Prospective Memory Acquisition in Multiple Sclerosis A Dissertation Submitted to the Faculty of Drexel University by Joshua D. McKeever in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2014

© Copyright 2014 Joshua Donald McKeever. All Rights Reserved.

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DEDICATION To my parents, who taught me patience, compassion, and resolve.

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ACKNOWLEDGEMENTS Over the past five years I have received support and encouragement from far too many people to list. Here are the highlights. Dr. Maria Schultheis has been a mentor, colleague, and friend. Her guidance has allowed me to grow in immeasurable ways, and, at various times, has kept me motivated, kept me restrained, or simply kept me balanced. I would like to thank my dissertation committee of Jennifer Gallo, Tania Giovannetti, Mary Spiers, and Steven Paul Woods for their consistent and invaluable support over the course of this project and throughout graduate school. Though not a committee member, Douglas Chute also deserves recognition here. I could not have completed this project without the time, effort, intelligence, and pragmatism of my research team, Jessica Goykhman and Kristina Patrick. I wish to thank several members of the University of Washington for their support in establishing UW as a recruitment and testing site, including Dawn Ehde, Kevin Alschuler, Myron Goldberg, and the UW/Harborview and Northwest MS Center research staff. Thanks also to labmates and friends Jocelyn Ang and Chelsea Morse, who were vital to the completion of this dissertation, and to all of the individuals who were kind enough to participate in this study. Lastly, to Anna Kawatsu Nomura, who saw me through it all without batting an eye.

iv Table of Contents List of Tables .................................................................................................................... vi List of Figures .................................................................................................................. vii Abstract ........................................................................................................................... viii 1. INTRODUCTION..........................................................................................................1 1.1 Project Aims...................................................................................................................1 1.2 Background: Cognitive Deficits Associated with Multiple Sclerosis............................2 1.3 Background: Everyday Prospective Memory ................................................................3 1.4 Background: Prospective Memory in Multiple Sclerosis ..............................................5 1.5 A Theoretical Model of Prospective Memory ...............................................................7 1.6 A New Approach to the Study of Prospective Memory in Multiple Sclerosis ............10 1.7 Significance of the Present Study ................................................................................14 2. METHODS ...................................................................................................................15 2.1 Study Overview ...........................................................................................................15 2.2 Participants ...................................................................................................................15 2.2.1 Recruitment ...............................................................................................................16 2.2.2 Power Analysis .........................................................................................................16 2.3 Assessment Measures ..................................................................................................18 2.3.1 Demographic Information .........................................................................................19 2.3.2 Selective Reminding Prospective Memory Paradigm ..............................................19 2.3.3 Neuropsychological Measures ..................................................................................22 2.3.4 Other Measures .........................................................................................................23 2.4 Procedures ....................................................................................................................24 2.5 Hypotheses and Plan of Analysis .................................................................................26

v 3. RESULTS .....................................................................................................................32 3.1 Analytical Strategy.......................................................................................................32

3.2 Characteristics of the samples ......................................................................................33 3.2.1 Comparison of Demographics and Clinical Characteristics .....................................33 3.2.2 Psychosocial outcome measures ...............................................................................34 3.3 Results of Aim 1 ..........................................................................................................35 3.4 Results of Aim 2 ..........................................................................................................43 3.4.5 Supplementary Analyses ...........................................................................................48 4. DISCUSSION ...............................................................................................................49 4.1 Main Findings ..............................................................................................................49 4.2 The Selective Reminding Prospective Memory Task ..................................................52 4.3 Prospective Memory Acquisition in MS......................................................................53 4.4 Implications for the Cognitive Psychology of Prospective Memory ...........................58 4.5 Implications for Cognitive Rehabilitation ...................................................................59 4.6 Limitations ...................................................................................................................61 4.7 Strengths ......................................................................................................................61 4.8 Future Directions .........................................................................................................62 4.9 Conclusions ..................................................................................................................63 List of References ..............................................................................................................65 Vita.....................................................................................................................................71

vi List of Tables

Table 1: Test Battery and Variables of Interest .................................................................18 Table 2. Study Variables ....................................................................................................27 Table 3: Demographic and Clinical Variables ...................................................................33 Table 4: Psychosocial Variables ........................................................................................34 Table 5: SRPM Task Variables, HC Group .......................................................................36 Table 6: SRPM Task Variables, MS Group.......................................................................38 Table 7: SRPM Task Variables, 1T Groups ......................................................................40 Table 8: SRPM Task Variables, SR Groups ......................................................................41 Table 9: Regression Models, Neuropsychological variables regressed on 3 PM Encoding variables .................................................................................................................44 Table 10: Regression Models, Retrospective Memory regressed on PM Recognition .....45 Table 11: Regression Models, Neuropsychological Variables regressed on SRPM Cue Detection Score ......................................................................................................46 Table 12: Regression Models, Neuropsychological Variables regressed on SRPM Execution Score .....................................................................................................47 Table 13: Supplementary Analyses ...................................................................................48

vii List of Figures

Figure 1: Multi-Phasic Process Model components ............................................................8 Figure 2: Group assignment ...............................................................................................20 Figure 3: Study Flow .........................................................................................................26 Figure 4: SRPM Performance, HC Group .........................................................................37 Figure 5: SRPM Performance, MS Group .........................................................................39 Figure 6: SRPM Task 1T Condition, Diagnostic Group Comparisons .............................40 Figure 7: SRPM Task SR Condition, Diagnostic Group Comparisons .............................42

viii Abstract Prospective Memory Acquisition in Multiple Sclerosis Joshua D. McKeever

Objective: Multiple sclerosis (MS) is associated with the presence of cognitive deficits. Prospective memory (PM), or “remembering to remember,” has significant functional relevance to the MS population. Individuals with MS show mild-to-moderate deficits in PM, which have been associated with increased risk of dangers such as medication nonadherence. Research has yet to determine which aspects of PM are particularly problematic for individuals with MS, and whether impairments in cognitive constructs underlying PM may contribute to overall PM errors. Selective reminding, a novel methodology within PM research, was used to delineate the contributions of each stage within the process of PM to overall PM ability. Participants: Groups consisted of two samples of individuals with MS (2 conditions: SR, n=11 and 1T, n=10) and two samples of healthy controls (SR, n=13 and 1T, n=9). Groups were matched on distributions of demographic variables, and MS groups were matched on disease-related variables. Methods: Participants underwent a two-hour battery of testing. The main measure of interest was a novel measure of PM, the Selective Reminding PM (SRPM) task. Both diagnostic groups (MS and HC) were randomly assigned to two conditions: MS-SR (full SRPM task) and MS-1T (only one encoding trial provided). Additional variables collected included performance in several neuropsychological domains as well as demographic, psychosocial, and MS disease-related factors. Results: Data indicated that the participants in the SR conditions (vs. 1T conditions)

ix demonstrated stronger PM performance in both MS and HC groups. Individuals with MS were impaired relative to HCs in the 1T condition, but performance was statistically equivalent between diagnostic groups in the SR condition. Conclusions: Overall, the current theoretically-driven examination of PM encoding in MS (as compared to healthy adults) provided intriguing and useful information about the process of PM in MS and the importance of the Intention Formation stage of processing. This project replicated previous findings (acquisition deficits) for PM in MS that have been well-established for retrospective memory in this group. These findings have significant implications for the cognitive psychology of PM and may also help provide guidelines for assessment and remediation of PM difficulties in MS and other populations.

