Neuropsychologia 72 (2015) 105–118

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Neuropsychologia

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Severely deficient autobiographical memory (SDAM) in healthy adults: A new mnemonic syndrome

Daniela J. Palombo a,b,1, Claude Alain a,b, Hedvig Söderlund c, Wayne Khuu a,b, Brian Levine a,b,d,n a Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada M6A 2E1 b Department of Psychology, University of Toronto, Toronto, ON, Canada M5S 1A1 c Department of Psychology, Uppsala University, Uppsala 751 42, Sweden d Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada M5S 1A1 article info abstract

Article history: Recollection of previously experienced events is a key element of human memory that entails recovery Received 13 January 2015 of spatial, perceptual, and mental state details. While deficits in this capacity in association with brain Received in revised form disease have serious functional consequences, little is known about individual differences in autobio- 7 April 2015 graphical memory (AM) in healthy individuals. Recently, healthy adults with highly superior autobio- Accepted 12 April 2015 graphical capacities have been identified (e.g., LePort, A.K., Mattfeld, A.T., Dickinson-Anson, H., Fallon, J. Available online 17 April 2015 H., Stark, C.E., Kruggel, F., McGaugh, J.L., 2012. Behavioral and neuroanatomical investigation of Highly Keywords: Superior Autobiographical Memory (HSAM). Neurobiol. Learn. Mem. 98(1), 78–92. doi: 10.1016/j. Episodic memory nlm.2012.05.002). Here we report data from three healthy, high functioning adults with the reverse Autobiographical memory pattern: lifelong severely deficient autobiographical memory (SDAM) with otherwise preserved Hippocampus cognitive function. Their self-reported selective inability to vividly recollect personally experienced Case study events from a first-person perspective was corroborated by absence of functional magnetic resonance imaging (fMRI) and event-related potential (ERP) biomarkers associated with naturalistic and laboratory episodic recollection, as well as by behavioral evidence of impaired episodic retrieval, particularly for visual information. Yet learning and memory were otherwise intact, as long as these tasks could be accomplished by non-episodic processes. Thus these individuals function normally in day-to-day life, even though their past is experienced in the absence of recollection. & 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction 2006) and more recently referred to as “highly superior autobiogra- phical memory” (HSAM; LePort et al., 2012), which refers to Current theoretical accounts of human episodic memory individuals with the uncanny ability to recall a vast amount of emphasize the subjective “re-living” that accompanies the retrie- episodic AM details (Ally et al., 2013; LePort et al., 2012; Parker val of events (Eichenbaum et al., 2007; Tulving, 2002). In natur- et al., 2006; Patihis et al., 2013). For example, when given randomly alistic contexts, this entails the recovery of spatial, perceptual, and selected dates or event cues from their past, HSAM individuals can mental state details associated with temporally-specific events in effortlessly recall many details of what happened, even if trivial (e.g., one's own past (i.e., episodic autobiographical memory; AM). what they had for dinner) without the use of mnemonic aids. They These details engender a subjective sense of re-experiencing that are neither savants nor calendar counters (although they possess is not present for factual or semantic knowledge, which can be extensive calendar knowledge from their own lifespan) and they are accomplished in the absence of autobiographical recollection (see distinct from other types of superior memorizers who possess vast Renoult et al., 2012 and Tulving, 1985 for review). learning and retention of meaningless information (e.g., digit strings; Recently, a new AM syndrome has been identified in healthy Maguire et al., 2003). Notably, performance on laboratory-based adults, initially termed “hyperthymestic syndrome” (Parker et al., memory tasks is not necessarily superior in HSAM, which highlights the specificity of their ability to the domain of AM as well as the importance of utilizing both laboratory and naturalistic stimuli in the n Corresponding author at: Rotman Research Institute, Baycrest Health Sciences, context of assessing mnemonic abilities. While only a small group þ þ Toronto, ON, Canada M6A 2E1. Tel.: 1 416 785 2500 x3593; fax: 1 416 785 2862. (approximately 20 cases) has been reported in the literature, many E-mail address: [email protected] (B. Levine). 1 Daniela J. Palombo is now at the VA Boston Healthcare System, Jamaica Plain more individuals with claims to this ability have emerged since (see and the Department of Psychiatry, Boston University School of Medicine. LePort et al., 2012; Patihis et al., 2013). http://dx.doi.org/10.1016/j.neuropsychologia.2015.04.012 0028-3932/& 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 106 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118

