied significantly in the older adults group, binding separate features into complex memories and increase with some individuals performing worse and some better than the number of hits (Henkel et al., 1998; McCabe et al., 2009). younger adults. The authors partly explained this finding through Higher scores on frontal function measures such as verbal differences in memory strategies used by the participants—an fluency, working memory, abstract reasoning and problem ecologically valid task might make it easier for older adults to solving were associated with less false alarms (Roediger and apply more efficient memory strategies, such as ‘‘mental travel,’’ Geraci, 2007; McCabe et al., 2009) and better evaluation of which they rely upon in everyday life. The performance on contextual features of memory traces (Henkel et al., 1998). the new memory task was predicted by the existing measures To account for this discrepancy in memory of episodic memory. Additionally and in contrast to existing performance with age, multiple explanations were proposed

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(Johnson and Raye, 1998; Roediger et al., 2001; Devitt and nervous system disorders such as neurodegenerative disorders Schacter, 2016). Although theories explaining age-related and affective disorders as well as mental retardation and increase in false alarms are numerous, three of them are addictive behavior were ruled out by taking medical history. The viewed as the most prominent to explain age-associated factors exclusion criteria for Mini Mental State Examination (MMSE) (Healey and Kahana, 2016). Associative deficit hypothesis and Montgomery-Asberg-Depression-Rating-Scale (MADRS) (Naveh-Benjamin, 2000; Old and Naveh-Benjamin, 2008) were <28 and >9, respectively. postulates that older adults are selectively impaired in the ability to bind separate features together into meaningful memory MATERIALS AND METHODS traces. This association deficit persists even when memory for features themselves is intact (Chalfonte and Johnson, 1996). The present study was designed as a non-randomized, cross- This hypothesis helps to explain the source monitoring deficits sectional study. All participants were briefed about the frequently reported in older adults and often viewed as a distinct study design. The neuropsychological assessment as well as false memory theory. Inhibitory deficit hypothesis (Hasher and experimental sessions took place at the Division of Mental Zacks, 1988; Healey and Kahana, 2016) argues that age-related Health and Old Age Psychiatry of Ulm University. The study increase in false alarms arises due to decreased ability to inhibit received approval of the local ethics committee and was done in irrelevant information. This hypothesis helps to explain the accordance with the local ethical standards of the Ulm University effects of interference (Hamm and Hasher, 1992; May and and the guidelines outlined in the Declaration of Helsinki (World Hasher, 1998; Manard et al., 2014) as well as effects of priming Medical Association, 2013). (Madden, 1986; Ikier et al., 2008) on memory. Last, according to cognitive slowing hypothesis (Salthouse, 1996a,b), aging is Neuropsychological Assessments associated with a general reduction in most cognitive abilities Clinical Scales (Ardila et al., 2000; Park et al., 2002; Darowski et al., 2008; Mini-Mental State Examination (MMSE; Folstein et al., Zahodne et al., 2011). According to this theory, a diminished 1975) performance results from an age-associated decrease of the speed The MMSE is a widely used instrument to give an overview of cognitive processing—controlling for speed explains up to over global cognitive functioning. It comprises questions on 70% of variance in memory tasks (Aminoff et al., 2012). orientation, registration, short-term memory, language use, Taken together the literature suggests that older persons are comprehension, and basic motor skills. The score ranges from more prone to false alarms. The studies, however, mostly used 0 to 30, with a score below 24 indicating a cognitive impairment. experimental paradigms loosely related to day-to-day situations. The goal of the present study was to investigate recognition Montgomery-Asberg-Depression-Rating-Scale (MADRS; memory with ecologically valid material (news and commercials) Montgomery and Asberg, 1989) in healthy aging. We hypothesized that older adults would have The score in the MADRS reflects the affective state of the more false alarms in an ecologically valid memory paradigm than examinee as assessed by a health care professional and consists young adults. Furthermore, we hypothesized that age differences of 10 aspects to be evaluated: apparent sadness, communicated would be explained by age-associated decline of performance on sadness, inner tension, sleep, appetite, concentration, impetus, other cognitive tasks such as measures of frontal function. callousness, pessimistic thoughts and suicidal ideation. Each of the aspects is given a score from 0 to 6 according to its severity. PARTICIPANTS The total score ranges from 0 to 60. Scores 0–8 indicate no depression, 8–16 a mild, 16–24 a moderate, and 24 and higher A statistical power analysis was performed for sample size a severe depression. estimation, based on data from a similar recognition memory Neuropsychological Tests study for advertisements (Fung and Carstensen, 2003). Using the Vocabulary Test (Wortschatztest, WST; Schmidt and means and standard deviations for neutral material the calculated Metzler, 1992) effect size d was 1.07. With an alpha = 0.05, and power = 0.90, In the Wortschatztest (WST), the examinee needs to find an the sample size estimated with this effect size is 16 per group for actual word among five non-word distractors. The word list between-group comparisons. The present study is a follow-up among which the actual word needs to be chosen increases in study to two prior studies assessing false alarms in healthy difficulty as the test progresses. The number of correct answers older persons and older persons with depressive disorder or (maximum 40) is counted and the raw values are converted into Alzheimer’s dementia (Sejunaite et al., 2017, 2018). The group IQ scores. of older persons in the present study was the same as in the prior studies. We, therefore, chose to use a similar sample size for California Verbal Learning Test (CVLT; Niemann et al., the group with young healthy adults. The sample in the present 2008) study comprised a total of 21 young adults [YA; age 21–35 years; The California Verbal Learning Test (CVLT) is a verbal memory 26.90 ± 3.55 (Mean ± Standard Deviation); 13 females] and test, assessing variables such as immediate recall, free and cued 20 older adults (OA; age 61–83 years; 69.80 ± 5.85; 10 females). recall after short delay, free and cued recall after long delay Both, YA and OA consisted of volunteers recruited by local as well as recognition. A list of 16 words (four words of each advertising to partake in a study on memory and aging. Central category: fruit, clothing, drinks, tools) is read to the participant

Frontiers in Aging Neuroscience| www.frontiersin.org 3 June 2019 | Volume 11 | Article 153 Sejunaite et al. Everyday Memory in Healthy Aging a total of five times (CVLT 1 ... CVLT 5). After each round, the News participant is encouraged to recall as many words as possible. Six news videos were shown to the participants with each video Immediate recall is followed by a free and cued delayed recall being between 27 s and 39 s. All videos were selected from after 5 (CLT short delay) and 20 min (CVLT long delay) intervals the same popular daily TV news show Tagesschau from the respectively, and a Yes/No recognition task (CVLT recognition). ARD-channel and were originally broadcasted between the 1980s and early 1990s. We selected old news to avoid familiarity bias. Digit and Visual Span (Wechsler Memory Scale Revised, The news topics pertained to domestic affairs (skateboard safety, WMS-R; Härting et al., 2000) merging of state-run train companies, changes in TV licence fee, The Digit Span test comprises digit span forward and digit river pollution, shortage in vocational training places, ferryboat span backward. In the digit span forward the participants are incident). All six videos had the same format with a speaker asked to repeat a sequence of digits until either the maximum (three female and three male speakers) and extra information number of eight digits per sequence is reached or until two such as a photo or a map being shown in the background. consecutive incorrectly repeated sequences of same length. In the digit span backwards condition, the same procedure is applied Commercials with the task to repeat the digits backward. The same principle Six commercials were shown to the participants with each video was implemented for the Visual Span using Corsi-block forward being between 25 s and 34 s. All clips were selected from the and backward. One point is given for each correct answer with internet and were originally broadcasted between the 1990s scores ranging from 0 to 12 except for the forward visual span and early 2000s. The content of the commercials pertained to with scores ranging from 0 to 14. groceries of the brands that are still on the market today (beer, flour, rice, chocolate, detergent and grocery retailer). Symbol Span (Wechsler Memory Scale—Fourth Edition, WMS-IV; Wechsler et al., 2012) Recognition Task The Symbol Span subtest of the Wechsler Memory Scale (WMS)- A recognition task with 12 statements was designed for each IV assesses sequential working memory using abstract symbols video to assess the number of correctly retrieved memory content as stimuli. The test requires recognizing previously presented from the respective video. The task for each video was presented symbols in their correct order. The number of symbols gradually immediately after watching the respective video. Six out of increases from one to seven symbols, with each string of symbols 12 statements contained information actually presented in the being presented one after the other. After four consecutive errors, video (signal) whereas the remaining six statements contained the test is terminated. Correctly recalled symbols in their right information that was made up by the investigators to assess sequence are given 2 points, correct symbols in the wrong order the number of erroneous memory items (noise). Out of the are given 1 point, incorrectly recalled symbols are given 0 points. six signal statements asking about actually present information, three of them contained original information, and the other three Trail Making Tests A and B (TMT-A and TMT-B; Reitan were negated. There were three possible answer choices: ‘‘Yes’’ and Wolfston, 1985) (the statement is true and directly corresponds to the video), The TMT are tests to assess visual attention and mental flexibility ‘‘No’’ (the statement is true, but negated), and ‘‘Unknown’’ (the and requires an examinee to draw pencil lines in ascending order information has not been addressed or shown in the video). from 1 to 25 Trail Making Test A (TMT-A) and 25 encircled Three examples of such statements and the scoring system are numbers and corresponding letters in an alternating order presented in Table 1. In contrast to conventional recognition (TMT-B) that are randomly dispersed on a DIN-A-4 sheet. The memory paradigms that rely on two answer choices (usually ‘‘old discrepancy between the TMT-A and TMT-B (i.e., TMT-B minus item’’ vs. ‘‘new item’’), we have introduced negated statements to TMT-A) is an indicator of deficits in mental flexibility. The diminish older adult’s reliance on gist (Schacter et al., 1997; Tun instructions require working as fast as possible while maintaining et al., 1998; Dennis et al., 2007) by encouraging a more conscious maximum accuracy. decision making process, which has been reported to reduce Fluency Tasks (Regensburg Verbal Fluency Test, RWT; the number of false alarms in older adults (Multhaup, 1995; Aschenbrenner et al., 2000) Grady and Craik, 2000). The original German questionnaires RWT assesses semantic and phonetic verbal fluency. An administered to the patients together with the links to the videos examinee is instructed to generate as many words as possible used in the study are available from the corresponding author in 1 min that belong to the category ‘‘animals’’ (semantic verbal upon request. fluency) as well as words starting with the letters ‘‘P’’ and ‘‘S’’ At the end of the experimental part, participants were asked (phonemic fluency). to evaluate subjective feeling of difficulty of the questions on a 5-point Likert scale with ‘‘1’’ being very easy and ‘‘5’’ being very Experimental Paradigms difficult as well as to give a subjective estimate of how many News and commercials were used as a memory task representing questions they answered correctly and how many questions were the daily memory processes. To assess the relevance of this task all non-answerable. participants were asked whether or not they regularly watch news and commercials. Fourteen and 20 of YA and OA respectively, Procedure regularly watch news programmes. Likewise, seven YA and Each participant completed a neuropsychological assessment six OA reported to watch commercials. prior to the experimental task. Before proceeding to the

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TABLE 1 | Scoring matrix for hits and false alarms used in the primary analysis.