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1. INTRODUCTION 1.1 Project Aims Individuals with multiple sclerosis (MS) often have cognitive deficits, but the ways in which these deficits affect individuals’ everyday lives (e.g., work or social life) are not well understood. Prospective memory (PM), or the ability to realize future intentions, is an ability that has significant functional relevance to everyday activities and basic well-being for all individuals. PM abilities are especially important in patient populations (such as MS) that have significant PM demands (e.g., medical adherence) concomitant with reduced cognitive abilities that may be required for successful PM (Kliegel, Jager, Altgassen, & Shum, 2008). The broad goal of this research project was to assess impairments in PM ability in MS, in order to inform a more comprehensive depiction and remediation of functional impairment in this population. This project attempts to further a line of research investigating the foundations of PM ability in MS (McKeever, 2012). Previous literature indicates that individuals with MS have more difficulty in memory acquisition than healthy individuals, especially with regard to traditional memory measures (e.g., verbal/spatial), and that acquisition deficits may explain deficits in overall memory performance in this population. This pattern of impairment may apply to PM as well, although this particular area (acquisition/encoding) of the PM process has received little attention. The current investigation anchored PM assessment with the Multi-Phasic Process (MPP) model, which designates that several distinct stages of processing are required for successful PM, and assessed whether individuals with MS demonstrate impaired performance during specific stages of PM (e.g., task acquisition, or the “Intention Formation” stage) than healthy individuals.

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Additionally, this project examined the neuropsychological correlates (e.g., learning, retrospective memory, processing speed) of deficits in PM component processes, to help determine the importance of neuropsychological factors when PM failures occur. These associations will be anchored with the proposed neuropsychological correlates of the MPP model. Lastly, the project introduced a novel methodology (Selective Reminding) to the assessment of PM, and thus, the utility of this methodology was evaluated. This study sought to make important contributions to both the cognitive/mechanistic literature (by examining contributors to the process of PM using the MPP model) and the rehabilitation/cognitive remediation literature (by examining strategies that could be used to augment PM abilities in clinical populations). 1.2 Background: Cognitive Deficits Associated with Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune inflammatory disorder associated with multiple demyelinating lesions found throughout the central nervous system, causing diffuse white and grey matter damage and widespread disruption of neural transmission. It is the most prevalent degenerative neurological illness affecting young to middle-aged adults (Johnson, 2007; Rao, Leo, & St. Aubin-Faubert, 1989). Several subtypes of the disease have been identified based on the rate and pattern of disease progression, which usually happens in discrete episodes called relapses or exacerbations. Symptoms of the disease vary widely, but generally fall into the broad categories of motor impairments, sensory impairments, emotional problems, bowel and bladder difficulties, and cognitive impairments, as well as pain and fatigue. Although MS is noteworthy because of the sheer number of potential symptoms, researchers have become increasingly interested in the cognitive symptoms associated with MS and how they affect the daily lives of people

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with the disease. Because individuals with MS are often relatively young and active compared with other neurocognitively impaired populations, they frequently retain a strong desire to be engaged in work, social life, and other activities. Studies have demonstrated that the ability to work and maintain productivity is a major concern for this population, and many sufferers have concerns related to the presence or anticipation of cognitive decline (Malcomson, Lowe-Strong, & Dunwoody, 2008; Shevil & Finlayson, 2006; Yorkston, Johnson, Klasner, Amtmann, Kuehn, & Dudgeon, 2003). Researchers estimate that between 50 and 72% of individuals with MS demonstrate cognitive impairment (Shevil & Finlayson, 2006; Bobholz & Rao, 2003). Domains shown to be impaired include processing speed and immediate memory (Marrie, Chelune, Miller & Cohen, 2005), attention, visuospatial abilities, and executive functions (Engel, Greim, & Zettl, 2007; Bobholz & Rao, 2003). Memory difficulties are the most common neuropsychological finding in this population and occur across many types of memory (DeLuca, Gaudino, Diamond, Christodoulou & Engel, 1998; Thornton & Raz, 1997). Studies have documented that memory acquisition, rather than retrieval per se, is probably the primary factor underlying deficient recall memory performance in MS (Demaree, Gaudino, DeLuca, & Ricker, 2000). Based on the literature, it is also evident that deficits in a type of memory called Prospective Memory (PM) are a concern for the MS population, and that PM has considerable functional relevance to this group (Rendell, Philips, Henry, Brumby-Rendell, et al., 2012; Kliegel, Jager, et al., 2008), but these conclusions are still preliminary. 1.3 Background: Everyday Prospective Memory Prospective Memory is the ability to realize future intentions when encountering

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the correct situational cue. PM can be distinguished from other types of memory in that it is concerned with remembering to do things (e.g., to make a phone call) rather than simply retrieving information (e.g., a word list that has been previously presented) (Eyad, 2011). PM has been conceptualized, neuropsychologically, as a function rather than a construct, such that a function, such as driving ability, is a set of context-dependent realworld behaviors that relies on multiple subordinate constructs, such as attention and motor abilities, which are more specialized cognitive processes (Burgess, Dumontheil, Gilbert, Okuda, Scholvinck, & Simons, 2008; Moscovitch, 2008). PM research has considered various aspects related to PM task demands, such as the distinction between Time-cued and Event-cued PM tasks. In other words, studies have attempted to understand how different aspects of environmental monitoring may be involved when a task must be initiated at a specific time (e.g., turn off the oven in 30 minutes) versus in response to a specific event (e.g., stop at the grocery store when in the vicinity). As is clear from this short inventory of a few of the factors inherent in PM function and research, PM is a complex, multifaceted ability. It is also essential to normal functioning in everyday life. The everyday uses of PM are extensive. As Ellis and Kvavilashvili (2000, p.S1) point out, PM “enables us to shape and direct our cognitive resources” to accomplish goals and plans. These types of goals occur in nearly all contexts of human life, but may have special relevance to things like health-related behaviors (such as medical adherence) and occupational concerns (such as remembering to return an email) that are essential to health and well-being. Additionally, PM demands may actually increase concomitantly with reduced cognitive abilities and processing resources, whether due to biological

