- Email: [email protected]
Autobiographical memory and structural brain changes in chronic phase TBI
Accepted Manuscript Autobiographical Memory and Structural Brain Changes in Chronic Phase TBI Carrie Esopenko, Brian Levine, Ph.D PII:
S0010-9452(17)30011-4
DOI:
10.1016/j.cortex.2017.01.007
Reference:
CORTEX 1919
To appear in:
Cortex
Received Date: 18 April 2016 Revised Date:
26 November 2016
Accepted Date: 1 January 2017
Please cite this article as: Esopenko C, Levine B, Autobiographical Memory and Structural Brain Changes in Chronic Phase TBI, CORTEX (2017), doi: 10.1016/j.cortex.2017.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Autobiographical Memory and Structural Brain Changes in Chronic Phase TBI
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Carrie Esopenkoa1 & Brian Levinea,b*
a. Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario
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b. University of Toronto, Toronto, Ontario
*Corresponding Author: Brian Levine, Ph.D
Baycrest Health Sciences
Toronto, Ontario
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Canada, M6A 2E1
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3560 Bathurst Street
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Rotman Research Institute
Email: [email protected] Phone: 416-785-2500 x. 3593; Fax: 416-785-2862
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Carrie Esopenko is now an Assistant Professor in the Department of Rehabilitation and Movement Sciences, at Rutgers, The State University of New Jersey
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 1 Abstract Traumatic brain injury (TBI) is associated with a range of neuropsychological deficits, including attention, memory, and executive functioning attributable to diffuse axonal injury
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with accompanying focal frontal and temporal damage. Although the memory deficit of TBI has been well characterized with laboratory tests, comparatively little research has
examined retrograde autobiographical memory at the chronic phase of TBI, with no prior
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studies of unselected patients drawn directly from hospital admissions for trauma.
Moreover, little is known about the effects of TBI on canonical episodic and non-episodic
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(e.g., semantic) autobiographical memory processes. In the present study, we assessed the effects of chronic-phase TBI on autobiographical memory in patients with focal and diffuse axonal injury spanning the range of TBI severity. Patients and socioeconomic- and agematched controls were administered the Autobiographical Interview (Levine, Svoboda,
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Hay, Winocur, & Moscovitch, 2002) a widely used method for dissociating episodic and semantic elements of autobiographical memory, along with tests of neuropsychological and functional outcome. Measures of episodic and non-episodic autobiographical memory were
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compared with regional brain volumes derived from high-resolution structural magnetic
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resonance imaging (MRI). Severe TBI (but not mild or moderate TBI) was associated with reduced recall of episodic autobiographical details and increased recall of non-episodic details relative to healthy comparison participants. There were no significant associations between AM performance and neuropsychological or functional outcome measures. Within the full TBI sample, autobiographical episodic memory was associated with reduced volume distributed across temporal, parietal, and prefrontal regions considered to be part
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 2 of the brain’s autobiographical memory network. These results suggest that TBI-related distributed volume loss affects episodic autobiographical recollection. Highlights
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The Autobiographical Interview was applied in 70 TBI and 22 comparison participants Brain structure was well-characterized with high-resolution structural MRI Severe TBI was associated with reduced episodic and increased non-episodic details Episodic detail reduction was associated with distributed brain volume loss in TBI The diffuse lesion of TBI causes inefficiency in autobiographical memory retrieval
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• • • • •
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 3 1. Introduction Autobiographical memory (AM) tasks draw upon multiple cognitive operations that bring to consciousness details about both personal past episodes (i.e., episodic
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autobiographical memory) or personal factual information (i.e., personal semantic
memory; Conway, 2001; Levine et al., 2002; Renoult, Davidson, Palombo, Moscovitch, & Levine, 2012). Past neuroimaging work has shown that AM is supported by a network of
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regions, including the medial and lateral prefrontal, posterior cingulate, and medial and lateral temporal cortices, and the medial temporal lobes (Cabeza & St Jacques, 2007;
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Svoboda, McKinnon, & Levine, 2006). Alterations to regions within this network, particularly in the medial temporal lobes, leads to deficits in episodic AM (for review, see Moscovitch, Cabeza, Winocur, & Nadel, 2016; Sheldon, Farb, Palombo, & Levine, 2016; Winocur & Moscovitch, 2011). Less is known about the effects of damage to other parts of
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the AM network (for exceptions, see Berryhill, Phuong, Picasso, Cabeza, & Olson, 2007; Bright et al., 2006; Davidson et al., 2008; Kopelman, Stanhope, & Kingsley, 1999; McKinnon et al., 2008).
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Traumatic brain injury (TBI) is characterized by diffuse axonal injury (DAI;
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Povlishock & Katz, 2005) causing volume loss across the cortical mantle (Levine et al., 2008) as well as focal cortical contusions in ventral frontal and anterior temporal regions (Gentry, Godersky, & Thompson, 1988; Levin, 1989). Given the distributed nature of the functional neuroanatomy of AM, TBI provides a unique lesion model for the understanding brain mechanisms underlying AM. Moreover, it is important for clinical reasons to clarify the effects of TBI on AM as memory complaints in general are a cardinal sign of post-TBI
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 4 cognitive changes (Stuss & Gow, 1992) and the most common cognitive complaint following TBI (Mateer, Sohlberg, & Crinean, 1987). Although TBI is associated with retrograde amnesia and confabulation in the acute
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phase (for review, see Schacter & Crovitz, 1977), few studies have assessed AM in chronic phase TBI patients. Severe TBI is associated with impaired episodic AM (Carlesimo et al., 1998; Coste et al., 2011; Coste et al., 2015; Knight & O'Hagan, 2009; Levin et al., 1985;
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Piolino et al., 2007; Rasmussen & Berntsen, 2014) whereas results in mild to moderate TBI have been mixed, with case study evidence of impairment (e.g., Starkstein, Sabe, & Dorrego,
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1997) and impairment in university students with concussion history (Barry & Tomes, 2015) but not in veterans with mild blast-related TBI (Palombo et al., 2015). All previous studies of TBI have used small samples recruited post-acute hospitalization, excluding patients with good recovery who did not present for treatment following hospitalization.
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We assessed AM in an unselected sample of 70 patients recruited from initial hospital admission spanning the full spectrum of TBI, along with socioeconomic-matched comparison subjects, using the Autobiographical Interview (AI; Levine et al., 2002). In this
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technique, naturalistic autobiographical protocols are transcribed and segmented into
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internal (episodic) or external (non-episodic) details. The AI allows for the parametric quantification of independent measures of episodic and non-episodic memory from within a single narrative, whereas other measures probe these memory processes through separate interviews (e.g., Kopelman, Wilson, & Baddeley, 1989) or focus only on episodic AM (e.g., Piolino, Desgranges, Benali, & Eustache, 2002). The AI assesses memory for events selected by participants prior to testing, isolating elaboration of event details from generation and selection of events that are highly dependent on executive processes.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 5 Finally, we probed five lifetime periods to assess of age-of-memory (i.e., temporal gradient) effects with the prediction that episodic AM impairment in TBI would show a flat temporal gradient, as expected with diffuse damage (Carlesimo et al., 1998; Piolino et al., 2007).
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The AI has been applied widely in samples of patients with brain disease (e.g., Addis, Moscovitch, & McAndrews, 2007; Irish et al., 2011; McKinnon et al., 2008; Murphy, Troyer, Levine, & Moscovitch, 2008; Rosenbaum et al., 2008), aging (Addis, Wong, & Schacter,
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2008; Levine et al., 2002), and psychiatric conditions (McKinnon et al., 2015; Söderlund et al., 2014). It has been applied in one study of nine individuals with moderate-severe TBI
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(Rasmussen & Berntsen, 2014) and one study of veterans with mild TBI due to blast exposure (Palombo et al., 2015). We predicted that patients with severe TBI would have reduced episodic autobiographical memory relative to comparison participants. Given the conflicting findings in the literature regarding mild-moderate TBI (Barry & Tomes, 2015;
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Palombo et al., 2015), we had no specific prediction for these groups. We also assessed the relationship of AM as assessed by the AI to performance on an extensive battery of neuropsychological tests, including tests of executive function that have been previously
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related to AM performance using other measures in TBI (Coste et al., 2011; Coste et al.,
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2015; Piolino et al., 2007).