Answer choices Item type Scene in ﬁlm Statement in questionnaire Yes No Unknown

Original signal The older woman1 offers rice2 The older woman1 offers rice2 to her Hit Miss Miss to her granddaughter3 granddaughter3 1 2 1 2 3 Reversed signal Skateboards are popular in Skateboards are unpopular ∗ in Germany Miss Hit Miss Germany3 Noise Not applicable The woman1 wears a blue dress2 while baking3 False alarm False alarm Correct rejection

Superscript numbers mark separate features of a complex statement. ∗Reversed feature of a recognition statement. Bold values mark correct responses. videos, participants were asked whether they watch news and in Germany is just a weak indicator of general intellectual commercials on a daily basis. Participants were then told that abilities due to the broken biographies in the sequels of WWII they will be shown short video clips of six news and six in Germany. Hence, the difference is representative of the commercials, which will be followed a recognition task with official statistics within the German population (Statistisches three answer choices: (1) yes, the statement is true; (2) no, Bundesamt, 2016). However, IQ scores for both groups were the statement is false; and (3) unknown, the information from within a normal range (IQ YA 114.67 ± 9.04; IQ OA the statement was not presented in the video. To illustrate 107.90 ± 10.71). Demographic variables are shown in Table 2. the answer choices participants were given the following Older persons had significantly lower scores for the example: ‘‘Imagine that recognition statement says ‘The apple vocabulary test, the MMSE, and significantly higher scores for the in video was red.’ If you remember seeing a red apple in MADRS. Despite the statistical significance, all scores for both the video, answer ‘yes.’ If you remember seeing a green groups were within a clinically normal range. apple in the video, answer ‘no.’ If you do not remember Older persons performed worse in measures of visual span seeing an apple in the video at all, answer ‘unknown’.’’ After and working memory, executive function (TMT), and most the instruction, participants proceeded to watch video clips. aspects of verbal memory than younger persons (Table 2). No Recognition task for the respective video clip was presented group differences were observed in digit span as well as semantic immediately after the respective video. Answer choices were and phonemic verbal fluency. repeated prior to each recognition task. After watching all videos An overview of the number of times YA and OA answered yes, participants were asked to evaluate the perceived difficulty of no or unknown for each item type (i.e., original signal, reversed the tasks and give an estimate of the number of correctly signal, noise) is presented in Table 3. recognized items (hits) and correctly rejected false statements Before calculating the group differences in recognition, (correct rejections). we compared the subjective difficulty, subjective performance estimate and the news and commercials watching habits Data Analysis between the two groups (Table 4). While potential group All statistical analyses were carried out using the SPSS differences of material relevance between YA and OA were not (SPSS 21.0 for Windows, Chicago, IL, USA, 2012). The directly measured, we measured frequency of watching news normality of distribution of hits and false alarms as well and commercials and subjective difficulty. Our results show as the neuropsychological measures was tested with the 2 that OA watch news significantly more often (χ(1) = 8.039, Kolmogorov-Smirnov Test for each group separately. There p = 0.005) and subjectively perceived questions to the news was a homogeneity of variance between OA and YA for material as significantly easier than YA (YA 3.48 ± 0.81, all the variables except MADRS, TMT-A, CVLT long delay, OA 2.84 ± 0.90; t(38) = 2.343, p = 0.024, effect size CVLT long-delay, CVLT hits, CVLT false alarms and subjective 0.84). Although there was no significant difference in the estimate of hits in commercials as assessed by Levene’s Test frequency of watching advertisements between the two groups for Equality of Variances. In case of unequal variances, degrees 2 (χ(1) = 0.053, p = 0.819), OA perceived the questions of freedom were adjusted. Group comparisons were calculated accompanying the advertisement videos as being significantly using t-test, correlations using Pearson’s correlation coefficient. harder (YA 2.71 ± 0.72, OA 3.26 ± 0.87; t(38) = −2.183, p = 0.035, Other statistical procedures were used as indicated. Apart from effect size 0.69). comparing raw scores, the number of hits and false alarms was To control for the effect of commercials watching habits used to calculate the discriminability (d’) and bias (C) according on the recognition outcome, we conducted a 2 (YA vs. to Signal Detection theory (Stanislaw and Todorov, 1999). Effect OA) × 2 (watching commercials vs. not watching commercials) sizes were calculated using Cohen’s d. ANOVA with hits in commercials recognition task as a dependent variable. There was no significant interaction RESULTS between the effects of age and commercials watching habits, F(1,37) = 0.345, p = 0.561. There was a significant main effect There was a significant difference in the years of formal education of age group F(1,37) = 8.619, p = 0.006; however not of among participants (YA 14.19 ± 2.14; OA 11.35 ± 2.60; the commercials watching habits F(1,37) = 0.526, p = 0.473. t(39) = 3.830, p < 0.001). However, education in older persons The same procedure was repeated with false alarms for

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TABLE 2 | Demographic and neuropsychological variables of young adults (YA) and older adults (OA).

YA (n = 21) OA (n = 20) M ± SD M ± SD t p Cohen’s d

Age 26.90 3.55 69.80 5.85 28.235 <0.001 8.87 ± ± − MADRS 0.71 1.35 2.55 2.72 2.715 0.011 0.86 ± ± − MMSE 30 0.00 29.65 0.67 2.333 0.031 0.74 ± ± WST 35.10 2.51 32.80 3.55 2.401 0.021 0.75 ± ± DS forward 9.62 1.53 8.70 1.69 1.826 0.075 0.57 ± ± DS backward 8.43 2.01 7.00 2.45 2.044 0.048 0.64 ± ± VS forward 10.14 2.24 7.00 1.69 5.053 <0.001 1.58 ± ± VS backward 9.38 1.75 6.40 1.98 5.114 <0.001 1.59 ± ± Symbol test 27.95 9.43 17.95 8.36 3.586 0.001 1.12 ± ± TMT_A 19.86 5.57 41.55 11.56 7.594 <0.001 2.39 ± ± − TMT_B 47.57 15.33 93.45 30.36 6.152 <0.001 1.91 ± ± − TMT (B—A) 27.71 13.56 51.90 27.34 3.616 <0.001 1.12 ± ± − Semantic fluency 23.43 4.90 24.50 5.74 0.644 0.523 0.20 ± ± − Phonemic fluency “P” 12.43 4.35 11.30 3.39 0.923 0.362 0.29 ± ± Phonemic fluency “S” 16.05 4.31 14.45 3.76 1.262 0.214 0.40 ± ± CVLT_1 7.38 1.69 5.10 2.05 3.899 <0.001 1.21 ± ± CVLT_5 14.95 1.43 12.70 2.20 3.902 <0.001 1.21 ± ± CVLT_1_5 60.62 8.75 47.35 8.88 4.819 <0.001 1.50 ± ± CVLT_long_delay 14.14 1.93 10.80 2.84 4.387 <0.001 1.38 ± ± CVLT_hits 15.90 0.30 15.55 0.76 1.949 0.063 0.61 ± ± CVLT FA 0.10 0.44 0.70 1.49 1.745 0.095 0.55 ± ± − Legend: CVLT, California Verbal Learning Test; DS, Digit Span; FA, false alarms; MADRS, Montgomery-Asberg-Depression-Rating-Scale; MMSE, Mini Mental State Examination; OA, older adults; TMT, Trail Making Test; VS, Visual Span; WST, vocabulary test (ger. Wortschatztest); YA, young adults.

TABLE 3 | Means and Standard Deviations (M SD) for the number of responses given to each type of item. ± Given answer Yes No Unknown Video Type Item Type YA OA YA OA YA OA

News Original signal (18 items) 14.52 ± 1.57 13.40 ± 2.46 1.52 1.40 2.40 1.35 0.90 0.89 1.15 1.60 ± ± ± ± Reversed signal (18 items) 3.48 1.60 4.05 2.01 13.86 ± 1.62 12.95 ± 1.57 1.43 1.29 1.45 1.76 ± ± ± ± Noise (36 items) 3.71 1.93 5.90 2.75 8.62 4.31 8.70 5.13 23.38 ± 4.44 20.90 ± 6.32 ± ± ± ± Commercials Original signal (18 items) 15.52 ± 1.78 14.35 ± 2.43 1.95 1.63 2.35 1.63 0.52 0.75 1.10 1.65 ± ± ± ± Reversed signal (18 items) 2.52 1.40 3.30 2.11 13.95 ± 1.75 11.80 ± 2.69 1.38 1.12 2.50 2.65 ± ± ± ± Noise (36 items) 4.76 3.79 4.45 2.28 6.05 3.01 7.35 4.57 24.57 ± 5.35 23.45 ± 5.04 ± ± ± ± Legend: OA, older adults; YA, young adults. Bold values mark correct responses.

TABLE 4 | Hits and false alarms on watching news and commercials in young adults (YA) and older adults (OA).

YA (n = 21) OA (n = 20) M ± SD M ± SD t p Cohen’s d

News Hits1 28.38 2.27 26.40 3.07 2.359 0.023 0.73 ± ± FA2 12.33 4.45 14.55 6.22 1.317 0.195 0.41 ± ± − Subjective Difficulty3 3.48 0.81 2.84 0.90 2.343 0.024 0.75 ± ± Hits subjective4 43.71 11.80 43.56 13.47 0.035 0.972 0.01 ± ± FA subjective4 20.29 8.09 19.17 6.99 0.419 0.678 0.15 ± ± Commercials Hits1 29.33 2.82 26.10 3.24 3.413 0.002 1.06 ± ± FA2 10.76 4.88 11.85 4.64 0.731 0.469 0.23 ± ± − Subjective Difficulty3 2.71 0.72 3.26 0.87 2.183 0.035 0.69 ± ± − Hits subjective4 48.50 10.43 39.61 18.05 1.748 0.091 0.60 ± ± FA subjective4 21.14 8.38 18.17 8.32 1.001 0.325 0.36 ± ± Legend: FA, false alarms; OA, older adults; YA, young adults. 1Hits as a sum of correct answers to original and reversed statements (see Table 1), total of 36 items; 2Total of 36 items; 3Difficulty measured on a 5-Point Likert Scale; 4Participants’ subjective estimates of the number of correct responses (hits and correct rejections) and false alarms out of 72 items. commercials as a dependent variable. There was no significant (F(1,37) = 0.377, p = 0.543) on false alarms. As all of the interaction between age and commercials watching habits participants claimed to watch news regularly, our data did not F(1,37) = 0.325, p = 0.572 and no significant main effect of allow us to look into the same effects for news; however, we either age (F(1,37) = 0.192, p = 0.664) or watching habits assume that the influence of news and commercials watching

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TABLE 5 | Scoring matrix for hits and false alarms used in the secondary analysis without the reversed signal items.

Answer choices Item type Scene in ﬁlm Statement in questionnaire Yes No Unknown

Original signal The older woman1 offers rice2 The older woman1 offers rice2 to her Hit Miss Miss to her granddaughter3 granddaughter3 Noise Not applicable The woman1 wears a blue dress2 while baking3 False alarm False alarm Correct rejection

Superscript numbers mark separate features of a complex statement. Bold values mark correct responses.

TABLE 6 | Scoring matrix for hits and false alarms used to assess sensitivity to gist signal.

Answer choices Item type Scene in ﬁlm Statement in questionnaire Yes No Unknown

1 2 1 2 3 Gist signal Skateboards are popular in Skateboards are unpopular ∗ in Germany Hit Miss Miss Germany3 Noise Not applicable The woman1 wears a blue dress2 while baking3 False alarm False alarm Correct rejection