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processes (such as aging combined with increased medication management) or life circumstances (such as having children, a high-stress job requiring complex multitasking, or both simultaneously) (Burgess et al., 2008). It is not hard to imagine why PM failures have been said to range from being “embarrassing…[or] frustrating” to “life-threatening” (Kliegel et al., 2008, p. 284), and there is a significant and growing body of literature demonstrating associations between PM and a variety of everyday functioning outcomes, including Quality of Life (Doyle, Weber, Atkinson, Grant & Woods, 2012), Instrumental Activities of Daily Living (Woods, Weinborn, Velnoweth, Rooney & Bucks, 2012), employment (Woods, Weber, Weisz, Twamley & Grant, 2011), and medical adherence (Zogg, Woods, Sauceda, Wiebe & Simoni, 2012). 1.4 Background: Prospective Memory in Multiple Sclerosis Most studies examining PM abilities in the MS population have identified deficits when compared to healthy controls (see Kliegel et al., 2008, for a review; Bruce, Hancock, Arnett, & Lynch, 2010; Kardiasmenos, Clawson, Wilken, & Wallin, 2008; Rendell, Jensen, & Henry, 2007; Bravin, Kinsella, Ong, & Vowels, 2000). The magnitude of the identified PM deficit in MS has been shown to be large in some studies (for example, Cohen’s d = 0.836 in Rendell, Jensen, & Henry, 2007). However, this finding is not universal, as some investigations have failed to identify frank PM deficits in MS compared to controls (McKeever, 2012). Researchers have attempted to increase the precision of these findings by examining differences in performance on Time-cued versus Event-cued PM tasks. Rendell et al. (2012) investigated Time-cued versus Eventcued PM effects in MS and HC samples using an experimental PM (Virtual Week) and found no evidence for an “MS status” X “cue type” interaction; thus, they concluded that

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deficits in PM were consistent across cue type and there was no evidence for a different effect of cue type in individuals with MS than would be expected in healthy adults. As noted above, PM is thought to be a complex function that relies on several underlying cognitive constructs. Much work is underway to investigate the most significant neuropsychological constructs underlying overall PM function, as well as function on the distinct stages of processing involved in successful completion of a delayed intention. Because PM processing is thought to rely strongly on brain structures such as prefrontal cortex, medial temporal lobes, and connections between these structures, neurologically affected populations such as MS are of particular interest to PM researchers. It is unknown whether proposed models of PM functions and their neuropsychological correlates that have been identified in other (e.g., healthy) populations would also apply to MS, and relatively few studies to date have examined this question. Bravin et al. (2000) demonstrated that while individuals with MS were somewhat impaired on a PM task compared to controls, greater deficits were observed for recall of the PM tasks. The authors concluded that PM deficits were attributable to retrospective memory problems in their MS sample compared to a control group. However, even studies that have ruled out deficits in component constructs (such as general intelligence, executive functioning, and retrospective memory) have identified PM problems in the MS population (Rendell, Jensen, & Henry, 2007; West, McNerney, & Krauss, 2007). This suggests that, at least in MS, PM function is more than the sum of its parts. Investigations with other populations have shown that, while PM ability correlates with domains such as retrospective memory, it is an independent factor (Gupta, Woods, Weber, Dawson, et al., 2010) and adds predictive value to models of behaviors

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such as medication adherence and self-reported instrumental activities of daily living (e.g., Woods et al., 2009). Thus, PM assessment may contribute important information to a comprehensive clinical profile of a given individual with MS. While it is known that individuals with MS have significant PM demands, both related to their disease (e.g., medication adherence, doctor’s appointments) and their relatively active lives (e.g., occupationally and socially), PM function in this population is not well understood. This is especially true with regard to factors such as a) the most common PM demands and deficits that these individuals experience, b) the contributions of component neuropsychological constructs to PM ability, and c) methods that may help support PM abilities in MS. Understanding these factors will contribute to the neurocognitive profile of MS (and of individual patients with the disease), and allow researchers and clinicians to recognize the real-world impact of PM deficits in the lives of these individuals and provide better treatment recommendations (which, at this point, are rarely provided at all with regard to PM). 1.5 A Theoretical Model of Prospective Memory Considerable research has been conducted to examine the intricate stages of processing that must generally occur to successfully complete a delayed objective. Because PM function is so complex, it is necessary to establish a theoretical framework to understand its components. Several models have been suggested to explain how PM occurs, including Shallice and Burgess’s (1991) Supervisory Attentional System (SAS) theory, the Preparatory Attentional and Motivational Processes theory (PAM; Smith & Bayen, 2004) and the Multi-Phasic Process model (Kliegel, Mackinlay, & Jager, 2008; Kliegel, Martin, McDaniel, and Einstein, 2002). The Multi-Phasic Process (MPP) or

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“Multiprocess” model, while broadest in scope, is potentially the most useful in a functional neuropsychology context. It seeks to specify the set of distinct stages of processing that are required for successful PM, and how each stage contributes to “strategic retrieval processes” when it becomes time to enact an intention (Ellis & Kvavilashvili, 2000). The stages of this model (see Figure 1) include Intention Formation (forming a plan of what is to be enacted), Intention Retention (retaining the details of the intention in memory), Intention Initiation (recognizing the circumstances in which the intention should be performed), and Intention Execution (actual performance of the intention). Researchers have proposed that an accurate depiction of the neuropsychological correlates that may underlie performance on each of these stages of processing may help understand why a given individual may experience PM problems. Performance on Intention Formation is thought to depend upon planning and information processing. Intention Retention is assumed to rely significantly on retrospective memory. Intention Initiation and Intention Execution are both likely to rely heavily on executive functions (EFs), with Initiation being associated with EFs such as monitoring and cognitive flexibility as well as processing speed, and Execution to inhibition and nonverbal fluency (Kliegel, Jager, et al., 2008; Kliegel, Mackinlay, & Jager, 2008).

Stage

Description

Example

Intention Formation

Encoding of PM task

Forming plan to take medication after dinner

Retention of details (“when” and “what”) in long-term memory Recognition of correct Intention Initiation circumstances (cue detection) Task performance Intention Execution Figure 1: Multi-Phasic Process Model components Intention Retention

Retaining goal in memory without rehearsal Noticing the correct time to take medication Taking the medication

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Most research regarding the cognitive process of PM has focused on the Intention Initiation stage (Figure 1, 3rd row). As such, most PM theories, along with most laboratory investigations of PM, are particularly concerned with the process of becoming aware that it is time to enact one’s intention (Hertzog, 2008). While this process (sometimes termed “cue identification” or “detection;” Simons, Scholvinck, Gilbert, Frith, & Burgess, 2006) is important and apparently is particularly convenient to study in the laboratory, it is certainly not the basis for all PM errors. The breadth of the MPP model is particularly useful for a more comprehensive assessment of PM errors; one can infer from the MPP model that if the intention formation stage never occurs (i.e., one never mentally forms the intention to complete a task), then it is very unlikely that the PM task will be completed. Despite its position as the foundational step of the model, very little empirical research has focused on the formation of delayed intentions (Rendell et al., 2012; McDaniel, 2010). This represents an important opportunity within the PM literature. As alluded to above, each stage of the MPP model influences cue detection and intention enactment, such that, for example, either exceptional encoding or highly salient (e.g., “focal”) cues can bolster PM performance to a similar degree (McDaniel, & Scullin, 2010; Ellis & Kvavilashvili, 2000). If this is the case, then it logically follows that, particularly in contexts where the individual has little control over the nature of cues (e.g., in time-based PM tasks), the intention formation stage must occur to a sufficient degree to make later task enactment likely to occur. Thus, Intention Formation is established as an indispensable stage of the PM process, especially for more difficult PM tasks; however, looming questions remain regarding what comprises a “sufficient degree” of encoding,