To our knowledge, there are no published studies assessing the relationship of AM
to structural brain changes in TBI. We assessed the relationship of AM performance to regional brain volumes quantified from high resolution structural MRI scans using a multivariate statistical technique, partial least squares (PLS). We predicted that the recall of internal details would be associated with reduced brain volume in the frontal, temporal, and medial parietal regions known to be associated with AM (Cabeza & St Jacques, 2007;
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 6 Svoboda et al., 2006). Furthermore, given that the AM network is functionally distributed, we predicted that distributed volume loss would be associated with reduced recollection of
2. Materials and Methods 2.1 Participants
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episodic autobiographical memory.
Patients were recruited from consecutive admissions to Sunnybrook Health
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Sciences Centre at approximately one year post-injury as part of the Toronto Traumatic Brain Injury Study (see Fujiwara, Schwartz, Gao, Black, & Levine, 2008; Guild & Levine,
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2015; Levine et al., 2005; Levine et al., 2008 for neuroimaging, neuropsychological, and behavioral description; Levine et al., 2013). Injury severity was determined by the Glasgow Coma Scale (GCS), as documented by the trauma team leader’s score at the time of discharge from the Trauma Unit. For most patients, this score corresponded to the
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recommended 6-hour GCS score (Teasdale & Jennett, 1974). Severity classification (mild/moderate/severe) was upgraded in 10 cases, where extended loss of consciousness (> 2 hr), post-traumatic amnesia (> 48 hr), or focal lesions suggested more severe injury
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than indicated by the GCS. The present study included 70 TBI patients, 15 classified as mild,
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31 classified as moderate, and 24 classified as severe (see Table 1), as well as 22 age-, education, and sex-matched comparison participants. To minimize the effects of socioeconomic factors specific to TBI patients, comparison participants were recruited from friends and family members of the patients. Participants with a history of neurological (aside from the TBI in the patient group) or psychiatric illness or medications known to affect cognitive functioning were excluded. To assess the presence of depression, which can affect AM performance (Söderlund et al., 2014), we examined TBI patients’ scores on
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 7 Component 2 of the Neurobehavioral Rating Scale –Revised (NRS-R; Vanier, Mazaux, Lambert, Dassa, & Levin, 2000; see Guild & Levine, 2015). The mean score was 1.53 (SD = 0.50, range = 2.33), with 91% scoring < 2 (i.e., absent or mild). All participants gave
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informed, written consent to be involved in the study, which was approved by the local ethics board. 2.2 The Autobiographical Interview
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AM was assessed following the Autobiographical Interview procedures as specified in Levine et al., (2002). They will be only briefly described here. Participants were asked to
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provide a detailed description of a significant personal event from early childhood (to age 11), teenage years (ages 11-17), early adulthood (ages 18-35; 2 events), and the past year. Participants were instructed to recall an event that occurred at a specific time and place. Each memory was assessed across free recall (extemporaneous), general probe
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(clarification of instructions), and specific probe (structured interview to elicit additional contextual details) conditions. We report AM performance analyzed cumulatively across the three levels of cueing.
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Transcribed AM protocols were segmented into informational bits or details.
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Details were classified as “internal”, or episodic, if they related directly to the main event described, were specific to time and place, and conveyed a sense of episodic reexperiencing. Internal details were assigned to one of five subcategories (event, place, time, perceptual, and emotion/thought). Details were classified as “external” if they consisted of factual or semantic information, extended to events that did not require recollection of a specific time and place, autobiographical events tangential or unrelated to the main event, repetitions, or other metacognitive statements or editorializing. We report data from the
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 8 main internal and external detail composites. To address significant positive skewness that is typical of AI data, we applied a Winsorization procedure to the data by which scores exceeding +/-2.5 SD from the mean were rescaled to be 2.5 SD from the mean (42 data
McKinnon et al., 2015). 2.3 Neuropsychological and functional outcome test battery
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points were winsorized, accounting for 3.8% of the scores; McKinnon et al., 2008;
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Participants completed a comprehensive battery of neuropsychological and
functional outcome measures described in detail elsewhere (Guild & Levine, 2015; Levine
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et al., 2013). The neuropsychological battery included the Symbol-Digit Modalities Test (SDMT; Smith, 1978), the Trail-Making Test (Army Individual Test Battery, 1944), the SelfOrdered Pointing Test (SOP; Petrides & Milner, 1982), the Hopkins Verbal Learning Test— Revised (HVLT-R; Benedict, Schretlen, Groninger, & Brandt, 1998), Phonemic Word List
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Generation (FAS; Spreen & Strauss, 1998) and the Wisconsin Card Sorting Test (WCST; Stuss et al., 2000). In addition to the NRS-R (see above), functional outcome measures included the Sickness Impact Profile (SIP; Bergner, Bobbitt, Carter, & Gilson, 1981), the
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Head Injury Family Interview Problem Checklist (HIFI; Kay, Cavallo, Ezrachi, & Vavagiakis,
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1995), the Dysexecutive Function Questionnaire (DEX; Burgess, Alderman, Evans, Emslie, & Wilson, 1998). Both self- and significant other ratings were included for the HIFI and the DEX.
2.4 Image acquisition and processing Sixty of the 70 patients in this sample received MRI scans. Two mild, 5 moderate, and 3 severe TBI patients were not scanned due to MRI contraindications (metal in body, claustrophobia). The procedure for image acquisition and processing is described
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 9 elsewhere (Levine et al., 2008, 2013). Briefly, all participants were scanned with a 1.5 Tesla MRI system at the time of data collection. T1-weighted, T2-weighted, proton density, and gradient echo T2 sequences were obtained. Twenty participants (10 moderate, 10 severe)
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were identified as having focal cortical contusions largely in frontotemporal areas (8 right, 4 left, and 8 bilateral). These focal lesions, appearing on at least two slices, had a minimal diameter of 3 mm and were manually defined in the axial plane. Further details on the
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lesion characteristics can be found in Levine et al., (2008) and Levine et al., (2013).
Brain MRI data were analyzed using a previously reported image processing
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pipeline (Levine et al., 2008, 2013) for template matching, brain extraction, segmentation of grey matter, white matter, sulcal and ventricular cerebrospinal fluid (CSF), and lesion volumes. A modified Semi-Automated Brain Region Extraction (SABRE) method was used to derive 38 regions of interest (ROIs) customized to fit each patient's brain anatomy.
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Regional CSF, grey matter, and white matter volumes were adjusted for total intracranial capacity using a regression-based method (Arndt, Cohen, Alliger, Swayze, & Andreasen, 1991).