Superscript numbers mark separate features of a complex statement. ∗Reversed feature of a recognition statement. Bold values mark correct responses. habits on recognition memory works similarly in news as memory mistakes as a result of similarity to signal items or in commercials. gist memory. An overview of subjective and objective hits, false alarms is According to this modification of signal detection theory we presented in Table 4. Subjective estimation of number of hits first compared discriminability and bias measures between the and correct rejections was comparable in YA and OA. YA had YA and OA using yes answers to original signal items (hits) to significantly more hits in the videos than OA in both, news and the sum of yes and no answers to noise items (false alarms) to commercials. In contrast, the number of false alarms was similar evaluate a baseline false alarm rate. This analysis omitted hits in OA and YA. to reversed items. The alternative scoring system is displayed in Analysis of discriminability has revealed a significant Table 5. There were no significant differences for the number difference in d0 between YA (1.26 ± 0.46) and OA (0.89 ± 0.55), of hits to original signal items between the groups (news: YA t(39) = 2.339, p = 0.025 (effect size 0.73) in news and commercials 14.52 ± 1.57, OA 13.40 ± 2.46, effect size 0.54, t(39) = 1.754, recognition task, t(39) = 2.821, p = 0.007 (YA 1.49 ± 0.46; OA p = 0.087; commercials: YA 15.52 ± 1.78, OA 14.35 ± 2.43, 1.08 ± 0.48; effect size 0.87). effect size 0.55, t(39) = 1.770, p = 0.085). There was a significant Both OA and YA displayed a liberal answering strategy difference in discriminability for news (YA 1.56 ± 0.57, OA with mean C values being below zero for both groups in 1.13 ± 0.56, effect size 0.65, t(39) = 2.465, p = 0.018) but not for news (YA −0.19 ± 0.21; OA −0.20 ± 0.30, effect size 0.04) commercials (YA 1.75 ± 0.59, OA 1.41 ± 0.74, effect size 0.73, and in commercials (YA −0.19 ± 0.26; OA −0.07 ± 0.21, t(39) = 1.624, p = 0.112). There were no differences in bias (news: effect size 0.50). The groups showed no differences in bias, YA −0.35 ± 0.29, OA −0.32 ± 0.42, effect size 0.08, t(39) = 2.465, t(39) = 0.086, p = 0.932 and t(39) = −1.505, p = 0.140 for news p = 0.018; commercials: YA −0.31 ± 0.30, OA −0.24 ± 0.28, and commercials, respectively. effect size 0.24, t(39) = −0.834, p = 0.409). Contrary to our hypothesis, OA and YA had a similar amount Similarly, we next compared discriminability and bias using of false alarms in both paradigms. However, in line with the yes answers to reversed signal items (hits for gist signal) and literature (e.g., Fraundorf et al., 2019), OA had significantly false alarms to assess gist memory. This analysis omits the fewer hits and inferior discriminability in both news and original signal items. The scoring system designed to measure commercials paradigm. the strength of the gist signal is displayed in Table 6. There As our paradigm represents a modified use of a signal were no significant differences in the hits to gist signal between detection theory by incorporating reversed signal items, we OA and YA (news: YA 3.52 ± 1.54, OA 4.35 ± 1.81, effect size wanted to rule out gist influence on older adults and ran an 0.49, t(39) = −1.576, p = 0.123, commercials: YA 2.48 ± 1.44, alternative analysis by dividing the signal items into original OA 3.35 ± 1.95, effect size 0.50, t(39) = −1.637, p = 0.110). statements and reversed statements. Koutstaal and Schacter There were also no group differences in either discriminability (1997) and Schacter et al.(1999) described a procedure in which (news: YA −0.49 ± 0.38, OA −0.47 ± 0.48, effect size 0.05, in addition to classical signal detection theory (comparison t(39) = −0.181, p = 0.858; commercials: YA −0.59 ± 0.65, of signal vs. noise) noise items are compared to items OA −0.51 ± 0.58, effect size 0.13, t(39) = −0.427, p = 0.671) strongly related to original signal items. This procedure was or bias (news: YA 0.68 ± 0.31, OA 0.48 ± 0.36, effect size developed to assess false recognition of lure items conceptually, 0.60, t(39) = 1.896, p = 0.065; commercials: YA 0.86 ± 0.23, perceptually, or semantically related to studied items and OA 0.72 ± 0.30, effect size 0.52, t(39) = 1.624, p = 0.112) aims to draw a distinction between baseline false alarms and for gist memory.

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DISCUSSION did not differ in younger and older persons. None of the deficits in older adults were clinically indicative of pathology. It is generally acknowledged that memory performance decreases This significantly reduces the possibility that the failure to with age. Research on age-associated memory deficits explored demonstrate age-related increase in false alarms was due different aspects of both recall and recognition. The majority of to unusually high cognitive performance in this sample of the paradigms in such studies employed stimuli that are only older adults. indirectly related to everyday life. The present study employed The present study supports earlier findings of aging-related a type of stimuli that younger and older adults encounter on a decrease in hits, however, it contradicts reports on age-associated daily basis. Participants were shown news and commercials and increase in false alarms (Seamon et al., 2002; Dennis et al., subsequently performed a recognition task to assess hits and false 2008; Rosa and Gutchess, 2013; Devitt and Schacter, 2016; Paige alarms for video content. et al., 2016). Out of the three recognition memory theories News and commercials watching habits did not have an described in the introduction, the associative deficit hypothesis effect on the recognition task outcome. Older adults subjectively (Naveh-Benjamin, 2000; Old and Naveh-Benjamin, 2008) offers found news recognition task easier, whereas young adults found a possible explanation for the absence of an increase in false commercials recognition task easier. Despite the differences in alarms among older adults in our study. Chalfonte and Johnson the subjective difficulty, there was no difference between the two (1996) argued that association (binding) of features belonging to groups in the subjective estimate of correct responses. This result the same stimulus enriches memory. Hence, what we remember helps to exclude possible adverse effects due to low performance is not blue and pen but rather blue pen as a single entity. expectations among older adults (Chasteen et al., 2005; Hess and The results of the current study can be interpreted in a Hinson, 2006; Hess et al., 2009). Contrary to our hypothesis, similar way. In order to make a decision about the truthfulness the older adults did not have more false alarms compared of a statement in our paradigm, participants were required not to young adults, despite younger adults scoring significantly only to memorize but also to bind the features together into a better in most of the neuropsychological variables. There was, single entity. In order to correctly accept a correct statement however, a difference in the number of hits, with younger [The older woman1 offers rice2 to a girl3], one needs to have adults performing significantly better in both experimental encoded and bound all three features correctly (square brackets paradigms. After calculating the effect size, we observed that indicate that the features form a single signal). The recognition older adults scored slightly over one half of a standard deviation of some item features is not enough for a hit, as our paradigm worse on news hits and one standard deviation worse on introduces ambiguity, where half of the original items are commercials hits. Signal detection theory supports these results. presented in the negated form. The recognition process for the Discriminability scores for news and commercials in young negated form of the original signal is similar: a composite item adults were significantly higher. Discriminability is a measure [Skateboards1 are popular2 in Germany3] needs to be bound calculated using both hits and false alarms. Group variance of and encoded as a single entity in order to recognize that the hits and group variance of false alarms was comparable. Thus, the statement presented in the recognition task, [Skateboards are observed discriminability difference results from the difference unpopular in Germany], is the negated form of the original in the number of hits. Older and younger adults showed no statement. Any information unit missing or being different differences regarding answering tendencies and both have shown negates the original message signal in a Boolean sense and moderately liberal bias. There have been some reports, that should induce a ‘‘no’’ in recognition of this composite item. response bias might be a stable cognitive trait (Kantner and Since the item is treated as one homogeneous signal it needs to Lindsay, 2012, 2014) and that the decision criterion shifts as be recognized or negated in its entirety. If it is not recognized a function of memory strength, strategy, personality and affect completely, it is missed: remembering only skateboards or (Aminoff et al., 2012). only Germany is not enough for a successful recognition. In As our hypothesis on increased false alarms in older adults contrast, items that present noise without any elements of a was rejected, we could not further pursue the original plan signal, e.g., [The woman1 wears a blue dress2 while baking3] of looking into what neuropsychological variables explain should only be answered with ‘‘unknown,’’ as in the whole differences in false alarms between young and older adults. videos sequence there is no [Woman wearing a blue dress while Nevertheless, the outcomes of neuropsychological assessment baking]. Anything but the response ‘‘unknown’’ represents a are in harmony with age-related cognitive deficits reported false alarm. in the literature (Ardila et al., 2000; Park et al., 2002; In their meta-analysis, Fraundorf et al.(2019) reported that Zahodne et al., 2011; Lipnicki et al., 2013). The present young adults mostly outperform older adults in easy recognition study observed a generally diminished episodic memory tasks but in some instances of more complex recognition tasks, performance in older persons. Differences were observed only older adults performed at least as good as or better than young in the tasks of free recall, and not recognition memory, adults. The authors were not able to identify any variables which most likely represent a ceiling effect in the test’s that would explain preserved memory performance in older sensitivity. Moreover, attention, working memory as well as adults in their meta-analysis. However, this special circumstance some aspects of executive function (as measured by the seems to appear in studies using ecologically valid tasks with Trail Making Test) were diminished. Other measures of complex recognition statements (LaVoie and Malmstrom, 1998; executive function (semantic and phonemic verbal fluency) Matzen and Benjamin, 2013). The present study offers additional

Frontiers in Aging Neuroscience| www.frontiersin.org 8 June 2019 | Volume 11 | Article 153 Sejunaite et al. Everyday Memory in Healthy Aging support to this possibility and is in-line with a repeatedly genuine absence of performance differences between young and documented decrease in binding ability among older adults older adults. (Chalfonte and Johnson, 1996; Naveh-Benjamin, 2000; Old and There are several limitations to the study. First, demographic Naveh-Benjamin, 2008; Fraundorf et al., 2019). While making a variables for general intellectual abilities, overall cognitive score, correct recognition harder due to the binding deficit, complex and assessment of mood were different between young and items might paradoxically offer an advantage to older adults, older persons. The differences were small and all scores in when it comes to correct rejection, because several false features both groups were within normal range and representative of within a noise item make this item more salient and easier to the general population, yet it cannot be excluded that it had identify as noise. an influence on the results. Moreover, the relevance of the After separating original and reversed statements in the information reported in the news clips and the familiarity with subsequent analysis we have found that statistically significant the products mentioned in the commercials was not assessed. difference in hits between the groups has disappeared, however, It was previously reported that factors such as selectivity in the trend has remained. It could be that statistical significance task engagement and perceived emotional goals affect memory was affected by the decrease in items after separating original performance in the older adults (Hess, 2005), thus we cannot and reversed signal items. Alternatively it could be speculated rule out that these differences exist between or within the age that inferior performance of older adults in recognition task for groups. Future paradigms addressing ecologically valid memory reversed statements might result from their reduced cognitive tasks should further explore the effects of familiarity and the processing abilities, as processing of sentential negation requires perceived meaningfulness of the task. additional neural resources of response inhibition to the original affirmative form of the particular item (Tettamanti et al., 2008; CONCLUSION Bartoli et al., 2013; Beltrán et al., 2018). Furthermore, using the same analysis the difference in the discriminability for Decrease in correct recognitions and increase in false alarms commercials disappears. This might indicate slight differences in among older adults has been well documented and explained ‘‘news’’ stimuli compared to ‘‘commercials’’ stimuli, which needs by deficits in feature binding, inhibition and cognitive slowing. to be addressed in future studies. Further studies are needed to The present study demonstrated that age-related increase in false address these issues. alarms is not universal but subject to the complexity of the Calculating susceptibility to gist memory by examining stimuli. An ecologically valid task requiring binding of several discriminability and bias estimates calculated from yes responses features increases the likelihood of a correct rejection. This to reversed signal items showed no group differences. Although demonstrates that while memory is patchy in older persons it is previous studies have reported a greater reliance on gist not distorted for real-life situations. among older adults (e.g., Koutstaal et al., 1999; LaVoie and Faulkner, 2000), the failure to observe it in our study could ETHICS STATEMENT be attributed to several factors. The participants in our study were given detailed information about the items they will be The study received approval of the local ethics committee of the confronted with in the recognition task and what type of Ulm University (Application No. 233/15). All persons gave their answer is appropriate for each item. Such a priori instructions informed consent prior to their participation in the study. and warnings have been shown to decrease memory errors in older adults (Carmichael and Gutchess, 2016). It is also AUTHOR CONTRIBUTIONS possible that the timing of the recognition task has contributed to a decreased reliance on gist. The recognition task in our KS and CL were involved in acquisition of the data, data analysis, study was performed right after seeing the actual material, and drafting and revising the manuscript. KS, CL and MR were which means that the verbatim traces were still robustly involved in designing the study, interpretation of the data, and represented in the participant’s memory and the reliance on drafting and revising the manuscript. All authors approved the gist, which increases with the temporal deterioration of the final version of the manuscript. verbatim traces, was not yet necessary (Abadie and Camos, 2018). It is important to note that despite susceptibility FUNDING to gist signal not providing a statistically significant group difference, it showed a moderate effect size. This suggests This research did not receive any specific grant from funding that this result might reflect a lack of power rather than a agencies in the public, commercial, or not-for-profit sectors.

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Original Paper 2: Everyday false memories in older persons with depressive disorder.

Reference: Sejunaite, K., Lanza, C., & Riepe, M. W. (2018). Everyday false memories in older persons with depressive disorder. Psychiatry Research, 261, 456-463. https://doi.org/10.1016/j.psychres.2018.01.030

Permission to reprint: Reprinted from Psychiatry Research, Vol. 261, Sejunaite, K., Lanza, C., & Riepe, M. W., Everyday false memories in older persons with depressive disorder, 456-463, Copyright 2018, with permission from Elsevier.