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and what cognitive processes are required to attain this criterion. 1.6 A New Approach to the Study of Prospective Memory in Multiple Sclerosis Significant progress has been made recently in establishing methods by which to assess PM, including standardized, commercially-available measures (Thone-Otto & Walthier, 2008; Woods, Moran, Dawson, Carey, & Grant, 2008). While these methods allow clinicians and researchers to differentiate between multiple components and types of PM (e.g., different response types; Event- versus Time-based cues), to date, few measures have been developed and validated that permit the analysis of PM performance with respect to a theoretical model such as the MPP framework (but see McDaniel (2010) for a discussion of a “complex prospective memory task”). Strong PM models should allow assessment tools to theoretically anchor the various aspects of PM performance, so that when errors occur they can be analyzed systematically and the specific reasons for the error can be delineated. Currently, assessment tools do not adequately weigh the importance of PM task acquisition, or the Intention Formation stage of the MPP model. The few available studies on the topic of PM encoding tentatively suggest that processes that are associated with impaired PM abilities, such as aging, impair PM because of their effects on executive planning abilities related to frontal systems of the brain (McDaniel, 2010). These authors explicitly specify the importance of future investigations of the neuropsychological constructs associated with PM planning, and (implicitly) the need for novel methodologies that allow conclusions to be drawn about the planning/acquisition aspect of PM tasks specifically. The dearth of research on PM encoding mirrors a similar opportunity for advancement within the retrospective memory literature that has been discussed for many

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years (Hart, 1994; Erickson & Scott, 1977). One way memory researchers have sought to examine the separate contributions of encoding and retrieval processes is using the Selective Reminding (SR) procedure. In the classic paradigm (à la Bushke, 1973), participants are presented with a set number of stimulus items (e.g., a word list), and asked to immediately recall as many items as they can. Subsequent learning trials are employed, but each time only the items that the participant did not recall on the previous trial are presented, followed by another recall trial. Learning trials persist for either a set number of trials, or, in recent incarnations of the task, until a specific criterion is reached (e.g., all items recalled correctly on two consecutive recall trials; Chiaravalloti, Balzano, Moore & DeLuca, 2009). Recall and recognition are then tested after a delay period. The SR procedure was created to “analyze simultaneously initial storage, retention, and retrieval from long-term storage… so that we can understand the nature of the patient’s impaired memory and learning” (Buschke 1974, p. 1019). Many subsequent studies have confirmed the usefulness of the task for this purpose, and have also shown the SR paradigm to be more sensitive to milder forms of memory impairment (Lezak et al., 2012). In addition to the more obvious performance variables such as delayed recall and recognition scores, many other variables can be created to help in the differentiation of retention, storage, and retrieval performance. Selective Reminding variables have been valuable for many purposes in the literature (e.g., in terms of identifying mild memory problems or predicting development of Alzheimer’s disease), and include variables that measure memory processing (e.g., storage) during the encoding trials, such as Consistent Long-Term Retrieval (CLTR; the number of words consistently recalled between trials

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without prompts) and Reminders (the sum of prompts given in the course of the learning trials; Lezak et al., 2012). This methodology, while still relatively uncommon clinically, has proven valuable in research studies and helped to demonstrate that encoding difficulties, and not retrieval deficits per se, are responsible for poor memory performance in populations such as traumatic brain injury (DeLuca, Schultheis, Madigan, Christodoulou, & Averill, 2000) and multiple sclerosis (Demaree, Gaudino, DeLuca, & Ricker, 2000). In a classic study, DeLuca et al. (1998) showed that individuals with MS required more SR trials to reach specified learning criterion, but that after controlling for differences in learning using the SR procedure, the MS group’s memory performance did not differ from the healthy control group’s performance. They (and many others) have interpreted this finding as evidence that the memory impairment observed in MS is not due to deficient retrieval from long-term storage but problems in initial acquisition of the material. The authors go on to discuss their belief that the reasons the SR procedure enhanced delayed memory performance in MS was not due to simply more exposure to the material, but likely to improved quality of the encoding permitted by the learning trials (e.g., information was better organized into memory units in long term storage). Authors such as Chiaravalloti et al. (2009) suggest that during investigations of memory performance in the MS population, new learning deficits must be controlled for in order to draw conclusions about subsequent memory retrieval or overall memory function. Authors have also proposed that any treatment for memory concerns in this population must focus on memory acquisition (Goverover, Hillary, Chiaravalloti, Arango-Lasprilla & DeLuca, 2009).

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Research on the ability of individuals with MS to acquire PM tasks in particular is nearly non-existent, but intriguing questions have been raised about how the acquisition of an intention may affect subsequent PM errors in this population. Kardiasmenos et al. (2008) conducted an investigation of PM performance in individuals with MS versus healthy controls in which the main manipulation involved training in an encoding technique known as implementation intentions (II), which the researchers defined as “specifying the circumstances under which one will carry out a planned task and visualizing oneself executing the action under those circumstances” (p. 747). One group of participants utilized this strategy, while the other group practiced rote (verbal) rehearsal of the tasks for 10 seconds. Results indicated that 1) individuals with MS were impaired on the PM task (Virtual Week) compared to controls; 2) individuals with MS showed smaller deficits when cues were highly associated with intention tasks versus when cues were nonassociated; and 3) use of the implementation intentions encoding strategy in the MS group increased performance to the level of healthy controls in the nonassociated condition. These results support the hypotheses that individuals with MS are impaired in their ability to acquire PM tasks (i.e., form intentions) compared to healthy individuals, but that encoding strategies can potentially remediate this difficulty. They also mirror some of the findings and conclusions from the SR literature discussed above, such as the fact that it is not simply greater exposure but increased depth of encoding (permitted by the II condition) that leads to better memory performance. Thus, a strong body of literature supports the concept that any procedure that enhances encoding depth during learning for individuals with MS will enhance later memory

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performance and may help prevent subsequent memory deficits. The current study examined these hypotheses empirically with regard to PM using the SR procedure. 1.7 Significance of the Present Study The current study represents the first investigation, to our knowledge, to use the SR procedure in an exploration of PM. This novel methodology aims to contribute to the literature on cognitive deficits in the MS population by examining whether a deficit in the encoding of prospective tasks, rather than deficits in later stages of the PM process, underlies the observed overall PM difficulties observed in this population. The overarching goal of the project was to use information about PM impairments to inform a more comprehensive depiction of functional impairment in MS, which could eventually be used to generate remediation interventions. The results of this study contribute to the fledgling literature base on cognitive remediation/rehabilitation of PM, as it identifies targets for intervention and may help to inform treatment planning and application. Healthy control participants also completed the study and serve as a benchmark with which to determine the presence of PM deficits as well as deficits in performance on MPP model stages and neuropsychological measures. This study contributes to the literature on the cognitive psychology of PM and may influence theory development and validation by examining multiple specific factors in the process of PM (according to the MPP model). In addition to an examination of the discrete stages of PM processing, the study employed a battery of neuropsychological measures which permit an analysis of individual differences in cognitive abilities as they relate to PM and its underlying processing. This assessment also attempts to inform cognitive remediation strategies, as interventions may be able to capitalize on cognitive

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strengths and target underlying neuropsychological constructs with the hope of improving functions such as PM.