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2.5 Statistical analyses
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Behavioral data were assessed via mixed model analysis of variance with planned contrasts coding for Group (i.e., three contrasts of mild, moderate and severe TBI to comparison participants), Time Period (childhood, teenage, early adult, adult, past year, coded as a single linear contrast), and Detail Type (internal, external). An additional ANOVA contrasted patients with lesions to patients without lesions, coding Detail Type and Time as specified above. As the lesion patients all had moderate or severe TBI, patients with mild TBI were excluded from this analysis.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 10 PLS correlation (Krishnan, Williams, McIntosh, & Abdi, 2011), a procedure that characterizes shared variance between two datasets, was used to characterize relationships among the brain and behavior measures. This was accomplished by
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calculating the correlation between the two covariance matrices, followed by singular value decomposition to identify mutually independent latent variables (LVs) that express the maximal covariance common to both datasets. The reliability of the association was
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estimated using split-half resampling with 100 split samples and 1500 permutations
(Kovacevic, Abdi, Beaton, & McIntosh, 2013). The stability of each brain region to the
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identified LV was determined through bootstrap resampling; subjects were resampled 500 times with 50% of observations resampled with replacement. A variable’s contribution to the LV was considered reliable given a ratio of salience to standard error (hereafter referred to as the bootstrap ratio, interpreted similar to a Z-score) was greater than 2,
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corresponding to 95% confidence limits. As PLS considers all variables in a single computational step, there is no requirement to correct for multiple comparisons. This same analysis was conducted to assess relationships between AI internal and external details
3. Results
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and the neuropsychological and functional outcome tests.
3.1 Behavioral Analysis: Effect of TBI Group and Detail Type To assess the effects of TBI severity on internal vs. external details across the tested
time periods, we examined three-way Group X Detail Type X Time Period interactions for each of the three group contrasts (i.e., mild, moderate, and severe TBI vs comparison participants). As none of these effects involving Time Period were significant, we assessed Group X Detail Type interactions collapsing across Time Period. There was a significant
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 11 Group X Detail Type interaction for the contrast of severe TBI vs. comparison participants, F (1, 88) = 10.06, p = .002, η2= .103. The interactions for the mild and moderate TBI groups as contrasted to the comparison participants were not significant (p > .05). As seen in
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Figure 1, severe TBI participants recalled fewer internal but more external details relative to comparison participants. Ignoring detail type, there was a significant effect of Time Period on detail generation, F (1, 88) = 20.36, p < .001, η2= .188, corresponding to the
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expected forgetting rates (Rubin & Schulkind, 1997). This effect was enhanced in severe TBI vs. comparison participants, F (1, 88) = 4.39, p = .039, η2= .048. These same
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interactions for the mild and moderate TBI groups vs. comparison participants were not significant. Importantly, there were no significant main effects of Group, suggesting that all three groups generated similar amounts of detail (regardless of detail type). This was supported by an ancillary non-significant one-way ANOVA testing for group effects on total
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details, F(3,88) = 0.687; p = .56). There were no significant main effects or interactions when the lesion and no lesion groups were contrasted. 3.2 Relationship of neuropsychological and functional outcome measures to detail type.
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PLS analyses assessing the relationship of AI internal and external details to
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neuropsychological and functional outcome measures yielded no significant LVs. Exploratory analyses of zero-order correlations between internal and external details revealed no significant correlations surviving correction for multiple comparisons. The highest correlations to internal details were noted for the Self Ordered Pointing Test (6, 10 and 12 item version, r’s (68) = .26, .29 and .28, p’s < .05), the Symbol Digit Modalities Test (oral and written, r’s (68) = .26 and .30, p’s < .05), the Trail Making Test (Parts A and B, r’s (68) = .24 and.28, p’s < .05) and Phonemic Word List Generation (FAS, r (68) = .25, p < .05).
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 12 External details were correlated with set loss on the WCST (r (68) = .26, p < .05). Among the functional outcome measures, the only measure to show even a weak relationship to internal details was the HIFI Affective scale (self-rated; r (68) = .25, p < .05). The HIFI
3.3 Relationship of volumetric brain measures to detail type.
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Physical scale (self rated) was weakly related to external details (r (67) = .24, p < .05).
A single significant LV (p = .004; accounting for 38% of cross-block variance)
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identified a pattern of volumetric brain changes across the TBI sample associated with internal, but not external details. Specifically, a lower number of internal details was
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associated with decreased right medial superior frontal, posterior cingulate gyrus, and bilateral lateral occipital grey matter, as well as left medial orbital frontal and bilateral middle frontal white matter regions. Decreased internal details were also associated with increased CSF volume in the bilateral genual cingulate gyrus, medial temporal lobe,
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anterior basal ganglia, left posterior cingulate gyrus, right anterior cingulate gyrus, and right posterior temporal, superior parietal, inferior parietal, and middle cingulate regions. The split-half permutation analysis indicated that the brain volume pattern and effect of
4. Discussion
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detail type were both reliable (p’s = 0.012 and 0.001, respectively).
AM is a multifaceted cognitive process that is supported by a network of brain
regions including the midline frontoparietal, lateral prefrontal and temporal cortices, as well as the medial temporal lobes (Cabeza & St Jacques, 2007; Svoboda et al., 2006). Alterations to this network, and in particular the medial temporal lobes, lead to deficits in episodic AM (for reviews, see Moscovitch et al., 2016; Winocur & Moscovitch, 2011), which occurs in neurodegenerative (Gilboa et al., 2005; Irish et al., 2011; McKinnon et al., 2008)
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 13 and developmental disorders (Addis et al., 2007; Willoughby, McAndrews, & Rovet, 2013), as well as healthy aging (Levine et al., 2002; Piolino et al., 2002). However, it is not well understood how damage outside the medial temporal lobes, as occurs in TBI, affects
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episodic AM, nor how episodic AM recall is affected by different levels of TBI severity. Nor is it known how AM relates to structural brain alterations in TBI.
We assessed episodic AM in a moderately large sample of patients with TBI using
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the AI, which derives separate estimates of episodic and non-episodic processes from within a single autobiographical narrative (Levine et al., 2002). As demonstrated
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previously (Knight & O'Hagan, 2009; Piolino et al., 2007; Rasmussen & Berntsen, 2014), patients with severe TBI recalled fewer internal, or episodic, details, but more external, non-episodic, details relative to comparison participants across time periods. This effect could not be accounted for by impaired detail generation in general (although severe TBI
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patients did generate fewer details for more remote memories). There was no significant effect of mild or moderate TBI on AM recall. Prior studies of mild TBI have yielded mixed results, with one study showing impaired AM in undergraduates with a history of
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concussion (Barry & Tomes, 2015) and another showing no effect on the AI in veterans
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with mild TBI due to blast injuries (Palombo et al., 2015), although the patients’ narratives in that study were less coherent when rated by other measures. AM performance as measured by the AI was neither significantly related to
neuropsychological performance measures nor to functional outcome measures. Considering the zero-order correlations, the neuropsychological tests shared no more than 10% of the variance explained by AI details, explaining why no latent variables relating the two sets of data were revealed by PLS, a sensitive data-driven multivariate analysis
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 14 technique. Previous studies have reported a relationship between measures of executive function and AM performance in TBI (Coste et al., 2015; Piolino et al., 2007; see also Kopelman et al., 2003). The associations were supported by stepwise regression, which
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yields inflated estimates of association by capitalizing on sampling error specific to the dataset (e.g., see Henderson & Denison, 1989; Judd, McClelland, & Ryan, 2008, pg. 204). Furthermore, the AM measures used, particularly autobiographical fluency (Coste et al.,
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2011; Coste et al., 2015), are themselves measures of executive search and generation, whereas in the AI events are generated and selected prior to testing. When specific detail
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generation was isolated from other generative aspects of event selection in a previous study of AM in TBI, the relationships to executive tasks were attenuated (Coste et al., 2011). At most, liberal interpretation of the zero-order correlations suggests a weak relationship between domain-general tests of executive functioning and internal detail
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generation. Intriguingly, there was an association between set loss on the WCST and external details, also reflecting a lack of task maintenance (i.e., including details not relevant to the central event in the narrative; McKinnon et al., 2015). Yet caution is
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warranted in these interpretations, as none of these correlations were significant after
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correction for multiple comparisons. This neuropsychological analysis suggested that AM as assessed by the AI is
independent from laboratory-based tests, particularly measures of executive function (for similar results in frontotemporal dementia, see Irish et al., 2013 and McKinnon et al., 2008). AM tasks that engage domain-general processes, such as fluency tasks, on the other hand, are expected to draw upon executive processes. As noted below, this does not rule
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 15 out the contribution of other prefrontally-mediated processes not assessed by the standardized test battery. The pattern of reduced internal and increased external details in severe TBI relative
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to comparison subjects mirrors that observed in normal aging (Levine et al., 2002)
corresponding to a general inefficiency in focused AM retrieval. This finding contrasts to previous studies that demonstrated deficits in semantic AM using fluency tasks reliant on
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domain-general processes (Coste et al., 2015). The effects in severe TBI could not be
accounted for by presence of focal lesions; they are attributable to diffuse injury. The PLS
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analyses illustrated the distributed nature of this brain-behavior relationship in TBI, which was consistent with the distributed functional neuroanatomy of AM (Svoboda et al., 2006), such that volume loss over frontal, parietal, temporal, and occipital regions corresponded with reduced production of internal details. Bilateral medial temporal and right posterior
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temporal lobe volumes were correlated with internal detail generation, corresponding to the notion of these regions as hubs in a network involving recovery of episodic details (Moscovitch et al., 2016; Sheldon & Levine, 2016; Winocur & Moscovitch, 2011; see also
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Bright et al., 2006). The contribution of the right inferior and superior parietal regions is
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consistent with the role of these regions in episodic recollection (Berryhill et al., 2007; Davidson et al., 2008; Rugg & Vilberg, 2013; Simons, Peers, Mazuz, Berryhill, & Olson, 2010).