Turning to the other extreme, deficits in episodic AM have been et al., 2011; Kwan et al., 2010; Vargha-Khadem et al., 1997, 2003), well documented in the context of brain disease, with serious there is neither any history of brain insult nor neuroimaging functional consequences (e.g., Kapur, 1999; Spiers et al., 2001). In evidence of neuropathology in the cases presented here. this paper, we report three cases of healthy individuals with a Given the novelty associated with this mnemonic profile, we lifelong, selective impairment in episodic AM, essentially the completed a comprehensive assessment of the SDAM cases' cognitive reverse syndrome to that of HSAM, here dubbed “severely defi- and brain function in comparison to carefully matched control cient autobiographical memory” (SDAM). Specifically, they report participants. In addition to standardized assessments of memory an inability to re-experience personal events. Although their and other cognitive functions, we conducted a detailed assessment of ability to learn and retain factual (i.e., semantic) information is memory. This battery included measures of recognition memory that normal on the basis of everyday functioning and performance on parcels out the specific contribution of recollection (Eichenbaum linguistic measures, they fail to subjectively re-live past events. et al., 2007; Yonelinas, 2001), a naturalistic measure (the Autobio- While these SDAM cases in some ways resemble individuals with graphical Interview; AI) designed to separate retrieval of episodic developmental amnesia, who sustain early hippocampal damage from non-episodic (e.g., semantic) autobiographical information as a result of perinatal hypoxia, resulting in a severe deficit in using text-based analysis (Levine et al., 2002),andanadaptationof episodic memory and relative sparing of semantic abilities (Cooper this measure for future events (Addis et al., 2008).

Table 1 Demographic and neuropsychological data for SDAM cases (N¼3).

A.A. B.B. C.C.

Demographic Age 52 40 49 Education 16 12 20 Sex F M M Handedness A R R General cognitive ability WASI; Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), standard score Verbal 121 110 117 Performance 119 107 115 Full scale 124 110 118 Language WRAT-3; Wide Range Achievement Test (Wilkinson, 1993), standard score Reading 114 100 118 Attention, working memory, processing speed WMS-III; Wechsler Memory Scale (Wechsler, 1997), scaled score Digit span 13 14 16 Forward longest digit, raw score 8 8 8 Backward longest digit, raw score 6 7 6 Symbol digits (Smith, 1976), z-score 1.78 0.46 0.58 Motor functioning Finger tapping (Bornstein, 1985), z-score Right 2.53 0.83 1.72 Left 1.20 0.22 1.64 Grooved pegboard (Bornstein, 1985), z-score Right 0.07 1.60 1.60 Left 0.41 1.32 1.01 Dynamometer (Bornstein, 1985), z-score Right 0.20 0.70 3.86 Left 0.31 0.18 3.12 Executive functioning WCST; Wisconsin Card Sorting Test (Heaton et al., 1993), z-score Categories 0.40 0.39 0.39 Set loss 0.64 0.39 0.39 Perseveration to response 0.06 0.19 0.46 TMT; Trail Making Test (Spreen & Strauss, 1998), z-score Part A 1.31 0.76 0.03 Part B 1.73 0.84 0.51 Verbal and visual memory CVLT-II; California Verbal Learning Test (Delis et al., 2000), T-score & standard score Immediate recall 64 46 53 Short delay free 2.0 1.0 1.5 Long delay free 1.5 1.0 1.5 Recognition number correct 0.0 1.5 1.0 WMS –III (Wechsler, 1997), scaled score Logical memory 16 11 9 BVMT-R; Brief Visual Memory Test-Revised (Benedict, 1997), T-score Total recall 58 40 39 Delayed recall 65 58 49 RCFT; Rey Complex Figure Test (Meyers and Meyers, 1995), z-score Copy 2.50 0.38 0.18 Immediate 1.84 1.49 3.13 Delay 2.83 2.21 2.36