2. METHODS 2.1 Study Overview The current study is a preliminary exploration of performance on specific components of the PM process (according to the MPP model) in a sample of individuals with MS as compared to healthy controls. Data were collected during a two-hour study visit in which individuals with MS and controls completed a selective reminding PM paradigm (based on a standardized objective PM assessment, the Memory for Intentions Test (MIST)), a more traditional Selective Reminding test of retrospective memory, and a measure of paired associate memory. Additional neuropsychological tests measured processing speed, executive functions, working memory, and motor abilities. Demographic information and several measures of psychosocial function (e.g., depression, fatigue, Quality of Life, subjective memory complaints) were also collected, including information pertaining to each patient’s MS diagnosis. Additional information about each measure is provided in relevant sections below and in Table 1. 2.2 Participants The groups consisted of two samples of individuals with diagnosed MS of any type and two samples of healthy controls. All participants were between 21 and 65 years of age, because of the rarity of receiving an MS diagnosis before age 21 and to reduce the potential effects of aging on cognitive performance. All participants (HC and MS) met the following exclusion criteria: 1) no significant alcohol/drug history, defined by current treatment or hospitalization; 2) no significant neurological diagnosis (other than MS),

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defined by diagnosis and/or treatment of a major neurological illness (e.g. TBI, seizure disorder); 3) no significant psychiatric history, defined by diagnosis and/or treatment of a major psychiatric illness (e.g., bipolar disorder). HC participants could not have a diagnosis of MS. MS participants were required to have carried their diagnosis of MS for at least one year, must not have had a relapse within the past 30 days and must not have been undergoing steroid treatment, because of the probability of acute symptoms during these periods and the influence of these medications on cognitive performance. 2.2.1 Recruitment MS participants were recruited from databases of former participants in the Applied Neuro-Technologies Lab at Drexel University and the University of Washington, local chapters (PA and NJ) of the National Multiple Sclerosis Society, and the MS clinics at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania and the Multiple Sclerosis Center of the University of Washington Medical Center in Seattle, WA. Healthy Control participants were recruited through flyers posted locally and given to former lab participants, and from a database of HC individuals involved in other studies in the Applied Neuro-Technologies Lab. 2.2.2 Power Analysis Power analyses were conducted using the program G*Power (Faul, Erdfelder, Buchner, & Lang, 2009) and assuming an alpha of .05 and target power of > .80. This project is a preliminary and exploratory analysis, and many comparisons are possible. One of the primary objectives was to determine whether the amount of information about PM tasks that individuals with MS are able to encode affects performance at PM retrieval (i.e., task execution). Planned analyses included assessing SRPM encoding condition

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group differences at task execution using independent-samples t-tests. Because of the lack of any available literature on the effects of one-trial vs. Selective Reminding procedures at task execution, data from Kardiasmenos et al. (2008) were used as a surrogate measure of effect size. The rationale for the employment of these data is that both selective reminding and implementation intentions can be conceptualized as PM encoding strategies, and target sample sizes were conservatively corrected to account for weaknesses in this method. Using the average calculated effect size (d = 1.154) for the main effect of interest from Kardiasmenos et al.’s (2008) MS data, 7 participants were projected to be required in each of the two MS groups to obtain statistical significance; conservative adjustment increased the target sample size to 20 per group. The second major analysis investigated the influence of encoding difficulties on PM task performance in individuals with MS relative to HCs. Planned analyses included assessing diagnostic group differences using independent-samples t-tests. Effect size estimates for this power analysis are only available for PM task execution, and were drawn from Rendell, Jensen, & Henry’s (2007) data comparing MS and HC groups on performance on a PM task (Virtual Week). Using the calculated effect size (d = 0.836), 19 participants were projected to be required in each group to obtain statistical significance. Though the preceding power analyses do not address all of the analyses planned in the current investigation, they address the main analyses of interest. Thus, based on the results of these power analyses, the initial target group size was 20 per group across the four groups (MS-SR, MS-1T, HC-SR and HC-1T).

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2.3 Assessment Measures A list of all planned assessment measures is provided in Table 1. Individual measures are discussed in relevant sections. All participants were assessed in the following domains: 1) demographic information; 2) Selective Reminding PM task; 3) neuropsychological measures; and 4) psychosocial measures.

Table 1: Test Battery and Variables of Interest Measure Variables Collected Experimental Prospective Memory Paradigm Selective Reminding MIST Total Score (PMT); MIST Time Cue score; MIST Event Cue score ; Prospective Memory MIST Retrospective Recognition (RRT) score; Cue Detection score; paradigm (SRPM) Execution score; Supraspan; Trials to Criterion (TTC) Neuropsychological Measures WMS-IV Verbal Paired VPA I Raw Score; VPA I Scaled Score; VPA II Raw Score; VPA II Scaled Associates Score; VPA Recognition Score (VPA) Open-Trial Selective Supraspan; Trials to Criterion (TTC); 30-minute Delayed Recall Score; Reminding Test (OT-SRT) Recognition score WMS-IV Symbol Span Symbol Span Raw Score; Symbol Span Scaled Score Multiple Sclerosis Functional TWT Average Time; 9-HPT Average Time; PASAT 2-second Raw Score; Composite (MSFC) PASAT 3-second Raw Score; MSFC Score Oral Symbol-Digit Modalities SDMT Raw Score Test (SDMT) Other Measures Beck Depression Inventory-II BDI score (BDI-II) Chicago Multiscale Depression CMDI Total Score; Mood symptoms score; Vegetative symptoms Inventory (CMDI) score; Evaluative symptoms score Fatigue Severity Scale FSS Total; FSS Average (FSS) Visual Analog Scale of Fatigue VAS-F Change Score (VAS-F) Self-reported Expanded SR-EDSS Rating Disability Status Scale (SR-EDSS) Prospective and Retrospective PRMQ Total Frequency Score; PRMQ Total Frustration Score; PRMQ Memory QuestionnaireProspective Memory Frequency Score; PRMQ PM Frustration Score Extended (PRMQ) Survey of Memory-Related SMRQoL Total Score; SMRQoL Retrospective Memory Score; SMRQoL Quality of Life (SMRQoL) PM Score