Lateral prefrontal regions are involved in strategic autobiographical retrieval,
including search and retrieval monitoring operations (Kopelman et al., 1999; Simons & Spiers, 2003). Here, white matter volumes in the middle lateral regions bilaterally contributed to the pattern. Although lateral prefrontal regions are not part of the canonical
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 16 AM network (Svoboda et al., 2006), prefrontal white matter is vulnerable to the effects of TBI (Wilde et al., 2012). Moreover, dorsolateral regions are implicated in monitoring processes when events are more confusable (Cabeza et al., 2004; Stuss et al., 1994), which
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may have been the case in individuals with more significant TBI. This finding was hinted at by modest correlations between the Self Ordered Pointing Test, a measure of monitoring within working memory, and internal details. Nonetheless, while AI internal details were
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not significantly related to behavioral measures of executive functions (see above), these executive measures were also unrelated to prefrontal volumes in this sample (Levine et al.,
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2013), suggesting that the prefrontally-mediated processes contributing to the AI may not be assessed standardized clinical executive function tasks.
We observed associations between occipital grey matter and internal details, which are strongly influenced by visual processes (Conway & Pleydell-Pearce, 2000; Greenberg &
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Knowlton, 2014), with evidence for an association between focal occipital damage and impaired AM (Rubin & Greenberg, 1998; Sheldon et al., 2016). Finally, midline regions including the extent of the cingulate gyrus and inferior and superior medial prefrontal
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regions, implicated across the three tissue compartments, are known to be involved in self-
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referential processes, including AM (Buckner & Carroll, 2007). These results provide further evidence that quantified brain volumes are superior to
acute injury characteristics in the assessment of brain-behavior relationships in TBI (Levine et al., 2013). Whereas acute TBI effects on memory (e.g., post-traumatic amnesia, retrograde amnesia) are similar to an amnesic state, the present results indicate that at the chronic stage, a distributed lesion affecting multiple aspects of the AM network causes a generalized inefficiency of retrieval (e.g., recovery of details, reconstruction, elaboration,
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 17 and monitoring) that is distinct from that observed in medial temporal lobe amnesia (Rosenbaum et al., 2008). Although episodic AM was only impaired in the patients classified as severe, the
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observed brain-behavior relationships held across the full sample of TBI patients,
indicating volumetric changes across the TBI severity spectrum can affect episodic AM even if they are only detectable at the group level in patients with severe TBI. When
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patients with chronic-phase TBI complain of memory changes, they are referring to
everyday memory such as AM, not lists of words of pictures. The distributed anatomy
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supporting AM is distinct from that supporting laboratory tasks (McDermott, Szpunar, & Christ, 2009). The present findings suggest that a complete understanding of the functional
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mnemonic deficits in chronic TBI require assessment of AM.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 18 Figure Captions Figure 1. Internal and external details recalled in mild, moderate, and severe TBI groups and comparison subjects. Details are averaged across time periods. A significant interaction
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between Detail Type (internal/external) and Group was noted for a planned contrast of the severe group vs. comparison participants, indicating that the severe TBI patients produced fewer internal and more external details than comparison participants. There were no
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significant effects of group for the mild and moderate TBI patients. Error bars represent standard error. Bars: white = comparison participants; dots = mild TBI; lines = moderate
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TBI; black = severe TBI.
Figure 2. Latent variable from PLS analysis indicating the association of internal details with patterns of volume changes across CSF, grey matter, and white matter in TBI patients. Panels A, B, and C reflect brain regions significantly correlated with internal details (r=
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0.19). The color bar indicates the coding scheme according to the level of the bootstrap ratio, interpreted as a Z-score. CSF values are negative (Panel A), indicating volume increases associated with fewer internal details, whereas grey and white matter values are
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positive (Panels B and C, respectively), indicating volume reductions associated with fewer
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internal details. Images were thresholded at a bootstrap ratio of 2.0, corresponding approximately to p < .05. Axial images are displayed in radiological convention (right hemisphere displayed on left side of image). The right and left cingulate volumes are displayed on the right and left side of the images, respectively.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 19 Acknowledgements The TBI and comparison participants are thanked for volunteering their time and effort to this research. Ann Campbell, Catherine Hynes, Sabitha Kanagasabai, Charlene
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O’Connor, Colleen O’Toole, Marina Mandic, Karen Philp, Adriana Fecko, Jovanka Skocic, and Gary Turner are thanked for technical assistance. Natasa Kovacevic, Fuqiang Gao, Joel
Ramirez, and Sandra Black are thanked for assistance with the neuroimaging pipeline. We
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gratefully thank the TBI participants and non-injured volunteers for participating in this research. This research was supported by grants from the Canadian Institutes of Health
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Research (Grant #sMT-14744, MOP-37535, and MOP-108540), and the NIH-NICHD (Grant #HD42385-01) to B.L., and an Alzheimer's Society of Canada’s Research Program Post
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Doctoral Fellowship awarded to C.E.
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Table 1: Characteristics of all TBI patients and comparison participants
SD 2.6 2.8 2.4 2.7 1.9
SD 6.0 5.9 6.4 5.7 -
GCS3 Mean 10.1 14.6 11.1 5.9 -
SD 3.9 0.7 2.2 2.5 -
LOC4 Median 48.0 0.0 18.0 144.0 -
IQR 167 0 149 276 -
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Vocabulary2 Mean 27.8 27.9 28.4 27.0 -
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70 (43) 15 (9) 31 (17) 24 (17) 22 (10)
SD 10.4 12.5 10.8 7.9 8.3
Education Mean 14.4 13.7 14.8 14.2 15.0
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Note: 1. Number of males in parentheses. 2. Raw score on the vocabulary subtest of the Shipley Institute of Living Scale (Zachary, 1986). 3. Glasgow Coma Scale score (Teasdale & Jennett, 1974). 4. Duration of loss of consciousness in hours 5. Duration of post-traumatic amnesia in hours 6. Time since injury in years
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TOTAL Mild Moderate Severe Controls
Age Mean 31.0 32.5 32.5 28.2 27.9
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N1
PTA5 Median 336 0 324 1008 -
IQR 810 2 354 936 -
TSI6 Mean 1.1 1.2 1.1 1.0 -
SD 0.4 0.5 0.4 0.2 -
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Figure 1.