Contribution: Development of the study design (hypotheses, methods); data collection, data analysis and interpretation; writing, submitting and revising the manuscript.

Psychiatry Research 261 (2018) 456–463

Contents lists available at ScienceDirect

Psychiatry Research

journal homepage: www.elsevier.com/locate/psychres

Everyday false memories in older persons with depressive disorder T ⁎ Karolina Sejunaite, Claudia Lanza, Matthias W. Riepe

Department of Psychiatry and Psychotherapy II, Mental Health & Old Age Psychiatry, Ulm University, Ulm, Germany

ARTICLE INFO ABSTRACT

Keywords: Generally we tend to think that memory in daily living is complete and accurate in healthy persons. However, Episodic memory current memory research has revealed inconspicuous memory faults. Rarely omissions and distortions of Working memory memory are researched with tasks resembling everyday life. We investigated healthy older control subjects (HC) Executive function and patients with depressive disorder (DD). Cognitive function was assessed with a comprehensive neu- Depressive disorder ropsychological test battery and mood with the Montgomery-Asberg Depression Scale (MADRS). We assessed everyday veridical and distorted memories on showing participants original news and commercials. In most aspects of attention, executive functions, and memory, patients with DD performed worse than HC. Regarding memory content on viewing news or commercials the diﬀerence between patients with DD and HC was more pronounced for false memory content than for veridical memory content. Linear regression analysis showed the extent of false memory content being associated with mental ﬂexibility as assessed with the Trail Making Test and mood as assessed with the MADRS for both information obtained on viewing news and commercials. Increase of false memories impedes overall accuracy of memory more than decrease of veridical memories in older persons with depressive disorder. Diminished executive functions and depressive mood partly explain these memory distortions.

1. Introduction Impairment of memory and other cognitive functions in depressive disorder just recently have come under more scrutiny (Porter et al., A slight decline of memory performance with aging is observed in 2003; Lee et al., 2012; Lim et al., 2013; Papakostas, 2014). Executive situations demanding high levels of attention and controlled processing function, which also acts as a mediator between neuropsychological (Buckner, 2004). Healthy older subjects do not report decline of domains and daily functioning (O’Bryant et al., 2011) was reported to memory in everyday life although a slight memory decline is observed be a core area of cognitive dysfunction in depression (Sheline et al., on objective assessment. Patients with depressive disorder (DD), how- 2006). Impaired executive functions bring about memory deficits in ever, frequently complain about memory impairment (O'Boyle et al., patients with depressive disorder (Fossati et al., 2002) and affect 1990; Fischer, 1996) sometimes culminating in a syndrome formerly memory processes at encoding, learning phase and retrieval (Elderkin- named “depressive pseudodementia” (Nussbaum, 1994; Zapotoczky, Thompson et al., 2007; Taconnat et al., 2010). Deficits in executive 1998). Self-perceived cognitive dysfunction in patients with DD is as- functions in patients with depressive disorder were interpreted as being sociated with severity of depressive mood rather than objective cogni- suggestive of functional impairment of the frontal lobes (Elderkin- tive dysfunction (Lovera et al., 2006). Thompson et al., 2011). Moreover, patients with DD have been reported Different profiles of cognitive impairment have been reported for to have smaller hippocampal volumes or diminished hippocampal re- young persons with depressive disorder. One cluster of patients has cruitment (Bremner et al., 2000)(Sheline et al., 1996; Steffens et al., predominantly memory deficits, another cluster has impaired mental 2000; Gron et al., 2002; Janssen et al., 2004). Impaired hippocampal flexibility, and yet another cluster has impaired attention and memory function was reported to be one further cause for inferior memory (Hermens et al., 2011). Data on similar profiles in older persons with performance in patients with depressive disorder (Young et al., 2011; DD are missing. Cognitive deficits in depressed patients may partly Turner et al., 2012). result from motivational shortcomings (Scheurich et al., 2008) and Investigation of memory impairment has focused overwhelmingly contextual factors not necessarily caused by the depressive syndrome on memory omissions, i.e. false negatives. Memory omissions result per se (Lee et al., 2009). However, it is unlikely that cognitive deficits in from a failure to recall or recognize information, which subjects have depressive disorder are solely explained by these non-cognitive factors. been exposed to in everyday life or under laboratory conditions. Errors

⁎ Correspondence to: Division of Mental Health & Old Age Psychiatry, Psychiatry II, Ulm University, Ludwig-Heilmeyer-Strasse 2, D− 89312 Günzburg, Germany. E-mail addresses: [email protected] (K. Sejunaite), [email protected] (C. Lanza), [email protected] (M.W. Riepe). https://doi.org/10.1016/j.psychres.2018.01.030 Received 19 June 2017; Received in revised form 12 January 2018; Accepted 14 January 2018 0165-1781/ © 2018 Elsevier B.V. All rights reserved. K. Sejunaite et al. Psychiatry Research 261 (2018) 456–463 of omission make memory incomplete. Beyond incompleteness of distortions were assessed with a task occurring in day-to-day life of memory other imperfections of memory such as errors of commission most adults – learning and recalling information from news videos and have been described (Schacter, 1999). Errors of commission distort commercials. memory content. Distortions of memory are a by-product of normal memory pro- 2. Methods cesses (Schacter, 1999) and have been loosely described as a failure to distinguish between perceived and internally generated information The present study was designed as an open-label, non-randomized, (Johnson and Raye, 1998). Previous research has broadly categorised cross-sectional, mono-centric study. The study received approval of the them as inability to separate information from pre-existing general ethics committee of Ulm University (233/15) and was done in ac- beliefs (bias), an unconscious fusion of information sources (mis- cordance with the ethical standards of the University of Ulm and the attribution), or errors due to external suggestions (suggestibility) guidelines outlined in the declaration of Helsinki. All persons gave their (Schacter, 1999). Theoretical frameworks used to explain false mem- informed consent prior to their participation in the study. ories suggest the influence of gist at encoding (Kim and Cabeza, 2007; Brainerd et al., 2008) and retroactive interference at consolidation 2.1. Participants (Wright and Loftus, 1998). The Source Monitoring Framework posits that false memories are formed at retrieval due to impaired monitoring The study sample comprised 23 healthy older controls (HC; 11 process, when external information is misattributed to the actual ex- males, 12 females) and 24 older patients with DD (12 males, 12 fe- perience on grounds of vividness or familiarity (Johnson et al., 1993; males). There is no universally accepted definition of old age. We have Mitchell and Johnson, 2009). According to this theory external stimuli defined “older adults” as being at least 60 years old. Sixteen and 18 of fi activate not only the speci c memory trace but also comparable and DD and HC, respectively, had at least 10 years of schooling. Four DD context related traces, and the executive system fails to discriminate patients and 2 HC received at least 13 years of schooling, with the re- between the two sources (McDonough and Gallo, 2008; Straube, 2012). maining 2 DD and 5 HC having a university degree with over 13 years Viewed from a neurobiological perspective, memory distortions can of schooling. There was no education difference between the groups further be explained by brain lesions, e.g. damage to the medial tem- (χ(2) = 2.050, p = .359). Healthy controls were volunteers recruited poral or frontal lobe. The prior impairs distinction of veridical from by local advertisements to take part in a study on memory and aging. false memory content (Cabeza et al., 2001) (Cabeza 2001 #21953) on Patients with DD were recruited from the Old Age Psychiatry from typical or comparable events (Chan and McDermott, 2007). The Department of Ulm University. Patients received a comprehensive processes mediated by the medial temporal and frontal lobe work sy- workup including analysis of medical history, neurological and psy- nergistically (Budson et al., 2002). Healthy older persons, who perform chiatric clinical findings and assessment of laboratory parameters. high on frontal lobe tests, have similar number of correct and false Neurodegenerative disorders, mental retardation, addictive behavior ff recognitions as younger persons in list learning paradigms (Beinho and other comorbid psychiatric disorders were ruled out; the Mini et al., 2008). Mental State Examination score needed to be > 24. However, patients The most widely used approach to investigate false memories in with DD on average had 5.2 ± 4.5 (mean ± SD) typical geriatric di- young and elderly subjects is the Deese, Roediger and McDermott task agnoses such as hypertension, diabetes mellitus, and musculo-skeletal (Jacoby, 1999; Hester et al., 2004). This test assesses false memories on conditions in addition to the depressive disorder and on average were learning and recall of semantic similarities of word lists. However, it treated for these conditions with 7.5 ± 4.6 (mean ± SD) drugs. All has been discussed whether a list learning paradigm indeed has eco- patients met criteria of mild, moderate, or severe depressive episode fl logical validity and can accurately re ect memory distortions in ev- according to the 10th version of the international statistical classifica- eryday life situations (Freyd and Gleaves, 1996; Pezdek and Lam, 2007; tion of diseases and related health problems (ICD-10) which was sup- Koriat et al., 2011). Nevertheless, such laboratory experiments have ported by self-report, third-parties report and MADRS (objective-report, high internal validity and have laid grounds to understanding of the Table 1). Considering the frequency of comorbid conditions in old age basic processes that also play their role in more complex ecologically and often insufficient documentation for determining the number of relevant materials (Wade et al., 2007). Whereas the selection of para- depressive episodes we diagnosed the depressive mood state phenoty- digms and theories of false memories is broad, the paradigms assessing pically without either organic exclusions or diagnostic hierarchy rules false memories in patients with depressive disorder focus on analysing (Kessler et al.) such that the group comprised patients with both first learning and recall in by experimentally manipulating the emotional time ever (n = 12) and recurrent depressive episode (n = 12). salience of the stimuli (Moritz et al., 2008; Joormann et al., 2009; Yeh Demographic variables are presented in Table 1. and Hua, 2009; Howe and Malone, 2011; Bookbinder and Brainerd, 2016). 2.2. Neuropsychological assessments Given the abundance of context information, distortions of memory content are almost inevitable in everyday life among (Kopelman, 1999). 2.2.1. Clinical scales The presence of false memories has been demonstrated in paradigms 2.2.1.1. Mini-Mental Status Examination (MMSE) (Folstein et al., with relevance to everyday life such as memory for domestic cata- 1975). The MMSE is a widely used instrument to give on overview strophes (Budson et al., 2004) or other political events (Frenda et al.,

2013), memory for graphic illustrations of everyday scenes (Miller and Table 1 Gazzaniga, 1998) or autobiographical events (Fernandes et al., 2008; Demographic variables of healthy controls (HC; n = 23) and patients with depressive McDonough and Gallo, 2013; Devitt et al., 2016), or eyewitness re- disorder (DD; n = 24). collections (Loftus et al., 1978; Dodson and Krueger, 2006; Dodson et al., 2015; Aizpurua et al., 2011; Memon et al., 2003). None of these HC DD studies, however, assessed false memories in older patients with de- Mean SD Mean SD tp pressive disorder. It was the goal of the present study to assess false memories in ev- Age 69.74 6.46 69.33 5.75 0.228 0.821 − eryday task in older patients with depressive disorder. We hypothesized MADRS 2.57 2.57 23.42 9.92 9.953 < 0.001 MMSE 29.70 0.64 28.67 1.58 2.953 < 0.001 that basal cognitive impairments associated with depressive disorder, e.g. impairment of executive function, explain the extent of false Legend: HC = healthy controls; MADRS = Montgomery and Asberg Depression-Rating- memories even in complex everyday tasks. To investigate this, memory Scale; DD = depressive disorder; MMSE = Mini Mental State Examination.