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2.3.1 Demographic Information Demographic variables of age, gender, occupational status, and years of education were collected from all participants. Variables collected from MS participants included MS subtype, duration of diagnosis, and duration since symptom onset. HCs were selected to match the demographic variables of the MS group in terms of age, gender, and years of education only. 2.3.2 Selective Reminding Prospective Memory Paradigm A novel Selective Reminding PM paradigm, the Selective Reminding Prospective Memory paradigm (SRPM), was the main measure of interest employed in this study. The paradigm is an adapted version of the Memory for Intentions Test (MIST; Raskin & Buckheit, 2010), a standardized objective measure of PM. The MIST includes eight prospective memory tasks, each of which is similar to a real-world task that one might have to perform in daily life. It includes 4 time-cued tasks (e.g., “in 2 minutes, ask me what time this session ends today”) and 4 event-cued tasks (e.g., “when I show you my tape recorder, tell me to rewind the tape”) (Woods, Moran, Dawson, Carey, & Grant, 2008). For the current study, modifications were made to the standard administration of the MIST. Modifications were employed at two levels: 1) task presentation (SR and 1T versions), and 2) minor revisions to the MIST procedure and stimuli. The major adaptation to the MIST is in the way the 8 tasks were presented in the experimental paradigm. This paradigm (SRPM) used two versions: Selective Reminding (SR) Version: All 8 tasks from the MIST were presented in a similar format to verbal list-learning Selective Reminding tests. Participants were

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verbally presented with all 8 tasks and asked to immediately recall as many as they could. On subsequent encoding trials, only the items that the participant did not recall on the previous trial were presented, and trials continued until all 8 tasks were freely recalled on two consecutive trials. The modified version of the MIST1 then took place. Half of the MS participants (MS-SR group) and half of the HC participants (HC-SR) were randomly assigned to this condition (see Figure 2). One-Trial (1T) Version: All 8 tasks from the MIST were presented in a similar format to verbal list-learning tasks. Participants were verbally presented with all 8 tasks and asked to immediately recall as many as they could. Only one learning/recall trial was provided in this condition. The modified version of the MIST then took place. Half of the MS participants (MS-1T group) and half of the HC participants (HC-1T) were randomly assigned to this condition (see Figure 2).

SR MS 1-T

Other measures

SR HC 1-T

Other measures

Figure 2: Group assignment 1

MIST: The Memory for Intention Test (MIST; Raskin & Buckheit, 2010) is normally administered as follows: Participants are told they will be asked to remember tasks and carry them out. They are then given a distractor task (word search) and eight prospective memory tasks are progressively presented and participants’ ability to complete them is assessed. Each of the eight tasks is similar to a real-world task that one might have to perform in daily life; for example, one item states, “in 2 minutes, ask me what time this session ends today” (Woods et al., 2008). It includes both time- and event-cued tasks, and both long (15minute) and short (2-minute) time delays. It takes approximately 30 minutes to administer.

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Other modifications to the standard MIST procedure were employed to standardize the task across participants and increase the demands at task performance: 1. In standard MIST administration, participants are given a digital clock, set to the current time, with which to monitor their time. The clock in this version was set to 12:00 PM at the beginning of the PM task, and the time cue specified for all timebased tasks was presented (during SR encoding trials) as “x number of minutes after the start of the task.” For example, one time-cued item is normally meant to be enacted at the 22 minute mark; thus, participants were told, “in 22 minutes, tell me two things you forgot to do this week,” and the correct time to perform the task was 12:22. Task instructions included a sample item to ensure that this was understood by all participants. 2. In standard MIST administration, a word-search is the distractor task that participants complete while the PM tasks are ongoing. The distraction in this version was augmented with additional tasks. This modification was meant to increase the cognitive demands of the distraction task so that constant mental rehearsal of the PM tasks could not occur, and may also provide a measure of ongoing task performance that can be used as a variable in later analysis (e.g., analyses of the effects of cue monitoring in each group). The distractor task set included a) the standard MIST word search; b) a set of arithmetic problems; and c) a picture-naming task. Participants were permitted to change tasks whenever they chose, but were required to change tasks twice during the 24-minute PM task (at 8 minutes and at 16 minutes).

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2.3.3 Neuropsychological Measures All study participants were administered a short battery of neuropsychological tests to examine cognitive constituents of PM according to the MPP model. The battery assessed aspects of retrospective memory, using both an open-trial SR procedure (Lezak et al., 2012; Chiaravalloti et al., 2009; Bushke, 1973) and a measure of verbal paired associate memory, the Verbal Paired Associates (VPA) subtest from the Wechsler Memory Scale-IV (WMS-IV; Wechsler, 2009). The OT-SRT is an experimental memory paradigm designed to evaluate new learning. The participant is required to learn a list of 12 words over a maximum of 15 trials. The learning trials are repeatedly administered until a certain learning criterion (i.e., all items) on two consecutive trials is demonstrated. Recall and recognition is then tested 20 minutes following the learning trials. The VPA subtest from the WMS-IV is a measure of the ability to encode and later recall a set of word pairs. Use of these two measures allows for the contributions of separate aspects of retrospective memory (e.g., encoding and retrieval) and paired associate (PA) memory to be examined in relationship to performance on the PM task variables (paired associate memory may have special relevance to PM because each PM task includes 2 associated components, a cue and a task). Other neuropsychological measures will examine aspects of speed of information processing (PS), working memory (WM), and executive functioning (EF). The oral Symbol-Digit Modalities Test is a motor-free measure of PS and WM (Smith, 1982). The Symbol Span subtest from the Wechsler Memory Scale-IV (WMS-IV; Wechsler, 2009) is a nonverbal analogue to digit span and was used to assess nonverbal WM and EF. The Multiple Sclerosis Functional Composite (MSFC) is a composite score composed of three measures of functions commonly impaired in MS:

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lower extremity function (measured with the Timed Walk Test (TWT)), upper extremity function (measured with the Nine-Hole Peg Test (9-HPT)), and cognitive function (PS, WM, and EF) measured with an MS-specific version (2- and 3-second trials) of the Paced Auditory Serial Additional Test (PASAT)) (Fischer, Rudick, Cutter, & Reingold, 1999). Utilization of these measures permits an assessment of the contributions of these neuropsychological domains to PM performance variables, as well as the computation of the Multiple Sclerosis Functional Composite (MSFC) score, an estimate of MS symptom severity. 2.3.4 Other Measures Testing also included several tests traditionally used to estimate the contribution of MS symptoms to neuropsychological test performance, as well as measures of depression (which has been frequently noted be a concern for the MS population; Middleton, Denney, Lynch, & Parmenter, 2006), memory complaints, and Quality of Life related to memory factors. State and overall symptomatic fatigue was measured with the Visual Analog Scale of Fatigue (VAS-F; Kos, Nagels, D'Hooghe, Duportail, & Kerckhofs, 2006) and the Fatigue Severity Scale (FSS; Krupp, LaRocca, Muir-Nash, & Steinberg, 1989), respectively. The VAS-F is a visual analogue scale used to assess levels of state fatigue and was administered at the beginning and end of the testing session to monitor the effects of fatigue during testing. The FSS is a 9-item self-report inventory commonly used in individuals with MS to evaluate their subjective level of fatigue over the past week using a 7-point Likert scale. Depression severity was measured using the Beck Depression Scale - II (BDI-II; Beck, Steer, & Brown, 1996) and the Chicago Multiscale Depression Inventory (CMDI; Nyenhuis, & Luchetta, 1998). Though