70
*
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30
*
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20
10
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Number of Details
50
0 Internal
External Detail Type
ACCEPTED MANUSCRIPT Figure 2.
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CSF
Panel A:
White Matter
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Panel C:
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Grey Matter
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Panel B:
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1
0
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S0010-9452(17)30011-4
DOI:
10.1016/j.cortex.2017.01.007
Reference:
CORTEX 1919
To appear in:
Cortex
Received Date: 18 April 2016 Revised Date:
26 November 2016
Accepted Date: 1 January 2017
Please cite this article as: Esopenko C, Levine B, Autobiographical Memory and Structural Brain Changes in Chronic Phase TBI, CORTEX (2017), doi: 10.1016/j.cortex.2017.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Autobiographical Memory and Structural Brain Changes in Chronic Phase TBI
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Carrie Esopenkoa1 & Brian Levinea,b*
a. Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario
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b. University of Toronto, Toronto, Ontario
*Corresponding Author: Brian Levine, Ph.D
Baycrest Health Sciences
Toronto, Ontario
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Canada, M6A 2E1
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3560 Bathurst Street
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Rotman Research Institute
Email: [email protected] Phone: 416-785-2500 x. 3593; Fax: 416-785-2862
1
Carrie Esopenko is now an Assistant Professor in the Department of Rehabilitation and Movement Sciences, at Rutgers, The State University of New Jersey
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 1 Abstract Traumatic brain injury (TBI) is associated with a range of neuropsychological deficits, including attention, memory, and executive functioning attributable to diffuse axonal injury
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with accompanying focal frontal and temporal damage. Although the memory deficit of TBI has been well characterized with laboratory tests, comparatively little research has
examined retrograde autobiographical memory at the chronic phase of TBI, with no prior
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studies of unselected patients drawn directly from hospital admissions for trauma.
Moreover, little is known about the effects of TBI on canonical episodic and non-episodic
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(e.g., semantic) autobiographical memory processes. In the present study, we assessed the effects of chronic-phase TBI on autobiographical memory in patients with focal and diffuse axonal injury spanning the range of TBI severity. Patients and socioeconomic- and agematched controls were administered the Autobiographical Interview (Levine, Svoboda,
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Hay, Winocur, & Moscovitch, 2002) a widely used method for dissociating episodic and semantic elements of autobiographical memory, along with tests of neuropsychological and functional outcome. Measures of episodic and non-episodic autobiographical memory were
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compared with regional brain volumes derived from high-resolution structural magnetic
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resonance imaging (MRI). Severe TBI (but not mild or moderate TBI) was associated with reduced recall of episodic autobiographical details and increased recall of non-episodic details relative to healthy comparison participants. There were no significant associations between AM performance and neuropsychological or functional outcome measures. Within the full TBI sample, autobiographical episodic memory was associated with reduced volume distributed across temporal, parietal, and prefrontal regions considered to be part
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 2 of the brain’s autobiographical memory network. These results suggest that TBI-related distributed volume loss affects episodic autobiographical recollection. Highlights
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The Autobiographical Interview was applied in 70 TBI and 22 comparison participants Brain structure was well-characterized with high-resolution structural MRI Severe TBI was associated with reduced episodic and increased non-episodic details Episodic detail reduction was associated with distributed brain volume loss in TBI The diffuse lesion of TBI causes inefficiency in autobiographical memory retrieval
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• • • • •
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 3 1. Introduction Autobiographical memory (AM) tasks draw upon multiple cognitive operations that bring to consciousness details about both personal past episodes (i.e., episodic
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autobiographical memory) or personal factual information (i.e., personal semantic
memory; Conway, 2001; Levine et al., 2002; Renoult, Davidson, Palombo, Moscovitch, & Levine, 2012). Past neuroimaging work has shown that AM is supported by a network of
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regions, including the medial and lateral prefrontal, posterior cingulate, and medial and lateral temporal cortices, and the medial temporal lobes (Cabeza & St Jacques, 2007;
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Svoboda, McKinnon, & Levine, 2006). Alterations to regions within this network, particularly in the medial temporal lobes, leads to deficits in episodic AM (for review, see Moscovitch, Cabeza, Winocur, & Nadel, 2016; Sheldon, Farb, Palombo, & Levine, 2016; Winocur & Moscovitch, 2011). Less is known about the effects of damage to other parts of
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the AM network (for exceptions, see Berryhill, Phuong, Picasso, Cabeza, & Olson, 2007; Bright et al., 2006; Davidson et al., 2008; Kopelman, Stanhope, & Kingsley, 1999; McKinnon et al., 2008).
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Traumatic brain injury (TBI) is characterized by diffuse axonal injury (DAI;
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Povlishock & Katz, 2005) causing volume loss across the cortical mantle (Levine et al., 2008) as well as focal cortical contusions in ventral frontal and anterior temporal regions (Gentry, Godersky, & Thompson, 1988; Levin, 1989). Given the distributed nature of the functional neuroanatomy of AM, TBI provides a unique lesion model for the understanding brain mechanisms underlying AM. Moreover, it is important for clinical reasons to clarify the effects of TBI on AM as memory complaints in general are a cardinal sign of post-TBI
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 4 cognitive changes (Stuss & Gow, 1992) and the most common cognitive complaint following TBI (Mateer, Sohlberg, & Crinean, 1987). Although TBI is associated with retrograde amnesia and confabulation in the acute
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phase (for review, see Schacter & Crovitz, 1977), few studies have assessed AM in chronic phase TBI patients. Severe TBI is associated with impaired episodic AM (Carlesimo et al., 1998; Coste et al., 2011; Coste et al., 2015; Knight & O'Hagan, 2009; Levin et al., 1985;
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Piolino et al., 2007; Rasmussen & Berntsen, 2014) whereas results in mild to moderate TBI have been mixed, with case study evidence of impairment (e.g., Starkstein, Sabe, & Dorrego,
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1997) and impairment in university students with concussion history (Barry & Tomes, 2015) but not in veterans with mild blast-related TBI (Palombo et al., 2015). All previous studies of TBI have used small samples recruited post-acute hospitalization, excluding patients with good recovery who did not present for treatment following hospitalization.
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We assessed AM in an unselected sample of 70 patients recruited from initial hospital admission spanning the full spectrum of TBI, along with socioeconomic-matched comparison subjects, using the Autobiographical Interview (AI; Levine et al., 2002). In this
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technique, naturalistic autobiographical protocols are transcribed and segmented into
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internal (episodic) or external (non-episodic) details. The AI allows for the parametric quantification of independent measures of episodic and non-episodic memory from within a single narrative, whereas other measures probe these memory processes through separate interviews (e.g., Kopelman, Wilson, & Baddeley, 1989) or focus only on episodic AM (e.g., Piolino, Desgranges, Benali, & Eustache, 2002). The AI assesses memory for events selected by participants prior to testing, isolating elaboration of event details from generation and selection of events that are highly dependent on executive processes.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 5 Finally, we probed five lifetime periods to assess of age-of-memory (i.e., temporal gradient) effects with the prediction that episodic AM impairment in TBI would show a flat temporal gradient, as expected with diffuse damage (Carlesimo et al., 1998; Piolino et al., 2007).
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The AI has been applied widely in samples of patients with brain disease (e.g., Addis, Moscovitch, & McAndrews, 2007; Irish et al., 2011; McKinnon et al., 2008; Murphy, Troyer, Levine, & Moscovitch, 2008; Rosenbaum et al., 2008), aging (Addis, Wong, & Schacter,
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2008; Levine et al., 2002), and psychiatric conditions (McKinnon et al., 2015; Söderlund et al., 2014). It has been applied in one study of nine individuals with moderate-severe TBI
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(Rasmussen & Berntsen, 2014) and one study of veterans with mild TBI due to blast exposure (Palombo et al., 2015). We predicted that patients with severe TBI would have reduced episodic autobiographical memory relative to comparison participants. Given the conflicting findings in the literature regarding mild-moderate TBI (Barry & Tomes, 2015;
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Palombo et al., 2015), we had no specific prediction for these groups. We also assessed the relationship of AM as assessed by the AI to performance on an extensive battery of neuropsychological tests, including tests of executive function that have been previously
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related to AM performance using other measures in TBI (Coste et al., 2011; Coste et al.,
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2015; Piolino et al., 2007).