457 K. Sejunaite et al. Psychiatry Research 261 (2018) 456–463 over global cognitive functioning. It comprises questions on orientation, forward and backward for healthy older persons are about 25–50 and registration, short-term memory, language use, comprehension, and 50–110 respectively (Gron et al., 2002; Widmann et al., 2012). basic motor skills. The score ranges from 0 to 30, with a score below 24 indicating a cognitive impairment. 2.2.2.5. Fluency Tasks (Regensburg Verbal Fluency Test; RWT) (Aschenbrenner et al., 2000). RWT assesses semantic and phonetic 2.2.1.2. Montgomery and Asberg Depression-Rating- Scale (MADRS) verbal fluency. An examinee is instructed to generate as many words (Montgomery and Asberg, 1989). The score in the MADRS reflects the as possible in one minute that belong to the category “animals” affective state of the examinee as assessed by a health care professional (semantic verbal fluency) as well as words starting with the letters and consists of 10 aspects to be evaluated: apparent sadness, “P” and “S” (phonemic fluency). Mean scores for semantic fluency and communicated sadness, inner tension, sleep, appetite, concentration, phonetic are about 18–28 (Riepe et al., 2010) and 6–8, respectively impetus, callousness, pessimistic thoughts and suicidal ideation. Each of (Gron et al., 2002; Widmann et al., 2012). the aspects is given a score from 0 to 6 according to its severity. The total score ranges from 0 to 60. Scores 0–8 indicate no depression, 8–16 2.3. Experimental paradigms a mild, 16–24 a moderate, and 24 and higher a severe depression. As a task relating to everyday life, news and commercials were used. 2.2.2. Specific neuropsychological tests The participants were told they would be shown a selection of 6 old 2.2.2.1. California Verbal Learning Test (CVLT) (Niemann et al., news and 6 old commercials, each lasting for an average of 30 s. They 2008). The CVLT is a verbal memory test, assessing variables such as were instructed to watch the video attentively and immediately after immediate recall, free and cued recall after short delay, free and cued each video they were asked to evaluate 12 statements about the video recall after long delay as well as recognition. A list of 16 words (four they had just seen based on their truthfulness and to select one of the words of each category: fruit, clothing, drinks, tools) is read to the three possible answer choices. The answer choices were repeated for participant a total of five times. After each round the participant is each participant after each video. encouraged to recall as many words as possible. Immediate recall is To assess the relevance of this task all participants were asked followed by a free and cued delayed recall after 5 and 20 min intervals whether or not they regularly watch news and commercials. Our results respectively, and a Yes/No recognition task. Depending on age, sex and show that 87% and 83% of HC and patients with DD, respectively, education the score or delayed recall and recognition are about 10 – 15 watch news programmes on a daily basis. There was no significant and 14 – 16, respectively. difference in news watching frequency between the two groups (chi-

squaredf=2 = 0.094). Likewise 26% of HC and 17% of patients with DD 2.2.2.2. Digit and Visual Span (Wechsler Memory Scale Revised, WMS-R) reported to watch commercials (chi-squaredf=2 = 0.329). All selected (Härting et al., 2000). The Digit Span test comprises digit span forward commercials have not been aired in the past years. Likewise, the topics and digit span backward. In the digit span forward the participants are of the news clips have not been discussed recently. Despite participants asked to repeat a sequence of digits until either the maximum number reporting that they less frequently watch commercials on purpose we of eight digits per sequence is reached or until two consecutive still consider this to belong to everyday life since participants are ex- incorrectly repeated sequences of same length. In the digit span posed to commercials on a daily basis in diverse settings (supermarket, backwards condition the same procedure is applied with the task to TV, public transport, and so forth). repeat the digits backward. The same principle was implemented for the Visual Span using Corsi-block forward and backward. One point is 2.3.1. News given for each correct answer with scores ranging from 0 to 12 except Six news videos were shown to the participants with each video for the forward visual span with scores ranging from 0 to 14. Mean being between 27 and 39 s. All videos were selected from the same scores for digit span forward and backward for healthy older persons German news agency (ARD) and were originally broadcasted between are about 7–9 and 6–8 respectively (Gron et al., 2002; Widmann et al., the 1980s and early 1990s. The news topics pertained to domestic af- 2012). Mean scores for digit span forward and backward for healthy fairs (increase of radio/TV licence fee, political discussions on skate- older persons are about 5–8 and 7–9 respectively (Gron et al., 2002; board ban, river pollution, merging of state-run train services, ferryboat Widmann et al., 2012). incident in the Baltic sea, shortage of apprenticeship training positions for the youth). All six videos had the same format with a speaker (three 2.2.2.3. Symbol Span (Wechsler Memory Scale – Fourth Edition, WMS-IV) female and three male speakers) and extra information such as a photo (Wechsler et al., 2012). The Symbol Span subtest of the WMS-IV or a map being shown in the background. assesses sequential working memory using abstract symbols as stimuli. The test requires recognizing previously presented symbols in 2.3.2. Commercials their correct order. The number of symbols gradually increases from Six commercials were shown to the participants with each video one to seven symbols, with each string of symbols being presented one being between 25 and 34 s. All clips were selected from the internet and after the other. After four consecutive errors the test is terminated. were originally broadcasted between the 1990s and early 2000s. The Correctly recalled symbols in their right sequence are given 2 points, content of the commercials pertained to groceries of the famous brands correct symbols in the wrong order are given 1 point, incorrectly that are still in the market today (beer, flour, rice, chocolate, detergent, recalled symbols are given 0 points. Normal scores are within the range grocery retailer). of around 12–18. 2.3.3. Questionnaires 2.2.2.4. Trail Making Tests A & B (TMT-A & TMT-B (Reitan and Wolfston, A questionnaire with twelve questions was designed for each video 1985). The TMT are tests to assess visual attention and mental to assess the amount of correctly retrieved facts from the respective flexibility and requires an examinee to draw pencil lines in ascending video. Six out of twelve questions could be answered from the in- order from 1 to 25 (TMT-A) and 25 encircled numbers and formation presented in the video whereas the remaining six questions corresponding letters in an alternating order (TMT-B) that are asked about details that were made up by the investigators to assess the randomly dispersed on a DIN-A-4 sheet. The discrepancy between the number of erroneous memory items. All questions were in a form of a TMT-A and TMT-B (i.e. TMT-B minus TMT-A) is an indicator of deficits statement and needed to be answered giving one of the three possible in mental flexibility. The instructions require working as fast as possible answer choices: “Yes” (the statement is true), “No” (the statement is while maintaining maximum accuracy. Mean scores for digit span false), and “Unknown” (the information has not been addressed or

458 K. Sejunaite et al. Psychiatry Research 261 (2018) 456–463 shown in the video). The total number of correct “Yes” and “No” re- Table 3 sponses was counted to give the total score of hits. Questions for which True and false memories on watching news and commercials in healthy controls (HC, n = the correct answer would have been “Unknown” but for which the 23) and patients with DD (n = 24). “ ” “ ” participant answered with Yes or No were counted as the total score HC DD of false positives. At the end of the experimental part participants were asked to MSDMSDtp evaluate subjective feeling of difficulty of the questions on a 5-point “ ” “ ” ffi News Likert scale with 1 being very easy and 5 being very di cult. Hits 26.61 2.92 24.96 3.32 1.808 0.077 FP 13.39 6.56 23.08 7.48 − 4.715 0.000 subjective difficulty 2.84 0.90 3.00 0.76 − 0.611 0.545 2.4. Data analysis Commercials Hits 26.10 3.24 23.63 3.81 2.294 0.027 FP 11.85 4.64 19.21 8.05 − 3.786 0.001 All statistical analyses were carried out using the SPSS (SPSS 21.0 subjective difficulty 3.26 0.83 3.05 1.17 0.665 0.510 for Windows, Chicago, Ill., 2012). The normality of distribution was tested with the Kolmogorov-Smirnov Test. Group comparisons were Legend: FP = false positives; HC = healthy controls; DD = depressive disorder. calculated using a student's t-test. To investigate underlying mechanisms of false memories we performed a stepwise regression analysis 3.3. Factors explaining the variance of false memories in HC and patients using basic neuropsychological variables (verbal memory, verbal flu- with DD ency, executive function, working memory and mood) as regressors. The diagnostic value of the false memories in everyday life paradigm A linear regression analysis was performed with long delay in the was further evaluated using ROC analysis. CVLT as a marker of memory consolidation, category and letter fluency as a markers for lexical access speed and executive function, and discrepancy between TMT-B and TMT-A as a marker of shifting and in- 3. Results hibition components of executive function, the symbol test score as a marker of visual working memory, the MADRS score, and the true 3.1. Neuropsychological assessment memories recalled from news and commercials, respectively (Table 4). False memories in the news task were partly explained by phonematic Digit span (t(45) = 1.357, p = 0.182) and memory supraspan (t(45) fluency “S” and MADRS score (R2 = 0.258). The number of false = 1.592, p = 0.118) were similar in HC and patients with DD. In all memories in the news increased with a lower score in phonemic fluency other variables patients with DD scored lower than HC (Table 2). and a higher score on a depression scale. Similarly, false memories in the task with watching the commercials was partly explained by difference between Trail Making Test B minus 3.2. False memories Trail Making Test A and MADRS score (R2 = 0.248). The number of false memories in commercials increased with a lower mental flexibility True memories for information memorized while watching news which is a component executive function, and a higher score on a de- segments was alike in HC and patients with DD (t(45) = 1.808, p = pression scale. In contrast, false memories in the CVLT recognition task 0.077). However, the number of false memories was larger for patients were explained by the number of items in long delay recall in the CVLT with DD than HC (t(45) = − 4.715, p < 0.000). In contrast, patients (R2 = 0.264). with DD had fewer true memories (t(42) = 2.294, p = 0.027) and more false memories (t(42) = − 3.613, p = 0.001) than HC on watching the 3.4. False memories as a diagnostic distinction between HC and patients commercials. There were no differences in the subjective difficulty in with DD either news or commercials (Table 3). ROC curves were calculated for true and false memories from the Table 2 commercials and the news videos. For both news and commercials false Results of neuropsychological testing in healthy controls (HC, n = 23) and patients with memories were a better diagnostic marker than true memories (Fig. 1). depressive disorder (DD, n = 24). Using veridical memories to distinguish between HC and DD the area HC DD under the curve was 0.635 ± 0.084 (mean ± standard error; p < 0.126; 95% confidence interval 0.470 – 0.801) and 0.726 ± 0.080 (mean ± Mean SD Mean SD tp standard error; p = 0.080; 95% confidence interval 0.569 – 0.883) for the news and commercials paradigm, respectively. Using false mem- Digit span forward 8.70 1.69 8.00 1.82 1.357 0.182 Digit span backward 7.35 2.57 5.00 1.91 3.543 0.001 ories to distinguish between HC and DD the area under the curve was Block span forward 7.17 1.80 6.13 1.19 2.345 0.024 0.817 ± 0.069 (mean ± standard error; p < 0.001; 95% confidence Block span backward 6.52 2.00 5.46 1.44 2.099 0.041 interval 0.681 – 0.952) and 0.786 ± 0.070 (mean ± standard error; p Symbol test 17.95 8.36 12.67 6.63 2.339 0.024 = 0.001; 95% confidence interval 0.649 – 0.924) for the news and TMT_A 39.13 12.78 52.33 18.44 − 2.841 0.007 TMT_B 91.48 29.25 136.67 57.00 − 3.440 0.002 commercials paradigm, respectively. TMT_B - TMT_A 52.35 25.61 84.33 47.22 − 2.903 0.006 Semantic fluency 25.00 5.70 19.04 5.06 3.795 0.000 4. Discussion Phonematic fluency "P" 11.48 3.41 8.38 4.10 2.817 0.007 fl Phonematic uency "S" 14.61 3.60 11.04 3.61 3.392 0.001 fi CVLT_1 5.04 2.18 4.17 1.55 1.592 0.118 4.1. Cognitive de cits in depressive disorder CVLT_5 13.13 2.34 10.25 2.79 3.829 0.000 CVLT_1_5 49.04 9.60 38.75 9.10 3.774 0.000 Similar to a previous report in the literature (Xu et al., 2012)we CVLT_long_delay 11.39 3.09 7.63 3.42 3.956 0.000 found attention, as measured by digit span forward, to be alike in CVLT_recognition 15.61 0.72 14.67 1.05 3.569 0.001 healthy (HC) and patients with depressive disorder (DD). Many other CVLT false positive total 0.61 1.41 1.88 1.75 − 2.725 0.009 reports on attention in depressive disorder use digit span backward. Legend: CVLT = California Verbal Learning Test; HC = healthy controls; DD = depres- This measure was reported to distinguish between HC and patients with sive disorder; TMT = Trail Making Test. DD (Lim et al., 2013), which also is found in the present study. Across

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Table 4 Regression analysis for false positives in the News paradigm, Commercials paradigm, and CVLT.