Note: For each test, data are expressed using age-corrected (and where available, education-corrected) normative scores derived from standardized test data. A: ambidextrous; R: right. D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 107

Our neuroimaging battery included structural hippocampal humorous word-definition pairings (e.g., “A talkative featherbrain – parakeet”) fi volumetrics and functional neuroanatomical investigations, using presented either auditorily or visually; 72 humorous de nitions were presented in four study blocks. Study items were randomly assigned to tests at 30 min or 24 h functional magnetic resonance imaging (fMRI) and electroence- delays. At test, participants completed cued recall (i.e., generating the word upon phalography (EEG). Using fMRI, we probed a core AM network in presentation of the definition), old/new recognition (i.e., discriminating previously which midline frontal and posterior regions are engaged in studied items from unstudied lures), source recall (i.e., determining whether the association with mental time travel and recollection of contex- items were presented auditorily or visually), and remember/know judgements, which refer to subjective reports of recollection of physical or mental associations tually specific details (Cabeza and St Jacques, 2007; Svoboda et al., from encoding (“remember” response) versus familiarity with the studied item in 2006). EEG was used to assess the presence of a late positive the absence of recollection (“know” response; Gardiner, 1988; Tulving, 1985). Given ongoing event-related brain potential (ERP) localized over parietal binary choice of the remember/know procedure, “know” responses are necessarily scalp areas that is a reliable neural marker of episodic recollection elevated when “remember” responses are low. Although an estimate of familiarity in association with correctly recognized stimuli (Addante et al., can be derived under the assumption of independence between recollection and familiarity (Yonelinas and Jacoby, 1995), we were unable to do so due to ceiling 2012; Düzel et al., 2001a; Rugg and Curran, 2007). effects in control participants. In accord with their intact everyday life functioning, we predicted Each of these indices was corrected for false alarms (FA; or spontaneously that neuropsychological performance in SDAM would be normal. completed lures in the case of cued recall), which were low in both groups for both Within memory, we predicted that they would show intact recogni- cued recall and recognition (see Supplementary Table 1), with the high variability at 24 h in cases due to C.C., whose FA rate was elevated for recognition memory tion but impaired recollection relative to comparison participants on (0.29; A.A. and B.B.'s rates were 0.08 and 0.0, respectively); a similar pattern of FA laboratory tests of recognition, as well as impaired recall of episodic was observed when examining only “remember” responses, with C.C.'s FA elevated autobiographical, but not personal semantic details on the AI. A at 24 h (0.21, as compared to 0.04 and 0.00 for A.A. and B.B., respectively). FA was similar pattern was predicted for future events. We lacked a strong also low for auditory and visual source memory, with elevated FA for C.C. for basis for prediction concerning structural hippocampal differences as auditory source memory for 24 h (0.21, as compared to 0.04 and 0.00 for A.A. and B. B., respectively). we anticipated the major effects to be reflected in functional neuroimaging (Maguire et al., 2003). We predicted that SDAM would be associated with reduced activation in key areas of the AM 2.2.2. Autobiographical Interview (AI) AM was formally assessed using a reliable and valid method for separating network, particularly midline areas associated with mental projection episodic from semantic AM for significant events across the lifespan based on of the self through time. Finally, we predicted that the SDAM cases categorization and rating of details from transcribed autobiographical protocols, would fail to show the late positive ERP component associated with the Autobiographical Interview (i.e., AI; Levine et al., 2002). Prior to testing, intact recognition. This latter prediction was crucial as it provided a participants selected two events from each of six lifetime periods (1 week ago, 1 month ago, 1 year ago, 10 years ago, teenage years, and childhood) that were putative neural marker of impaired recollection in the context of specific in time and place. The titles of the events were recorded and used as intact memory performance via non-episodic processes. retrieval cues during testing. Participants were encouraged to consult their calendars or their significant other or loved one if necessary for the provision of the occurrence of prior events without accompanying details (e.g., trip to Cape 2. Methods Cod). Participants were also provided with a list of typical life events (Levine et al., 2002), including those that were likely to have occurred in the previous week. Comparison groups containing 15 age- and education-matched participants were 2.1. SDAM cases selected from two prior studies that used identical procedures, but covered the different time periods assessed in the present study. The first group (44.776.7 Demographic information for each of the three SDAM cases (A.A., B.B., C.C.) is years old; 15.4 71.6 years of education) was used for