To our knowledge, there are no published studies assessing the relationship of AM
to structural brain changes in TBI. We assessed the relationship of AM performance to regional brain volumes quantified from high resolution structural MRI scans using a multivariate statistical technique, partial least squares (PLS). We predicted that the recall of internal details would be associated with reduced brain volume in the frontal, temporal, and medial parietal regions known to be associated with AM (Cabeza & St Jacques, 2007;
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 6 Svoboda et al., 2006). Furthermore, given that the AM network is functionally distributed, we predicted that distributed volume loss would be associated with reduced recollection of
2. Materials and Methods 2.1 Participants
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episodic autobiographical memory.
Patients were recruited from consecutive admissions to Sunnybrook Health
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Sciences Centre at approximately one year post-injury as part of the Toronto Traumatic Brain Injury Study (see Fujiwara, Schwartz, Gao, Black, & Levine, 2008; Guild & Levine,
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2015; Levine et al., 2005; Levine et al., 2008 for neuroimaging, neuropsychological, and behavioral description; Levine et al., 2013). Injury severity was determined by the Glasgow Coma Scale (GCS), as documented by the trauma team leader’s score at the time of discharge from the Trauma Unit. For most patients, this score corresponded to the
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recommended 6-hour GCS score (Teasdale & Jennett, 1974). Severity classification (mild/moderate/severe) was upgraded in 10 cases, where extended loss of consciousness (> 2 hr), post-traumatic amnesia (> 48 hr), or focal lesions suggested more severe injury
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than indicated by the GCS. The present study included 70 TBI patients, 15 classified as mild,
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31 classified as moderate, and 24 classified as severe (see Table 1), as well as 22 age-, education, and sex-matched comparison participants. To minimize the effects of socioeconomic factors specific to TBI patients, comparison participants were recruited from friends and family members of the patients. Participants with a history of neurological (aside from the TBI in the patient group) or psychiatric illness or medications known to affect cognitive functioning were excluded. To assess the presence of depression, which can affect AM performance (Söderlund et al., 2014), we examined TBI patients’ scores on
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 7 Component 2 of the Neurobehavioral Rating Scale –Revised (NRS-R; Vanier, Mazaux, Lambert, Dassa, & Levin, 2000; see Guild & Levine, 2015). The mean score was 1.53 (SD = 0.50, range = 2.33), with 91% scoring < 2 (i.e., absent or mild). All participants gave
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informed, written consent to be involved in the study, which was approved by the local ethics board. 2.2 The Autobiographical Interview
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AM was assessed following the Autobiographical Interview procedures as specified in Levine et al., (2002). They will be only briefly described here. Participants were asked to
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provide a detailed description of a significant personal event from early childhood (to age 11), teenage years (ages 11-17), early adulthood (ages 18-35; 2 events), and the past year. Participants were instructed to recall an event that occurred at a specific time and place. Each memory was assessed across free recall (extemporaneous), general probe
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(clarification of instructions), and specific probe (structured interview to elicit additional contextual details) conditions. We report AM performance analyzed cumulatively across the three levels of cueing.
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Transcribed AM protocols were segmented into informational bits or details.
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Details were classified as “internal”, or episodic, if they related directly to the main event described, were specific to time and place, and conveyed a sense of episodic reexperiencing. Internal details were assigned to one of five subcategories (event, place, time, perceptual, and emotion/thought). Details were classified as “external” if they consisted of factual or semantic information, extended to events that did not require recollection of a specific time and place, autobiographical events tangential or unrelated to the main event, repetitions, or other metacognitive statements or editorializing. We report data from the
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 8 main internal and external detail composites. To address significant positive skewness that is typical of AI data, we applied a Winsorization procedure to the data by which scores exceeding +/-2.5 SD from the mean were rescaled to be 2.5 SD from the mean (42 data
McKinnon et al., 2015). 2.3 Neuropsychological and functional outcome test battery
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points were winsorized, accounting for 3.8% of the scores; McKinnon et al., 2008;
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Participants completed a comprehensive battery of neuropsychological and
functional outcome measures described in detail elsewhere (Guild & Levine, 2015; Levine
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et al., 2013). The neuropsychological battery included the Symbol-Digit Modalities Test (SDMT; Smith, 1978), the Trail-Making Test (Army Individual Test Battery, 1944), the SelfOrdered Pointing Test (SOP; Petrides & Milner, 1982), the Hopkins Verbal Learning Test— Revised (HVLT-R; Benedict, Schretlen, Groninger, & Brandt, 1998), Phonemic Word List
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Generation (FAS; Spreen & Strauss, 1998) and the Wisconsin Card Sorting Test (WCST; Stuss et al., 2000). In addition to the NRS-R (see above), functional outcome measures included the Sickness Impact Profile (SIP; Bergner, Bobbitt, Carter, & Gilson, 1981), the
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Head Injury Family Interview Problem Checklist (HIFI; Kay, Cavallo, Ezrachi, & Vavagiakis,
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1995), the Dysexecutive Function Questionnaire (DEX; Burgess, Alderman, Evans, Emslie, & Wilson, 1998). Both self- and significant other ratings were included for the HIFI and the DEX.
2.4 Image acquisition and processing Sixty of the 70 patients in this sample received MRI scans. Two mild, 5 moderate, and 3 severe TBI patients were not scanned due to MRI contraindications (metal in body, claustrophobia). The procedure for image acquisition and processing is described
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 9 elsewhere (Levine et al., 2008, 2013). Briefly, all participants were scanned with a 1.5 Tesla MRI system at the time of data collection. T1-weighted, T2-weighted, proton density, and gradient echo T2 sequences were obtained. Twenty participants (10 moderate, 10 severe)
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were identified as having focal cortical contusions largely in frontotemporal areas (8 right, 4 left, and 8 bilateral). These focal lesions, appearing on at least two slices, had a minimal diameter of 3 mm and were manually defined in the axial plane. Further details on the
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lesion characteristics can be found in Levine et al., (2008) and Levine et al., (2013).
Brain MRI data were analyzed using a previously reported image processing
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pipeline (Levine et al., 2008, 2013) for template matching, brain extraction, segmentation of grey matter, white matter, sulcal and ventricular cerebrospinal fluid (CSF), and lesion volumes. A modified Semi-Automated Brain Region Extraction (SABRE) method was used to derive 38 regions of interest (ROIs) customized to fit each patient's brain anatomy.
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Regional CSF, grey matter, and white matter volumes were adjusted for total intracranial capacity using a regression-based method (Arndt, Cohen, Alliger, Swayze, & Andreasen, 1991).