RR2 corrected Regression coeﬃcient B Standard error Beta tp

News false positives Phonematic fluency "S" 0.437 0.172 − 0.694 0.275 − 0.345 − 2.522 0.016 MADRS 0.541 0.258 0.208 0.086 0.332 2.428 0.020 Model including CVLT long delay, semantic fluency, phonematic fluency "P", phonematic fluency "S", TMT B – TMT A, symbol test, MADRS, news true positives

Commercials false positives TMT B – TMT A 0.445 0.179 0.066 0.025 0.367 2.682 0.011 MADRS 0.532 0.248 0.178 0.081 0.302 2.210 0.033 Model including CVLT long delay, semantic fluency, phonematic fluency "P", phonematic fluency "S", TMT B – TMT A, symbol test, MADRS, commercials true positives

CVLT total false positives CVLT long delay 0.513 0.264 − 0.252 0.065 − 0.513 − 3.878 0.000 Model including CVLT long delay, semantic fluency, phonematic fluency "P", phonematic fluency "S", TMT B – TMT A, symbol test, MADRS, CVLT 1–5

Legend: CVLT = California Verbal Learning Test; MADRS = Montgomery and Asberg Depression-Rating- Scale; TMT = Trail Making Test. almost all other cognitive tasks patients with depressive disorder per- relevance. Furthermore, none have been repeatedly discussed in the formed worse than healthy controls. This finding is in good harmony media in the recent years, therefore it can be assumed that news had a with previous reports on cognitive deficits in depressive disorder per- personal relevance to neither the young nor the older participants. On taining to executive functions, working and episodic memory (Gron the other hand, due to positive nature of the advertising, commercials et al., 2002; Porter et al., 2003; Lee et al., 2012; Lim et al., 2013; may have some positive emotional salience. Papakostas, 2014). The impact of mood itself on false memories is less well understood. A recent meta-analysis reports group differences between HC and In the Deese-Roediger-McDermott paradigm the number of false patients with DD for executive functions using category fluency and memories in patients with DD seems to be subject to the emotional phonemic fluency (Lim et al., 2013). Findings on the performance of salience of the stimuli. Patients with DD have been found to be more patients with DD in the Trail Making Test are ambiguous in the lit- likely to falsely recall negative lures, but not positive or neutral lures erature. A recent meta-analysis reported the Trail Making Test B to be (Joormann et al., 2009). In contrast, another study using the DRM re- alike in HC and patients with DD (Lim et al., 2013) but several studies ported that false memories for emotionally charged content are more included in this meta-analysis and recent other studies do find the time frequent in patients with DD than in healthy controls (Moritz et al., to complete the TMT-B to be longer in patients with DD than in HC 2005) regardless of the direction of the emotional salience. In the (Barabassy et al., 2010; Cotrena et al., 2016). present study false memories are more frequent in both the news and There are clear differences between HC and DD groups in the list the commercials paradigm in patients with DD than in HC. A similar learning task. In agreement with previous findings using the auditory result has been found in younger patients with depression (Yeh and Verbal Learning Test we find similar performance for word supraspan in Hua, 2009). It is one limitation of the present study that the individual HC and patients with DD (Thomas et al., 2009). In contrast, the total emotional salience of neither news nor commercials were measured, sum of words memorized during five learning trials and the number of especially since it has been shown that in patients with DD mood alters correctly recalled items in free recall condition is lower in patients with the respective emotional salience of stimuli compared to healthy con- DD, which indicates a proneness to errors of omission in this group. trols (Yeh and Hua, 2009). These findings are in accordance with previous reports on memory performance of older persons with depressive disorder (Gron et al., 4.3. Mechanisms memory impairment in depressive disorder 2002; Lim et al., 2013; Papakostas, 2014; Thomas et al., 2009). The mechanisms of false memories and their neuroanatomical as- 4.2. False memories in controls and patients with depressive disorder sociations remain under discussion. A recent review summarised that a multiplicity of cognitive domains comprising among others working It was the primary goal of the present study to assess whether and episodic memory and executive function and a widespread neu- memory deficits in patients with DD go beyond errors of omission. The roanatomical network comprising among others the medial temporal present results demonstrate that memory in patients with DD is both lobe and the medial and lateral prefrontal cortex are linked to the fragmentary and distorted. In fact, the difference is more pronounced formation of true and false memories (Straube, 2012). for distortions than for omissions. Regression analysis of the data in the present study shows two In the list learning paradigm healthy controls on average named factors to independently contribute to the explanation of memory dis- little less than one false item during recognition task, while patients tortion – executive function and mood. In fact, impaired executive with DD named almost two, mostly words from the interference con- function and mood may be closely linked to one another as it has been dition. Although the difference is statistically significant, it is not in- reported previously that impaired executive function is a core cognitive dicative of a clinically relevant deficit. The low number of false mem- symptom of impaired mood (Rock et al., 2014). Likewise in neuroa- ories may result from the nature of the task – it has been reported natomical terms executive functions have been linked to the integrity of previously that false recognition decreases with repeated presentation the frontal lobes (Duncan and Owen, 2000) and low mood in patients of word lists in young control subjects (Budson et al., 2000) and to a with DD has been found to be suggestive of frontal lobe malfunction somewhat smaller degree in older persons (Budson et al., 2000). (Elderkin-Thompson et al., 2011). Our findings are also in good ac- Memory performance is subject to mood congruence/divergence of cordance with recent results that older control subjects with low frontal stimuli (Wittekind et al., 2014) and it has been recently shown that functioning indicated by impaired executive functions are more sus- patients with depressive disorder have difficulties processing positive ceptible to false memories (Butler et al., 2004). Likewise, previous material (Lemoult et al., 2012). We hypothesize that this is a reason studies have reported that negative mood foments false memory why we observed a difference between HC and patients with DD re- (Moritz et al., 2005, 2008; Yeh and Hua, 2009). garding veridical memory. In the present study all of the news segments Several theoretical frameworks have been used to explain the for- reported about past events and thus had no noteworthy affective mation of false memories at different stages. We hypothesize that the

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Brainerd, 2016). This also partly explains the reduced number of hits among patients with depressive disorder. Secondly, given the abundance of conceptually and semantically related information in everyday life, memory distortions could have been facilitated by reduced executive function and thus impaired source monitoring of already “fuz- zily” encoded memory traces (Johnson et al., 1993; McDonough and Gallo, 2008; Straube, 2012).

4.4. Diagnostic value of false memories

It has been previously reported that age-related increases in false memories are as reliable in discerning patients with Alzheimer's disease from healthy controls as age-related decreases in veridical memories (Ally et al., 2009). In the present study the discernment between healthy controls and subjects with DD was even better on grounds of false memories than on grounds of veridical memories. We interpret the present finding as reflecting a task-specific demand for intact executive (frontal) function that is more pronounced than for established paradigms based on semantic similarity of word lists. While it may not yet be useful for clinical diagnosis of depressive disorder the findings in the present study contribute to a better understanding of impairment of patients with depressive disorder in daily life. The area under the curve for veridical memory is larger for true memories in the commercials paradigm than in the news paradigm. Again, this is in good accordance with the difficulty of depressed patients to process positively charged material like commercials (Lemoult et al., 2012).

4.5. Limitations and future research

When interpreting the results of the study some limitations need to be observed. Firstly, the emotional salience of the videos presented to the participants has not been measured. Despite the attempt to choose emotionally neutral material, the nature of the commercials is more positive and engaging than it is that of the news videos. We have at- tempted to reduce the impact of this limitation by analysing news and commercials separately. Secondly, we did not collect additional information about how much time participants spent watching news or commercials and what where the topics that they perceived as most relevant. The factor or personal interest and extent of familiarity with such a task might have increased the level of attention and aﬀected memory processes. The strength of the present study is that it assesses false memories in older persons and older patients with depressive disorder while most studies on false memories investigate younger persons. A second strength of the study is that the task used to assess distortions of memory occurs in patients’ lives on a daily basis.

5. Conclusion

In summary, patients with depressive disorder not only show incompleteness of memory but also distortions of memory in paradigms resembling day-to-day tasks. The consequences and impact of distortions of memory in patients with depressive disorder need to be addressed in further detail in future studies.

Fig. 1. ROC curves for discerning between healthy controls and patients with DD using Acknowledgements (A) true memories in the News and Commercials paradigm and (B) false memories.

KS and CL were involved in acquisition of the data, data analysis, ﬂ results observed in our study might have been in uenced by two main and drafting and revising the manuscript. KS, CL and MWR were in- processes. Firstly, as outlined by the fuzzy trace theory, the emotional volved in designing the study, interpretation of the data, and drafting context of encoding, impairs memory for the exact verbatim details and and revising the manuscript. All authors approved the ﬁnal version of thus foment false memories by depressed mood (Bookbinder and the manuscript.

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Research Article

Original Paper 3: Everyday Memory in Patients with Alzheimer’s Disease: Fragmentary and Distorted.

Reference: Sejunaite, K., Lanza, C., & Riepe, M. W. (2017). Everyday Memory in Patients with Alzheimer’s Disease: Fragmentary and Distorted. Journal of Alzheimer's Disease, 60(4), 1489-1498.

Permission to reprint: Reprinted from Journal of Alzheimer’s Disease, Vol. No. 60, Sejunaite K. Lanza. C., Riepe, M. W., Everyday Memory in Patients with Alzheimer’s Disease: Fragmentary and Distorted, 1489-1498, Copyright (2017), with permission from IOS Press.

The publication is available at IOS Press through http://dx.doi.org/10.3233/JAD-170493

Contribution: Development of the study design (hypotheses, methods); data collection, data analysis and interpretation; writing, submitting and revising the manuscript.

Everyday memory in patients with Alzheimer’s disease – fragmentary and distorted

Running Title: Everyday false memories in AD

Karolina Sejunaite1, Claudia Lanza1, Matthias W. Riepe1

1 Department of Psychiatry and Psychotherapy II, Mental Health & Old Age Psychiatry, Ulm University, Ulm, Germany

Correspondence: Prof. Matthias W. Riepe, MD Division of Mental Health & Old Age Psychiatry, Psychiatry II, Ulm University Ludwig-Heilmeyer-Strasse 2, D-89312 Günzburg, Germany : +49 8221 96 2355 : +49 8221 96 28125 : [email protected]

Other authors e-mail addresses: KS: [email protected] CL: [email protected]

Abstract Background: Errors of omission are an established hallmark of memory impairment in Alzheimer’s disease (AD). Much less is known about other memory errors in AD such as false memories. Objective: We investigated false memories in healthy elderly controls (HC; n = 23) and patients with AD (n = 20) using real-life tasks of watching news and commercials. Method: Participants received a comprehensive neuropsychological assessment and were shown original news and commercials with a subsequent recognition task to assess veridical and false memories. Results: Subjective estimate of the number of errors were alike in HC and patients with AD. However, memory performance in both the news and the commercials task was significantly worse in patients with AD. Trail-Making Test and Symbol-Span Test were significant predictors of false memories on viewing news and commercials. In patients with AD, levels of Aβ1-42, but not levels of tau-protein were correlated with false memories in both tasks. Conclusions: Everyday life in patients with AD is impeded not due to the incompleteness of memory but also due to its distortions. Furthermore, it is hindered by the lack of awareness towards these deficits. False memory content in patients with AD is associated with Aß42 levels in the CSF as a surrogate of the overall extent to which the brain has been affected by AD pathology. Future studies will need to address the impact of this duality of memory failure on everyday life of patients with AD and their proxies in greater detail.

Keywords: Alzheimer disease, CSF markers, episodic memory, false memories, memory disorders, neuropsychology, everyday life

Introduction Alzheimer’s disease (AD) is characterized by accruing cognitive deficits beginning with a progressive decline of episodic memory and spatial orientation [1]. Until recent years, research on memory deficits in AD has focused on failures to remember and omissions of memory content. However, several other impairments of memory have been researched in other contexts [2]. Among these are errors of commission, i.e. remembering events and details that have never happened or information that was never presented in the context of a memory task – ‘false’ memories or ‘distorted’ memories.