the time periods dated from reported in Table 1. All individuals were successfully employed (one with a PhD one week to 10 years ago (Söderlund et al., 2014). The second group (48.877.3 degree; C.C.), with no evidence of functional impairment owing to their memory years old; 16.573.0 years of education) was used for the two remote time periods syndrome. They were healthy with no evidence of secondary gain or active psycho- (Levine et al., 2002; McKinnon et al., 2008). pathology; each contacted our lab without solicitation to learn about their memory, Administration and scoring of the AI was done according to previously such that each case reported a lifetime inability to recollect events from a first-person described methods (Levine et al., 2002; Söderlund et al., 2014). During Free Recall, perspective, but with full recognition of their memory syndrome occurring in the late participants spoke about the event extemporaneously until it was evident that they teenage or early adulthood years. There was no history of birth complications, seizures, had reached a natural ending point or five minutes had passed. This was followed stroke, traumatic brain injury or neurological disease in any of the SDAM cases, nor by General Probe, where instructions were clarified and greater recall of event was there evidence of psychological trauma. details was encouraged. General probes were limited to non-specific statements or A remote history of depression (single episode, no recurrence) was reported by repetitions of the instructions (“Is there anything else you can remember about the two of the SDAM cases in association with early adulthood transitions during late event?”). Again, a five-minute cut-off was applied. The Specific Probe phase teenage years (B.B. and C.C.); however, at the time of testing, there was no evidence of consisted of a structured interview designed to elicit additional sensory, perceptual, depression or other psychopathology on clinical interview with a board-certified and mental state details of the event (e.g., “Do you remember any objects in the psychologist (B.L.); all SDAM cases were functioning well in their occupational and environment?”). social roles. Two of the cases (A.A. and C.C.) were in committed relationships (married, Participants' descriptions of the selected events were audio-recorded for later common-law, respectively); B.B. was single. This study was approved by the Baycrest transcription and analysis. Each memory was segmented into informational bits or Health Sciences Research Ethics Board. All participants provided written informed details. Each detail was then classified by raters who had previously attained high consent. reliability on a separate set of memories already scored by an expert rater (for Standardized neuropsychological tests assessing intellectual abilities and aca- reliability procedures, see Levine et al., 2002). These transcriptions were scored demic achievement, attention and working memory, motor functioning, executive from within a larger pool containing memories from studies on healthy adults, functioning, and verbal and visual memory were administered (see Table 1). SDAM emotion, frontal lobe damage, depression, and amnesia due to various causes. All cases' scores were compared to the standardization sample for each test. For the memories were independently censored for information that would identify group remaining behavioral and neuroimaging measures, separate groups of age- and membership or diagnosis. Censored details were replaced with equivalent details education-matched comparison participants were recruited, or where available, that did not reveal group membership. The SDAM cases' memories were each selected from healthy adults tested in our laboratory. All participants were healthy, scored by two separate raters, whose scores were subsequently averaged. with no history of neurological or significant medical illness, and free of psychoac- Details were classified as “internal” or episodic if they were related directly to tive medications. the main event described, were specific to time and place, and conveyed a sense of episodic re-experiencing. These details were assigned to one of five detail categories (event, place, time, perceptual, and emotion/thought) that were 2.2. Behavioral tests summed to form an internal detail composite score (see Levine et al., 2002). To avoid subjectivity in detail categorization, the AI scoring instructions stipulate that 2.2.1. Remember/know source any detail that could reasonably be interpreted to reflect episodic re-experiencing We sought laboratory concordance to the SDAM cases' self-reports of natur- be scored as “internal.” Otherwise, details were considered “external,” and alistic memory function using a test of delayed cued recall, recognition and source consisted of semantic facts (factual information or extended events that did not memory (see Söderlund et al., 2008 for detailed methodology). Fifteen age- and require recollection of a specific time and place), autobiographical events tangential education-matched comparison participants (47.1710.3 years old; 16.972.5 years or unrelated to the main event, repetitions, or other metacognitive statements (“I of education) were used. SDAM cases and comparison participants studied can't remember”) or editorializing (“It was the best of times”). 108 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118