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2.5 Statistical analyses
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Behavioral data were assessed via mixed model analysis of variance with planned contrasts coding for Group (i.e., three contrasts of mild, moderate and severe TBI to comparison participants), Time Period (childhood, teenage, early adult, adult, past year, coded as a single linear contrast), and Detail Type (internal, external). An additional ANOVA contrasted patients with lesions to patients without lesions, coding Detail Type and Time as specified above. As the lesion patients all had moderate or severe TBI, patients with mild TBI were excluded from this analysis.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 10 PLS correlation (Krishnan, Williams, McIntosh, & Abdi, 2011), a procedure that characterizes shared variance between two datasets, was used to characterize relationships among the brain and behavior measures. This was accomplished by
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calculating the correlation between the two covariance matrices, followed by singular value decomposition to identify mutually independent latent variables (LVs) that express the maximal covariance common to both datasets. The reliability of the association was
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estimated using split-half resampling with 100 split samples and 1500 permutations
(Kovacevic, Abdi, Beaton, & McIntosh, 2013). The stability of each brain region to the
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identified LV was determined through bootstrap resampling; subjects were resampled 500 times with 50% of observations resampled with replacement. A variable’s contribution to the LV was considered reliable given a ratio of salience to standard error (hereafter referred to as the bootstrap ratio, interpreted similar to a Z-score) was greater than 2,
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corresponding to 95% confidence limits. As PLS considers all variables in a single computational step, there is no requirement to correct for multiple comparisons. This same analysis was conducted to assess relationships between AI internal and external details
3. Results
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and the neuropsychological and functional outcome tests.
3.1 Behavioral Analysis: Effect of TBI Group and Detail Type To assess the effects of TBI severity on internal vs. external details across the tested
time periods, we examined three-way Group X Detail Type X Time Period interactions for each of the three group contrasts (i.e., mild, moderate, and severe TBI vs comparison participants). As none of these effects involving Time Period were significant, we assessed Group X Detail Type interactions collapsing across Time Period. There was a significant
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 11 Group X Detail Type interaction for the contrast of severe TBI vs. comparison participants, F (1, 88) = 10.06, p = .002, η2= .103. The interactions for the mild and moderate TBI groups as contrasted to the comparison participants were not significant (p > .05). As seen in
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Figure 1, severe TBI participants recalled fewer internal but more external details relative to comparison participants. Ignoring detail type, there was a significant effect of Time Period on detail generation, F (1, 88) = 20.36, p < .001, η2= .188, corresponding to the
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expected forgetting rates (Rubin & Schulkind, 1997). This effect was enhanced in severe TBI vs. comparison participants, F (1, 88) = 4.39, p = .039, η2= .048. These same
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interactions for the mild and moderate TBI groups vs. comparison participants were not significant. Importantly, there were no significant main effects of Group, suggesting that all three groups generated similar amounts of detail (regardless of detail type). This was supported by an ancillary non-significant one-way ANOVA testing for group effects on total
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details, F(3,88) = 0.687; p = .56). There were no significant main effects or interactions when the lesion and no lesion groups were contrasted. 3.2 Relationship of neuropsychological and functional outcome measures to detail type.
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PLS analyses assessing the relationship of AI internal and external details to
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neuropsychological and functional outcome measures yielded no significant LVs. Exploratory analyses of zero-order correlations between internal and external details revealed no significant correlations surviving correction for multiple comparisons. The highest correlations to internal details were noted for the Self Ordered Pointing Test (6, 10 and 12 item version, r’s (68) = .26, .29 and .28, p’s < .05), the Symbol Digit Modalities Test (oral and written, r’s (68) = .26 and .30, p’s < .05), the Trail Making Test (Parts A and B, r’s (68) = .24 and.28, p’s < .05) and Phonemic Word List Generation (FAS, r (68) = .25, p < .05).
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 12 External details were correlated with set loss on the WCST (r (68) = .26, p < .05). Among the functional outcome measures, the only measure to show even a weak relationship to internal details was the HIFI Affective scale (self-rated; r (68) = .25, p < .05). The HIFI
3.3 Relationship of volumetric brain measures to detail type.
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Physical scale (self rated) was weakly related to external details (r (67) = .24, p < .05).
A single significant LV (p = .004; accounting for 38% of cross-block variance)
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identified a pattern of volumetric brain changes across the TBI sample associated with internal, but not external details. Specifically, a lower number of internal details was
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associated with decreased right medial superior frontal, posterior cingulate gyrus, and bilateral lateral occipital grey matter, as well as left medial orbital frontal and bilateral middle frontal white matter regions. Decreased internal details were also associated with increased CSF volume in the bilateral genual cingulate gyrus, medial temporal lobe,
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anterior basal ganglia, left posterior cingulate gyrus, right anterior cingulate gyrus, and right posterior temporal, superior parietal, inferior parietal, and middle cingulate regions. The split-half permutation analysis indicated that the brain volume pattern and effect of
4. Discussion
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detail type were both reliable (p’s = 0.012 and 0.001, respectively).
AM is a multifaceted cognitive process that is supported by a network of brain
regions including the midline frontoparietal, lateral prefrontal and temporal cortices, as well as the medial temporal lobes (Cabeza & St Jacques, 2007; Svoboda et al., 2006). Alterations to this network, and in particular the medial temporal lobes, lead to deficits in episodic AM (for reviews, see Moscovitch et al., 2016; Winocur & Moscovitch, 2011), which occurs in neurodegenerative (Gilboa et al., 2005; Irish et al., 2011; McKinnon et al., 2008)
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 13 and developmental disorders (Addis et al., 2007; Willoughby, McAndrews, & Rovet, 2013), as well as healthy aging (Levine et al., 2002; Piolino et al., 2002). However, it is not well understood how damage outside the medial temporal lobes, as occurs in TBI, affects
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episodic AM, nor how episodic AM recall is affected by different levels of TBI severity. Nor is it known how AM relates to structural brain alterations in TBI.
We assessed episodic AM in a moderately large sample of patients with TBI using
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the AI, which derives separate estimates of episodic and non-episodic processes from within a single autobiographical narrative (Levine et al., 2002). As demonstrated
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previously (Knight & O'Hagan, 2009; Piolino et al., 2007; Rasmussen & Berntsen, 2014), patients with severe TBI recalled fewer internal, or episodic, details, but more external, non-episodic, details relative to comparison participants across time periods. This effect could not be accounted for by impaired detail generation in general (although severe TBI
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patients did generate fewer details for more remote memories). There was no significant effect of mild or moderate TBI on AM recall. Prior studies of mild TBI have yielded mixed results, with one study showing impaired AM in undergraduates with a history of
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concussion (Barry & Tomes, 2015) and another showing no effect on the AI in veterans
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with mild TBI due to blast injuries (Palombo et al., 2015), although the patients’ narratives in that study were less coherent when rated by other measures. AM performance as measured by the AI was neither significantly related to
neuropsychological performance measures nor to functional outcome measures. Considering the zero-order correlations, the neuropsychological tests shared no more than 10% of the variance explained by AI details, explaining why no latent variables relating the two sets of data were revealed by PLS, a sensitive data-driven multivariate analysis
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 14 technique. Previous studies have reported a relationship between measures of executive function and AM performance in TBI (Coste et al., 2015; Piolino et al., 2007; see also Kopelman et al., 2003). The associations were supported by stepwise regression, which
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yields inflated estimates of association by capitalizing on sampling error specific to the dataset (e.g., see Henderson & Denison, 1989; Judd, McClelland, & Ryan, 2008, pg. 204). Furthermore, the AM measures used, particularly autobiographical fluency (Coste et al.,
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2011; Coste et al., 2015), are themselves measures of executive search and generation, whereas in the AI events are generated and selected prior to testing. When specific detail
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generation was isolated from other generative aspects of event selection in a previous study of AM in TBI, the relationships to executive tasks were attenuated (Coste et al., 2011). At most, liberal interpretation of the zero-order correlations suggests a weak relationship between domain-general tests of executive functioning and internal detail
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generation. Intriguingly, there was an association between set loss on the WCST and external details, also reflecting a lack of task maintenance (i.e., including details not relevant to the central event in the narrative; McKinnon et al., 2015). Yet caution is
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warranted in these interpretations, as none of these correlations were significant after
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correction for multiple comparisons. This neuropsychological analysis suggested that AM as assessed by the AI is
independent from laboratory-based tests, particularly measures of executive function (for similar results in frontotemporal dementia, see Irish et al., 2013 and McKinnon et al., 2008). AM tasks that engage domain-general processes, such as fluency tasks, on the other hand, are expected to draw upon executive processes. As noted below, this does not rule
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 15 out the contribution of other prefrontally-mediated processes not assessed by the standardized test battery. The pattern of reduced internal and increased external details in severe TBI relative
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to comparison subjects mirrors that observed in normal aging (Levine et al., 2002)
corresponding to a general inefficiency in focused AM retrieval. This finding contrasts to previous studies that demonstrated deficits in semantic AM using fluency tasks reliant on
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domain-general processes (Coste et al., 2015). The effects in severe TBI could not be
accounted for by presence of focal lesions; they are attributable to diffuse injury. The PLS
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analyses illustrated the distributed nature of this brain-behavior relationship in TBI, which was consistent with the distributed functional neuroanatomy of AM (Svoboda et al., 2006), such that volume loss over frontal, parietal, temporal, and occipital regions corresponded with reduced production of internal details. Bilateral medial temporal and right posterior
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temporal lobe volumes were correlated with internal detail generation, corresponding to the notion of these regions as hubs in a network involving recovery of episodic details (Moscovitch et al., 2016; Sheldon & Levine, 2016; Winocur & Moscovitch, 2011; see also
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Bright et al., 2006). The contribution of the right inferior and superior parietal regions is
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consistent with the role of these regions in episodic recollection (Berryhill et al., 2007; Davidson et al., 2008; Rugg & Vilberg, 2013; Simons, Peers, Mazuz, Berryhill, & Olson, 2010).