In a broader sense false memories result from a “failure to distinguish between perceived and internally generated information” [3]. False memories have been explained within both a psychological and a biological framework. The fuzzy-trace theory hypothesizes that memorizing events or items generates item-specific information (‘verbatim traces’) and general information about the item that goes beyond the event-specific information and includes other general contextual information (‘gist traces’). It is suggested that gist traces are more robust than verbatim traces and may lead to unintended false memories via proactive interference [4, 5]. Alternatively, incoming post-event information may alter the content of memories via retroactive interference – misinformation theory [6]. The more detailed this new post-even information is, the greater is its misinformation effect. Fuzzy-trace theory and misinformation theory primarily focus on the formation of false memories during encoding and consolidation [7]. A third theory hypothesized that false memories may be formed during retrieval due to an impaired monitoring process [8]. According to this theory external stimuli activate not only the event specific memory trace, but also context-related memory traces, and the executive system fails to discriminate between these memory traces [9], [7].

Neurobiological explanations of false memories focus on the multiplicity of memory systems in the frontal and medial temporal lobes of both hemispheres. Failure of one of these systems or of their connectivity leads to memory distortions [10], [11]. In good harmony with the psychological theories of false memory formation, brain imaging studies have demonstrated specific neural circuits in the frontal and temporal lobes to be the neural substrate of false memory formation for proactive [4] and retroactive interference [12], [13], [14]. In yet another imaging study hippocampal volumes predicted delayed recall and recognition discriminability, whereas frontal volumes were linked to response clustering and answering bias [15].

Research on false memories has been dominated by the Deese-Roediger-McDermott (DRM) procedure [16], [17], which accounts for nearly a half of the paradigms used in the false memory research [18]. This paradigm uses semantic similarity between verbal targets and distractors. Other paradigms in false memory research have used similarity between pictures [19] or congruence of stimuli with personal beliefs and pre-existing attitudes [20]. Aside from similarity paradigms, repeated exposure to manipulated stories [21] or pictures [22], [23], [19], [24], [25] has also been used. Rarely, paradigms relating to everyday life have been employed to investigate false memories [26], [27], [20].

False memories in patients with AD mostly have been studied in paradigms luring patients to falsely report information based on semantic similarities. Patients with AD have been reported to show a greater rate of false memories than healthy controls in both short- and long-term memory, with non-semantic intrusions being particularly prevalent [28]. In various studies false memories ranged from mild provoked confabulations in early stages to elaborated and spontaneous confabulations in advanced stages of the disease. Some of these have demonstrated that patients with AD are more prone to confabulate when they are required to retrieve a personal episode as opposed to a personal plan [29], little gain in memory for words with emotional salience [30], and are unable to use distinctiveness heuristic to reduce false memories [31], [32]. Apart from word and picture learning approaches similar proneness to false memories has been observed in imagination inflation tasks, which required the participants to endorse their own actions in previous experimental phases as true or false [33].

It was the goal of the current study to investigate whether memory failure hallmarking AD extends beyond the well-known errors of omission to distorting errors of commission in patients with very mild AD. Using an ecologically valid task we intended to shed some light on everyday impairment resulting from these deficits.

Methods The present study was designed as an open label, non-randomized, cross-sectional, mono- centric study. The study received approval of the ethics committee of Ulm University (233/15) and was done in accordance with the ethical standards of the Ulm University and the guidelines outlined in the declaration of Helsinki. All participants gave their informed consent prior to participation in the study.

Participants The study sample consisted of two groups – healthy controls (HC) and patients with Alzheimer disease (AD) (Table 1.). AD patients were recruited in the Ulm University hospital during in- or outpatient treatment. HC group consisted of healthy adults recruited by local advertising to partake in a study on memory and aging. Patients received a comprehensive workup including analysis of medical history ruling out CNS disorders including mental retardation and addictive behavior, clinical neurological and psychiatric examination, imaging, and assessment of laboratory parameters. The diagnosis for AD was confirmed through a neuropsychological examination and lumbar puncture or positron emission tomography (PET). All patients met criteria of very mild Alzheimer’s disease according to the 10th version of the international statistical classification of diseases and related health problems (ICD-10). Patients with a MMSE score below 25 were excluded from the study. The demographic variables are shown in Table 1.

Table 1: Demographic variables of study participants HC AD p N 23 20 Gender (male/female) 11/12 9/11 0.857 Age (years: mean ± SD) 69.74 ± 6.46 72.20 ± 5.87 0.201 MMSE (mean ± SD) 29.70 ± 0.64 26.85 ± 1.90 0.000 WST (mean ± SD) 32.00 ± 3.56 29.35 ± 5.80 0.031 Legend: AD = patients with Alzheimer's disease; HC = healthy controls; MMSE = Mini Mental State Examination; WST = Vocabulary Test.

Materials

Neuropsychological test battery Mini Mental State Examination (MMSE) [34] The MMSE is a standard instrument to stage the severity of dementia. It comprises questions on orientation, short-term memory, language use, comprehension, and basic motor skills. The score ranges from 0 - 30.

California Verbal Learning Test (CVLT) [35] The CVLT is a verbal memory test, assessing variables such as immediate recall, free and cued recall after short delay, free and cued recall after long delay as well as recognition. A list of 16 words (four words of each category: fruit, clothing, drinks, tools) is read to the 66 participant a total of five times. After each round the participant is encouraged to recall as many words as possible. Immediate recall is followed by a free and cued delayed recall after 5 and 20 min intervals respectively, and a Yes/No recognition task.

Digit and Visual Span ( Wechsler Memory Scale Revised, WMS-R) [36] The Digit Span test comprises digit span forward and digit span backward. In the digit span forward the participants are asked to repeat a sequence of digits until either the maximum number of eight digits per sequence was reached or until two consecutive incorrectly repeated sequences of same length. In the digit span backwards condition the same procedure is applied with the task to repeat the digits backward. The same principle was implemented for the Visual Span forward and backward. One point is given for each correct answer with scores ranging from 0-12 except for the forward visual span with scores ranging from 0-14.

Symbol Span (Wechsler Memory Scale – Fourth Edition, WMS-IV) [37] The Symbol Span subtest of the WMS-IV assesses sequential working memory using abstract symbols as stimuli. The test requires recognizing previously presented symbols in their correct order. The number of symbols gradually increases from one to seven symbols, with each string of symbols being presented one after the other. After four consecutive errors the test is terminated. Correctly recalled symbols in their right sequence are given 2 points, correct symbols in the wrong order are given 1 point, incorrectly recalled symbols are given 0 points.

Trail Making Tests A & B (TMT-A & TMT-B [38] The TMT tests assess visual attention and mental flexibility and requires an examinee to draw pencil lines in ascending order from 1 to 25 (TMT-A) and 25 encircled numbers and corresponding letters in an alternating order (TMT-B) that are randomly dispersed on a DIN- A-4 sheet. The instructions require working as fast as possible while maintaining maximum accuracy.

Vocabulary Test (WST) [39] In the WST an examinee is asked to mark an actual word among five non-word distractors.

Experimental paradigms As a task relating to everyday life news and commercials were used. To assess the relevance of this task all participants were asked whether or not they regularly watch news and commercials. Our results show that 87% and 80% of HC and AD respectively regularly 67 watch news programmes. There was no significant difference in news watching frequency between the two groups (p = .064). Likewise 26 % of HC group and 20% of AD group reported to watch commercials (p = 0.587).

News Six news videos were shown to the participants with each video being between 27 and 39s. All clips were selected from the same German news agency (ARD) and were originally broadcasted between the 1980s and early 1990s. The news topics pertained to domestic affairs. All six videos had the same format with a speaker (three female and three male speakers) and extra information such as a photo or a map being shown in the background.

Commercials Six commercials were shown to the participants with each video being between 25 and 34 s. All clips were selected from the internet and were originally broadcasted between the 1990s and early 2000s. The content of the commercials pertained to groceries.

Questionnaires A questionnaire with twelve questions was designed for each video to assess the amount of correctly retrieved facts from the respective clip. Six out of twelve questions could be answered from the information presented in the video, whereas the remaining six questions asked about details that were made up by the investigators to assess erroneous memory content. All questions were in a form of a statement and needed to be answered giving one of the three possible answer choices: ‘Yes’ (the statement is true), ‘No’ (the statement is false), and ‘Unknown’ (the information has not been addressed or shown in the video). ‘Don’t know’ responses were not explicitly indicated, but were nevertheless marked if participants used them spontaneously. The questionnaire was administered by the investigator in a form of an interview. At the end of the experimental part participants were asked to evaluate subjective feeling of difficulty of the questions on a 5-point Likert scale with “1” being very easy and “5” being very difficult as well as to give a subjective estimate of how many questions they answered correctly and how many questions were non-answerable.

Data Analysis All statistical analyses were carried out using the SPSS (SPSS 21.0 for Windows, Chicago, Ill., 2012). The normality of distribution was tested with the Kolmogorov-Smirnov Test. Parametric statistical procedures were used throughout the study, unless indicated otherwise.

Results Neuropsychological Assessment The AD group performed significantly worse on all measures of the neuropsychological assessment (Table 2) and memory testing (Table 3) than the HC group.

Table 2: Between group comparisons of performance in standard neuropsychological battery Mean ± SD p HC AD HC vs AD DS forward 8.70 ± 1.69 7.60 ± 1.90 0.052 DS backward 7.35 ± 2.57 4.30 ± 1.59 0.000 VS forward 7.17 ± 1.80 5.75 ± 1.52 0.008 VS backward 6.52 ± 1.99 4.40 ± 2.23 0.002 Symbol Span 17.95 ± 8.36 8.17 ± 5.18 0.000 TMT A 39.13 ± 12.78 80.70 ± 44.91 0.001 TMT B 91.48 ± 29.25 210.30 ± 79.72 0.000 TMT difference 52.35 ± 25.61 129.60 ± 59.62 0.000 Legend: AD = patients with Alzheimer's disease; DS = digit span; HC = healthy controls; RWT = verbal fluency test; TMT = Trail making test; VS = visual span.

Table 3: Between group comparisons of verbal memory performance

Mean ± SD p HC AD HC vs AD CVLT 1 5.04 ± 2.18 3.00 ± 1.34 0.001 CVLT 5 13.13 ± 2.34 6.35 ± 2.50 0.000 CVLT sum 49.04 ± 9.60 25.25 ± 6.37 0.000 CVLT long delay 11.39 ± 3.09 2.75 ± 3.63 0.000 CVLT long delay cue 13.00 ± 2.30 5.40 ± 3.66 0.000 CVLT recognition 15.61 ± 0.72 13.70 ± 3.13 0.007 Legend: AD = patients with Alzheimer's disease; CVLT = California verbal learning test; FP = false positives; HC = healthy controls.

Memory for news and commercials Hits and false recognitions A similar trend was observed in the memory assessment using news and commercials. The HC group was significantly more accurate in correctly identifying the statements, that were actually presented in the news compared to AD group and were significantly more accurate in identifying the scenes that were shown in the commercials (Table 4). The AD group also had significantly more false recognitions in both news and commercials. Estimated by the sum of the correct recognitions and correct rejections (total correct), there was no difference between the memory for news and commercials in HC (news total correct 49.22 ± 7.10, commercials total correct 50.25 ± 5.99; p = 0.117) and in AD (news total correct 34.44 ± 9.51, commercials total correct 31.39 ± 8.76; p = 0.064) groups.

Subjective estimate The two groups did not differ in the perceived difficulty for news or the commercials (Table 4). There was also no difference in the subjective estimate of the number of total correct answers (sum of correct recognitions and correct rejections) in the news and commercials and in the subjective estimate of the correctly identified misleading questions in the news and in the commercials (Table 4).