– For each internal detail category, a rating of 0 3 was assigned by the examiner 2.3.2. Event related potentials (ERP) fi to describe the level of speci city in recall, with the exception of an episodic Following the methods in Schiltz et al. (2006), participants studied 225 – richness rating (corresponding to event details), scored on a scale of 0 6. An individually presented faces (2500 ms) in 15 blocks. Immediately following the additional time integration rating was assigned to characterize the degree to which study phase, participants were presented with a distracter task in which they the event was integrated into a larger timescale (i.e., reference to personal events determined the gaze direction (i.e., right, left, up, down, and straight) of a novel occurring before or after the main event). These ratings were summed to form an face. Each face was presented for 1000 ms and separated from others by a fixation overall rating composite, which was the variable analyzed in the present study. The cross for 500 ms. At test, which occurred immediately following the distracter task, ratings composite provides only partially overlapping information to the internal 15 blocks of old and new (15 each) faces were presented (300 ms) followed by a detail composite, as it takes into consideration quality of details in addition to fixation cross (3500 ms). Participants made an old/new decision as quickly and quantity. Thus, for example, someone who provided a richly evocative event accurately as possible. All judgements were indicated by button press on a description would receive a high rating even if they did so in a few words, and a keyboard. Neuroelectric data were acquired continuously (band-pass 0.05– verbose description that does not convey richness would be rated low. Scores 100 Hz, sampling rate 500 Hz) using a 64-channel tin electrode cap (Electro-Cap fi obtained from speci c probe (cumulatively summed across all probing levels) are International) using Neuroscan software and a Synamps neural amplifier (Compu- reported. medics). During recording, the reference electrode was Cz. Finally, participants provided subjective ratings for each event, which included For data analysis, the ERPs were re-referenced to an average reference. Epochs the following: (1) how clearly can you visualize this event (1, vague; to 6, highly including deflections exceeding 100–180 mV were excluded. ERPs for hits and vivid), (2) how much did your emotional state change from before the event correct rejections (CR) were averaged separately. Ocular artefacts were corrected occurred to after it happened (1, no change; to 6, tremendous change), (3) how by means of ocular source components. ERPs were measured after referencing personally important is this event to you now, and (4) how personally important voltages to a pre-stimulus baseline. Nine age- and education-matched comparison was this event to you then (1, not important; to 6, of great importance). participants (47.0711.6 years old; 17.372.7 years of education) were used. Behavioral data (i.e., hits) were corrected for FA, which were relatively low in both groups (comparison group: 0.1070.08; SDAM cases: 0.0970.12), although C.C.'s FA 2.2.3. Future events rate was elevated (0.23 as compared to 0.01 and 0.02 for A.A. and B.B., respectively). Cue words were used to elicit two imagined future events from each of two different time periods (next few weeks, next few years; see Addis et al., 2008 for detailed methodology). Participants were asked to describe everything they could 2.3.3. High resolution structural imaging imagine about future events that were plausible (i.e., something that they could Whole hippocampal volumes were manually traced by a trained operator on likely experience given the context of their life), novel (i.e., something that has not the high-resolution (1 mm3) T1-weighted images using reliable landmarks and yet happened), and specific to one time and place (i.e., occurring over minutes or procedures established elsewhere (Amaral and Insausti, 1990; Callen et al., 2001). hours but not longer than a day). A three-minute time limit was applied to The tracer was blind to group membership. Volumes were corrected for intracranial participants' responses. Scoring procedures for the AI (described above) were used volume using a regression-based technique (Arndt et al., 1991). SDAM cases were to derive internal and external composite scores and examiner ratings. As there compared to 9 age- and education-matched comparison participants (49.077.2 were no effects involving time period, the two time periods were collapsed for years old; 16.773.2 years of education) for the left and right hippocampal volume. simplicity. Fifteen age- and education-matched comparison participants (50.177.0 We also compared SDAM cases to the comparison group for the degree of years old; 17.673.3 years of education) were used. asymmetry between the right and left hippocampal volume (see Section 3).