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neurovegetative symptoms of MS have been shown to elevate BDI-II score, evidence is equivocal, and research has shown that all BDI-II items do indeed tap depression in MS (Moran & Mohr, 2005), and the CMDI may permit an analysis of these factors because it separates depression symptoms into subscales. MS disease progression was assessed using the Self-Reported Expanded Disability Status Scale (SR-EDSS). This measure has been shown to correlate well with clinically-based assessments (Arnett, Higginson, & Randolph, 2001; Solari, Amato, Bergamaschi, Logroscino, et al., 1993). The self-reported effects of memory difficulties on daily life were assesses with the Prospective and Retrospective Memory Questionnaire-Extended (PRMQ; Smith, Della Sala, Logie, & Maylor, 2000) and the Survey of Memory-Related Quality of Life (SMRQoL; Weber, Weisz, Cameron, Grant, Atkinson, & Woods, 2010). 2.4 Procedures Figure 3 provides an overview of study flow. To determine eligibility, a pre-study phone screening interview was conducted. Using a predetermined script, the researcher asked several questions to ensure that all of the exclusion and inclusion criteria were met. Following the pre-screening phone interview, if eligible, the participant was invited to participate and given written informed consent including HIPAA approved by the Drexel University Institutional Review Board (IRB) and/or the University of Washington Human Subjects Division. After obtaining informed consent, eligible participants proceeded to study enrollment. All participants participated in one session lasting approximately two to three hours. All testing was conducted either in the Schultheis Applied Neuro-Technologies Laboratory at Drexel University in Philadelphia, PA or at the University of Washington’s

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MS Center/Harborview Medical Center in Seattle, WA. At the beginning of the testing session, participants completed an initial VAS-F scale to obtain a pre-testing rating of fatigue, and then proceeded to the main task of interest, the appropriate version (based on group assignment) of the SRPM paradigm. Individuals with MS were randomly assigned to two groups. One (MS-SR group) underwent the full Selective Reminding PM paradigm (i.e., encoding trials persist until criterion is reached). The second group (MS1T group) underwent only one encoding trial before beginning the PM paradigm. Analogous assignment and task protocol occurred for the HC participants. After completing the PM task, participants completed VPA I, and then were asked to provide a brief medical and psychosocial history, followed by the PASAT. Participants then completed VPA II, followed by being offered a short break. After the break, the Symbol Span test and SRT task encoding trials took place, followed by the measures comprising the MSFC, the SDMT, and the questionnaires (FSS, SR-EDSS, BDI-II, CMDI, SRMQ, and SMRQoL). The retrieval trials of the SRT task were then be completed. At the end of the study participants completed a final VAS-F and were debriefed and compensated for their time.

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Figure 3: Study Flow

2.5 Hypotheses and Plan of Analysis Preliminary analyses were conducted to compare demographic and psychosocial variables between the groups and ensure an equal distribution of these variables in each group. Independent-samples t-tests for continuous variables or chi-square tests of independence for categorical variables were used to examine whether the groups’ distributions differ significantly. The data were checked to determine to what degree the assumptions for each statistical test were violated. If assumptions were not met, data

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transformations or other remedial procedures were undertaken to account for the violations. Analyses addressed the aims of the study. See Table 2 for a description of study variables and associated constructs.

Table 2. Study Variables Measure/Variables SRPM SRPM Supraspan SRPM Trials to Criterion (TTC) MIST Task 1 (etc.) Score MIST Total Score (PMT) MIST Time Cue Score MIST Event Cue Score MIST Recognition (RRT) Score Cue Detection Score Execution Score

Function Measured Performance on SRPM Learning Trial 1; - Intention Formation stage performance # of trials required to achieve perfect recall x2; - Intention Formation stage performance Performance on each of the 8 PM tasks Overall PM performance PM performance on time-based cue tasks PM performance on event-based cue tasks Forced-Choice recognition of MIST tasks; - Intention Retention stage performance Ability to correctly detect MIST cues; - Intention Initiation stage performance Ability to correctly enact MIST tasks; - Intention Execution stage performance

Neuropsychological Measures Verbal Paired Associates (VPA) I raw Immediate paired associate memory score/SS VPA II raw score/SS/Recognition Delayed paired associate memory Symbol Span raw score/SS Nonverbal working memory, executive function Open-Trial Selective Reminding Test (OT- Retrospective memory encoding SRT) Supraspan/Trials to Criterion OT-SRT Delayed Recall/Recognition Retrospective memory retrieval Oral Symbol Digit Modalities Test (SDMT) Information processing speed Paced Auditory Serial Addition Test Information processing speed/working (PASAT), 2 sec/3 sec raw score memory/executive function MSFC Score MS symptom severity (composite score) Questionnaires FSS Total score/Average score Self-reported Symptomatic fatigue BDI-II score Self-reported Depression severity Chicago Multiscale Depression Inventory Self-reported Depression severity (CMDI) score Self-Reported EDSS Self-reported MS symptom severity Prospective and Retrospective Memory Frequency of and Frustration with self-reported Questionnaire-Extended (PRMQ): Overall memory errors; overall memory errors and PM-specific Frequency/Frustration and PM-specific errors Frequency/Frustration Survey of Memory-Related Quality of Life Self-report of memory-related influences on Quality of (SMRQoL) Retrospective/Prospective Life; retrospective- and prospective-specific scales scores

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Aim 1. To examine the contributions of the Intention Formation stage of the MultiPhasic Process model to prospective memory function in multiple sclerosis. Hypothesis 1.1: The Selective Reminding component of the SRPM paradigm will improve PM performance in both HC and MS. To examine differences in performance between the SR and 1T groups, a series of independent-samples t-tests was conducted to examine group differences on SRPM performance variables of interest, including SRPM Total Score (i.e., performance on the PM tasks of the MIST; possible scores range from 0-48), SRPM Recognition Score (i.e., performance on eight MIST post-test recognition items; possible scores range from 0-8), SRPM Time- and Event-Cued Task Scores (i.e., performance on each set of 4 MIST items cued by either a certain clock time or a specific event; each possible score ranges from 0-8), and individual scores on each of the eight MIST tasks (possible scores for each item range from 0-2). Comparisons for these analyses were conducted separately for the MS and HC samples. It was hypothesized that SR groups will outperform 1T groups on all variables of interest. Hypothesis 1.2: Individuals with MS will score more poorly on PM tasks compared to HCs when both groups receive only one learning trial. A series of independent-samples t-tests was conducted to examine differences between the MS and HC groups on SRPM 1T Version performance variables of interest, including SRPM Total Score, SRPM Recognition Score, SRPM Supraspan score (i.e., immediate recall of the 8 MIST tasks during encoding trial 1), MIST Time Cue Score, MIST Event Cue Score, SRPM Cue Detection score (i.e., total number of times the