Lateral prefrontal regions are involved in strategic autobiographical retrieval,
including search and retrieval monitoring operations (Kopelman et al., 1999; Simons & Spiers, 2003). Here, white matter volumes in the middle lateral regions bilaterally contributed to the pattern. Although lateral prefrontal regions are not part of the canonical
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 16 AM network (Svoboda et al., 2006), prefrontal white matter is vulnerable to the effects of TBI (Wilde et al., 2012). Moreover, dorsolateral regions are implicated in monitoring processes when events are more confusable (Cabeza et al., 2004; Stuss et al., 1994), which
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may have been the case in individuals with more significant TBI. This finding was hinted at by modest correlations between the Self Ordered Pointing Test, a measure of monitoring within working memory, and internal details. Nonetheless, while AI internal details were
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not significantly related to behavioral measures of executive functions (see above), these executive measures were also unrelated to prefrontal volumes in this sample (Levine et al.,
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2013), suggesting that the prefrontally-mediated processes contributing to the AI may not be assessed standardized clinical executive function tasks.
We observed associations between occipital grey matter and internal details, which are strongly influenced by visual processes (Conway & Pleydell-Pearce, 2000; Greenberg &
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Knowlton, 2014), with evidence for an association between focal occipital damage and impaired AM (Rubin & Greenberg, 1998; Sheldon et al., 2016). Finally, midline regions including the extent of the cingulate gyrus and inferior and superior medial prefrontal
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regions, implicated across the three tissue compartments, are known to be involved in self-
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referential processes, including AM (Buckner & Carroll, 2007). These results provide further evidence that quantified brain volumes are superior to
acute injury characteristics in the assessment of brain-behavior relationships in TBI (Levine et al., 2013). Whereas acute TBI effects on memory (e.g., post-traumatic amnesia, retrograde amnesia) are similar to an amnesic state, the present results indicate that at the chronic stage, a distributed lesion affecting multiple aspects of the AM network causes a generalized inefficiency of retrieval (e.g., recovery of details, reconstruction, elaboration,
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 17 and monitoring) that is distinct from that observed in medial temporal lobe amnesia (Rosenbaum et al., 2008). Although episodic AM was only impaired in the patients classified as severe, the
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observed brain-behavior relationships held across the full sample of TBI patients,
indicating volumetric changes across the TBI severity spectrum can affect episodic AM even if they are only detectable at the group level in patients with severe TBI. When
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patients with chronic-phase TBI complain of memory changes, they are referring to
everyday memory such as AM, not lists of words of pictures. The distributed anatomy
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supporting AM is distinct from that supporting laboratory tasks (McDermott, Szpunar, & Christ, 2009). The present findings suggest that a complete understanding of the functional
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mnemonic deficits in chronic TBI require assessment of AM.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 18 Figure Captions Figure 1. Internal and external details recalled in mild, moderate, and severe TBI groups and comparison subjects. Details are averaged across time periods. A significant interaction
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between Detail Type (internal/external) and Group was noted for a planned contrast of the severe group vs. comparison participants, indicating that the severe TBI patients produced fewer internal and more external details than comparison participants. There were no
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significant effects of group for the mild and moderate TBI patients. Error bars represent standard error. Bars: white = comparison participants; dots = mild TBI; lines = moderate
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TBI; black = severe TBI.
Figure 2. Latent variable from PLS analysis indicating the association of internal details with patterns of volume changes across CSF, grey matter, and white matter in TBI patients. Panels A, B, and C reflect brain regions significantly correlated with internal details (r=
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0.19). The color bar indicates the coding scheme according to the level of the bootstrap ratio, interpreted as a Z-score. CSF values are negative (Panel A), indicating volume increases associated with fewer internal details, whereas grey and white matter values are
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positive (Panels B and C, respectively), indicating volume reductions associated with fewer
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internal details. Images were thresholded at a bootstrap ratio of 2.0, corresponding approximately to p < .05. Axial images are displayed in radiological convention (right hemisphere displayed on left side of image). The right and left cingulate volumes are displayed on the right and left side of the images, respectively.
ACCEPTED MANUSCRIPT Autobiographical memory in TBI - 19 Acknowledgements The TBI and comparison participants are thanked for volunteering their time and effort to this research. Ann Campbell, Catherine Hynes, Sabitha Kanagasabai, Charlene
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O’Connor, Colleen O’Toole, Marina Mandic, Karen Philp, Adriana Fecko, Jovanka Skocic, and Gary Turner are thanked for technical assistance. Natasa Kovacevic, Fuqiang Gao, Joel
Ramirez, and Sandra Black are thanked for assistance with the neuroimaging pipeline. We
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gratefully thank the TBI participants and non-injured volunteers for participating in this research. This research was supported by grants from the Canadian Institutes of Health
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Research (Grant #sMT-14744, MOP-37535, and MOP-108540), and the NIH-NICHD (Grant #HD42385-01) to B.L., and an Alzheimer's Society of Canada’s Research Program Post
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Doctoral Fellowship awarded to C.E.
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Table 1: Characteristics of all TBI patients and comparison participants
SD 2.6 2.8 2.4 2.7 1.9
SD 6.0 5.9 6.4 5.7 -
GCS3 Mean 10.1 14.6 11.1 5.9 -
SD 3.9 0.7 2.2 2.5 -
LOC4 Median 48.0 0.0 18.0 144.0 -
IQR 167 0 149 276 -
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Vocabulary2 Mean 27.8 27.9 28.4 27.0 -
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70 (43) 15 (9) 31 (17) 24 (17) 22 (10)
SD 10.4 12.5 10.8 7.9 8.3
Education Mean 14.4 13.7 14.8 14.2 15.0
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Note: 1. Number of males in parentheses. 2. Raw score on the vocabulary subtest of the Shipley Institute of Living Scale (Zachary, 1986). 3. Glasgow Coma Scale score (Teasdale & Jennett, 1974). 4. Duration of loss of consciousness in hours 5. Duration of post-traumatic amnesia in hours 6. Time since injury in years
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TOTAL Mild Moderate Severe Controls
Age Mean 31.0 32.5 32.5 28.2 27.9
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N1
PTA5 Median 336 0 324 1008 -
IQR 810 2 354 936 -
TSI6 Mean 1.1 1.2 1.1 1.0 -
SD 0.4 0.5 0.4 0.2 -
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Figure 1.
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