Table 4: Between group comparisons of objective and subjective performance in news and commercials memory tasks Mean ± SD p HC AD Objective score News hits 26.61 ± 2.92 21.00 ± 3.46 0.000 News FM 13.39 ± 6.56 22.50 ± 9.08 0.000 Commercials hits 26.10 ± 3.24 19.56 ± 4.31 0.000 Commercials FM 11.85 ± 4.64 24.17 ± 10.16 0.000 Subjective estimate News hits* 43.56 ± 13.47 38.88 ± 11.66 0.282 News FM 19.17 ± 6.99 15.88 ± 9.64 0.255 Commercials hits * 39.61 ±18.05 38.06 ± 15.28 0.782 Commercials FM 18.17 ± 8.32 15.94 ± 9.18 0.452 Legend: * = total correct (sum of hits and correct rejections); AD = patients with Alzheimer's disease; HC = healthy controls; FM = false memories.

The subjective estimate of the hits and false memories in the videos displayed no significant correlation with the respective objective measures (news hits: r = 0.036, p = 0.836; commercials hits r = 0.097, p = 0.574; news false memories r = – 0.250, p = 0.147; commercials false memories r = – 0.168, p = 0.327). Likewise, there was no correlation between the severity of the cognitive impairment (measured by MMSE) and subjective estimate of the hits (news: r = 0.167, p = 0.338; commercials r = 0.065, p = 0.708) and false memories (news: r = 0.245, p = 0.156; commercials: r = 0.192, p = 0.262). There was, however, a significant correlation between the MMSE and objective measure of hits (news: r = 0.695, p = 0.000; commercials: r = 0.785, p = 0.000) and false memories (news: r = – 0.577, p = 0.000; commercials: r = – 0.666, p = 0.000).

Answer tendencies An important variable to take into account when interpreting the number of correct answers and false recognitions is the tendency to stick with a particular response option. Irrespective of accuracy, there was a significant difference between the groups in the number of ‘Yes’ (HC 22.61 ± 5.36, AD 35.10 ± 14.55; p = 0.001), ‘Unknown’ (HC 23.65 ± 7.26, AD 10.55 ± 10.36; p = 0.000), ‘No’ (HC 23.65 ± 4.88, AD 19.10 ± 8.35; p = 0.032) and ‘Don’t know’ (HC 1.96 ± 3.55, AD 7.25 ± 8.19; p = 0.013) responses given by the two groups in the questionnaires assessing memory for the news sequences. Recognition test for the material in the commercials videos showed a significant difference in the number of times answered ‘Yes’ (HC 22.25 ± 5.07, AD 34.83 ± 19.29; p = 0.015) and ‘Unknown’ (HC 27.05 ± 6.83, AD 13.22 ± 14.80; p = 0.001), but not in the number of times answered ‘No’ (HC 21.55 ± 7.08, AD 19.56 ± 12.14; p = 0.547) and ‘Don’t know’ (HC 1.40 ± 2.28, AD 4.56 ± 6.85; p = 0.077).

Regression A multiple linear regression was used to explore the variance in the number of false memories in the two paradigms in the AD and HC groups. The predictors entered into the regression were symbol span as a marker of visual memory, the difference value between TMT A and TMT B (TMT-B-A) as a marker of executive function, CVLT trial 1 as a marker of short-term verbal memory, and the number in hits in news videos or commercials, respectively, to account for the information registered by participants on viewing the news videos or commercials. A significant model (F (1, 36) = 7.175, p = 0.011) predicted 16.6% of the variance in false memories for news (Adj. R2 = 0.143). The number of false memories increased with TMT-B-A (B = 0.062, t = 2.679, p = 0.011), (Table 5). Similarly, a significant 71 model (F (2, 35) = 10.547, p = 0.000) predicted 37.6% of the variance in false memories for commercials (Adj. R2 = 0.340). A worse performance in the symbol span (B = -0.425, t = -

2.323, p = 0.026) and larger TMT-B-A (B = 0.056, t = 2.103, p = 0.043) increased the likelihood of the false memories for commercials (Table 5).

Table 5: Multiple linear regression analysis of false memories in news and commercials News Predictor R² Adj. R² R²/change F p Gradient t p Model 0.166 0.143 7.175 0.011 TMT Difference 0.166 0.062 2.679 0.011 Commercials Predictor R² Adj. R² R²/change F p Gradient t p Model 0.376 0.340 10.547 0.000 Symbol Span 0.297 -0.425 -2.323 0.026 TMT Difference 0.079 0.056 2.103 0.043 Regression model including variables CVLT 1, TMT difference, symbol span, news hits or commercials hits, respectively. Legend: TMT = Trail Making Test.

Correlation with CSF markers in patients with AD For ethical reasons, neurobiological markers were only assessed in the AD group. Six patients received PET and 14 received lumbar puncture. The values of the CSF markers are displayed in Table 6. Due to decreased sample size in, correlations in AD group were assessed using a non-parametrical Spearman’s rho test. Level of Aß42 strongly correlated with false memories for both news (r = – 0.629, p = 0.016) and commercials (r = – 0.636, p = 0.019) (Figure 1.), but not with hits (news: r = – 0.018, p = 0.952; commercials: r = 0.014, p = 0.964) (Figure 2.). No correlation was observed between levels of tau-protein and false memories (news: r = – 0.320, p = 0.265; commercials: r = –0.493, p = 0.087) or hits (news: r = – 0.431, p = 0.124; commercials: r = – 0.526, p = 0.065).

Table 6: Values of the CSF markers of the patients, who received lumbar puncture Total-tau phospho-tau Aβ42 (pg/ml) Aβ40 (pg/ml) Aβ42 / Aβ40 (pg/ml) (pg/ml) 342 10,200 0.0335 1,320 224 208 2,910 0.0715 186 36 * 577 8,470 0.0681 476

312 4,730 0.0660 318

662 15,100 0.0438 817 109 459 5,490 0.0836 657 87 363 5,440 0.0667 452 #

366 10,300 0.0355 1,130

432 11,000 0.0393 964 128 557 9,560 0.0583 655 90 360 7,340 0.0490 732 88 291 6,390 0.0455 288 77 631 9,690 0.0651 416 63 513 11,900 0.0431 623 91 Amyloid ratio <0.10 and elevated total-tau (controls: <466 pg/ml) or elevated phospho-tau (controls: <61 pg/ml) are considered to be consistent with AD. For some patients phospho- tau levels were not available due to laboratory problems. *Amyloid pathology was also confirmed by C11-PIB-PET. #MRI showed predominant hippocampal and mediotemporal atrophy.

Figure 1: Correlation analysis of Aß42 and false memories scores in news (A) and commercials (B).

Figure 2: Correlation analysis of Aß42 and hits scores in news (A) and commercials (B).

Discussion Incomplete memory for everyday events or facts is the hallmark of Alzheimer’s disease and has been researched frequently. It was the goal of the present study to assess a less well known impairment of memory in AD – false or distorted memories. The present study clearly demonstrates such distortions even in patients with very mild AD. Both omission of information and distortion of information were more pronounced in patients with AD in the news as well as commercials tasks. To our knowledge the present study is the first to assess false memories with ecologically valid real-life tasks, i.e. watching news and commercials, in patients with very mild AD. The results are similar to previous reports demonstrating an increased rate of false memories judging less complex information presented as pictures [22] or a task requiring participants to answer questions about a recent domestic affairs [27, 26].

It could be argued that patients are less familiar with watching news or commercials. However, in the present study AD patients self-reported to be watching the news and commercials just as frequently as the HC group. It is one limitation of the study that we did not have a proxy report to substantiate self-report of the patients. Beyond frequency of watching news or commercials, both patients and control subjects rated the difficulty of the tasks similarly and estimated errors of their performance for both omissions and distortions similarly. Nevertheless, the objective performance showed a clear-cut difference between patients and control subjects. This is in good harmony with the well-known lack of awareness of deficits in patients with AD [40], [41], [42], [43], [44]. These studies concentrated on assessing awareness for errors of omission and general cognitive dysfunction. The data from the present study contributes to the existing literature showing that patients lack awareness of their memory distortions in an everyday memory task.

It is under dispute whether anosognosia for memory deficits is related to severity of cognitive deficits [45], [46]. The present study supports the findings that anosognosia for memory omissions does not correlate with dementia severity in patients with very mild AD and is the first to report this for memory distortions.

There was a clear tendency of patients with Alzheimer’s disease to answer ‘Yes’ significantly more often and choose the answer ‘Unknown’ significantly less often than the HC group. Interestingly, the corresponding subjective measure of correctly recognised misleading questions did not differ between the groups. Although the ‘Don’t know’ responding was not explicitly indicated as a response option, it was nevertheless used by

76 participants spontaneously; however, healthy controls used it significantly more frequent than the AD group. It has been suggested that don’t know responding is related to the monitoring of the memory content [47] and relies considerably on the frontal lobes [48], [49], [50]. The decreased frontal lobe functioning even in the patients with mild Alzheimer’s disease together with their tendency to underestimate cognitive deficits, offers an explanation of the ‘Yes’ and ‘Don’t know’ answers dissociation between AD and HC groups. Furthermore, our study also shows a clear ‘Yes’ answering pattern in the AD group. The tendency to favour ‘Yes’ answers (i.e. item was present in the learning trials) in the recognition tasks is one of the distinct features of the Alzheimer’s disease, which results in the high rate of false positives.

Regression analysis shows that mental flexibility and visual working memory partly explain the amount of false memories on watching news or commercials. Both these abilities tap into executive function and depend heavily on the prefrontal cortex [51]. It is plausible that mental flexibility is necessary to process both visual and auditory information while watching the news videos. Watching commercials requires even better performing visual working memory due to the larger number of scenes and their higher complexity. Decreased mental flexibility and deficient working memory hinder encoding [52], [53], [54] and thus likely impair verbatim trace formation. Within the fuzzy trace theory framework, this would lead to increased dependence on gist and greater susceptibility to false memories [5, 4, [55], [56]. Again, compared to the HC group, AD group presented with larger frontal impairments, which might have led to the misattribution of the information in the question to the actual information in the video [48].

It is another limitation of the study that CSF markers were available for patients, only. For ethical reasons, however, we abstained from CSF tap in control subjects. In the AD group

CSF levels of Aß42 strongly correlated with memory distortions but not with memory omissions. Speculatively, this indicates that the neural network conferring false memories is more widespread than the neural network conferring true memories. Lower CSF levels of

Aß42, probably indicate more amyloid depositions in the brain [57], [58], [59]. Accruing amyloid deposition, resulting in widespread neuronal malfunction, bring about a larger number of false memories. This could indicate that discerning true from false memories requires a larger neural network than recall of true memories per se. Alternatively, the mechanism to discern true from false memories may be more dependent on brain structures affected from amyloid deposition early on in the disease process. Lack of association of CSF 77

Aß42 levels with hits during verbal and visual episodic memory retrieval is in good harmony with previous reports [60]. Contrary to our expectations, true memories did not correlate with CSF tau-protein. One explanation could be that the association of CSF tau protein with verbal and visual memory is gender-dependent [60] and for reasons of group size no gender- specific analysis was performed.

Conclusion Everyday life in patients with AD is impeded not only due to the incompleteness of memory content but also due to its distortions. Furthermore, it is hindered by the lack of awareness towards both incompleteness and distortions. Future studies will need to address the impact of this duality of memory failure on everyday life of patients with AD and their proxies in greater detail. Conflict of interest The authors have no conflict of interest to report.

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ACKNOWLEDGEMENTS

The objective nature of this work does not capture the essence of the wonderful journey that I was privileged to take in the past few years.

I am sincerely grateful to my supervisor Prof. Matthias W. Riepe. His knowledge and experience were a crucial component of this work. His daring insight and sense of humour helped me to expand my own horizons. He has taught me more than I could ever thank him for.

I would like to thank my co-author and dear colleague Dr. Claudia Lanza for her help in all stages of this work, practical tips and many motivating conversations along the way. In her I have found a kindred spirit.

I wish to extend my gratitude to Prof. Dr. Georg Grön for agreeing to review this dissertation.

A sincere thank you goes to all participants, who have dedicated their time and enabled this project.

My deepest appreciation belongs to my mother Nina for her unfailing support through the years. Be tavęs nebūčiau pasiekusi to, ką pasiekiau. Ačiū, kad visada esi šalia.

Finally, thank you to my fiancé Semi, my ally from Krypton, for helping me to structure my time and thoughts during the periods of creative struggle.