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participant made any type of response (correct or not) to an event- or time-based cue; possible scores range from 0-16) and SRPM Execution Score (total number of responses that correspond to one of the tasks presented, regardless of the timing of the response; possible scores range from 0-16). It was hypothesized that HCs will outperform MS participants on all variables of interest. Hypothesis 1.3: Individuals with MS will perform equally on PM tasks compared to HCs when presented with sufficient learning trials to reach criterion. A series of independent-samples t-tests was conducted to examine differences between the MS and HC groups on SRPM SR Version performance variables of interest, in the same manner as described above for the 1T Version (Hypothesis 1.2), but this analysis also included the SR-specific variable Trials to Criterion (TTC; the number of trials required to reach criterion; scores can range from 2 to 15). It was hypothesized that groups’ performance will be statistically equivalent on all variables of interest. Hypothesis 1.4: Individuals with MS will require more learning trials and/or more reminder prompts to reach criterion on the SRPM task learning trials. An independent-samples t-test was conducted to examine differences between the MS and HC groups on a) SRPM (SR Version) Trials to Criterion performance and b) SRPM Reminders (the sum of prompts given in the course of the learning trials). It was hypothesized that the HC group will require fewer trials and/or fewer reminder prompts to reach criterion than the MS group.

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Aim 2. To examine the neuropsychological correlates of performance on specific Multi-Phasic Process model stages. Hypothesis 2.1: PM encoding (i.e., Intention Formation) performance is associated with processing speed and/or executive functioning performance. A series of stepwise multiple linear regression analyses was conducted to examine potential models that demonstrate whether processing speed and executive function performance variables are predictive of PM encoding. To examine group differences, stepwise multiple linear regression analyses were performed separately for each of the four groups (or two groups for SR-paradigm specific variables) and using the combined experimental groups (e.g., SR (MS + HCs) versus 1T (MS + HCs)), using 3 separate SRPM encoding variables as dependent variables (SRPM TTC, SRPM supraspan, and SRPM Reminders) and the following as predictor variables: SDMT raw score, PASAT 3s raw score, PASAT 2s raw score, Symbol Span raw score, and Symbol Span scaled score. Hypothesis 2.2: PM retention (i.e., Intention Retention) performance is associated with retrospective memory performance. A series of stepwise multiple linear regression analyses was conducted to examine potential models that demonstrate whether retrospective memory performance variables are predictive of PM retention. To examine group differences, stepwise multiple linear regression analyses were performed separately for each of the four groups and using the combined experimental groups (e.g., SR (MS + HCs) versus 1T (MS + HCs)), using SRPM Recognition score as the dependent variable and the following as predictor variables: OT-SRT Trial 1 score, OT-SRT Trials to Criterion (TTC), OT-SRT Delayed Recall score, OT-SRT Recognition Discrimination score, VPA I Trial 1 score, VPA I

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Immediate Recall raw score, VPA I Immediate Recall scaled score, VPA II Delayed Recall raw score, VPA II Delayed Recall scaled score, and VPA II Recognition score. Hypothesis 2.3: PM initiation (i.e., Intention Initiation) performance is associated with processing speed and/or executive functioning performance. A series of stepwise multiple linear regression analyses was conducted to examine potential models that demonstrate whether processing speed and executive functioning performance variables are predictive of PM Initiation. To examine group differences, stepwise multiple linear regression analyses were performed separately for each of the four groups and using the combined experimental groups (e.g., SR (MS + HCs) versus 1T (MS + HCs)), using SRPM Cue Detection score as the dependent variable and the following as predictor variables: SDMT raw score, PASAT 3s raw score, PASAT 2s raw score, Symbol Span raw score, and Symbol Span scaled score. Hypothesis 2.4: PM execution (i.e., Intention Execution) performance is associated with executive functioning performance. A series of stepwise multiple linear regression analyses was conducted to examine potential models that demonstrate whether executive functioning variables are predictive of PM Execution. To examine group differences, stepwise multiple linear regression analyses were performed separately for each of the four groups and using the combined experimental groups (e.g., SR (MS + HCs) versus 1T (MS + HCs)), using SRPM Execution score as the dependent variable and the two PASAT raw scores as predictor variables.

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3. RESULTS 3.1 Analytical Strategy All analyses were performed using SPSS 20. Analyses in the current study used descriptive analyses, comparisons of group means and distributions, and stepwise multiple linear regressions. Between-group analyses used either 1) presence of MS diagnosis (i.e., MS group versus Healthy Control (HC) group) or 2) SRPM version (i.e., Selective Reminding versus One-Trial (1T) version) as the grouping variable. Descriptive analyses were performed for demographic variables, neuropsychological and experimental paradigm variables, and psychosocial outcome variables. Means and standard deviations (or percentage/frequencies for categorical variables) for variables of interest are reported for each group. Where possible, raw scores were converted to standardized scores to facilitate comparison-making. The distribution of each variable of interest was tested for normality using the Shapiro-Wilk Test and visual inspection of Q-Q plots. The data were examined for presence of outliers, which identified several extreme values across variables of interest. These values were excluded from all analyses because of their potential for skewing measures of central tendency and introducing systematic error on variables of interest. Furthermore, one participant (HC21) was removed from all analyses due to extreme scores/noncompliance with task instructions on several measures of interest. Non-directional hypotheses were tested using two-tailed tests. The criterion for statistical significance was p < .05 unless otherwise noted.

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3.2 Characteristics of the samples 3.2.1 Comparison of Demographics and Clinical Characteristics Sample characteristics were compared with a series of one-way ANOVAs, independent samples t-tests, and chi-square tests. These analyses are presented in Table 3. The four samples did not differ significantly on age, education, racial distribution, gender distribution, or MSFC Score. The MS samples did not differ significantly on MS subtype distribution. As expected, EDSS score differed significantly across groups. These group differences were driven by differences between diagnostic groups (MS vs. HC). Within the MS groups, length of MS diagnosis did not differ significantly. All MS participants were on a stable regimen of medications at the time of the study.

Table 3: Demographic and Clinical Variables SRPM Version n Age Education Gender (F/M) Race (AA/As/C/H) MSFC Score EDSS

MS Groups SR 1T M (SD) 11 10 51.4 (8.7) 48.9 (9.0) 16.7 (1.0) 15.7 (2.5) 9/2 8/2

HC Groups SR 1T

Test Statistic

13 41.6 (14.6) 14.7 (2.3) 8/5

9 44.9 (13.8) 16.3 (3.0) 7/2

F(3,39)=1.52, p=0.22 F(3,39)=1.78, p=0.17 χ2(3) = 1.7, p=0.64

0/0/11/0

2/0/8/0

5/0/7/1

4/1/4/0

χ2(9) = 14.0, p=0.12

0.4 (0.3) 5.0 (1.0)

-0.9 (2.4) 4.6 (2.1)

0.31 (0.6) 0.1 (0.3)

0.5 (0.4) 0.6 (1.7)

F(3,39)=2.79, p=0.05 F(3,35)=34.81, p