2.3. Neuroimaging 3. Results

2.3.1. Functional magnetic resonance imaging (fMRI) To explore the functional neuroanatomical correlates of the SDAM cases' 3.1. Neuropsychological testing memory impairment, individuals were scanned with fMRI using a cued recall paradigm involving recall of past personal events from verbal cues harvested from With the exception of one test (see below), the SDAM cases' participants prior to scanning (e.g., Jason's wedding ceremony; for full methods, see neuropsychological test performance was at a normal range or Söderlund et al., 2012). Twenty-one age- and education-matched comparison participants (47.179.7 years old; 16.573.2 years of education) were used. higher when compared to published normative data (see Table 1). Participants were presented with titles of 40 temporally-specific events as retrieval All SDAM cases had high average to superior intellectual abilities, cues for events across four lifetime periods ranging from two weeks to 10 years with little discrepancy between estimates of verbal and non- prior to scanning, followed by an 18s retrieval period, then by subjective ratings of verbal IQ. Word reading as a measure of academic achievement recollection. An 18s odd-number detection task (Stark and Squire, 2001) was used was also average to superior, in accordance with the SDAM cases' as a control condition. All participants were scanned on a whole body 3.0 T (Siemens Magnetom Trio occupational and educational attainments. Auditory span of appre- Tim, Numaris/4Syngo MR B13; Siemens, Germany) with a 12 Channel Matrix Coil. hension for recall of digits was average, as was manipulation of Prior to acquisition of functional images, a volumetric anatomical MRI was digits held on-line for backward recall, with standardized digit performed, using a 3D T1-weighted images (MP-RAGE sequence; TR/TE¼2000/ span composite scores falling in the high average to superior 2.63ms), 176 oblique coronal slices perpendicular to the long axis of the hippo- 3 ranges. Speeded number transcription was average across SDAM campus, with a 256 256 acquisition matrix, voxel size¼1mm , and FOV¼25.6 cm. Functional imaging was performed using a T2*-weighted EPI cases, except for A.A., who had superior performance. sequence (TR/TE¼2000/30ms, flip angle¼701,64 64 acquisition matrix, 32 Motor speed on finger tapping and manual dexterity on the oblique coronal slices perpendicular to long axis of the hippocampus, 5 mm thick, grooved pegboard were generally normal, with the exception of ¼ ¼ ¼ voxel size 3.1 3.1 mm, slice spacing 0, and FOV 20 cm). superior motor speed for A.A. (right hand) and C.C. (both hands) in Data were processed and analyzed using Analysis of Functional Images soft- fi ware (AFNI; Cox and Hyde, 1997). Time series were first corrected for physiological nger tapping, and mildly impaired manual dexterity for B.B. and motion (i.e., heart rate and respiration) via linear filtering. Data were despiked C.C. for the right hand on the grooved pegboard. On the hand using AFNI's 3dDespike program. Next, the data were spatially co-registered to dynamometer task, C.C. showed significant bilateral upper extre- correct for head motion, using the 3dvolreg program in AFNI, which aligns the data mity weakness; the other SDAM cases were normal. All SDAM to a reference scan chosen from within one of the runs using Fourier interpolation. cases demonstrated normal concept formation and set shifting on Then the data were normalized temporally within each run and concatenated across runs. Next, the time series was deconvolved with AFNI's 3dDeconvolve the Wisconsin Card Sorting Test. Alternating number–letter con- plugin. T-statistics were calculated for each voxel for each participant, contrasting necting on the Trail Making Test, Part B was normal across SDAM each experimental condition to a baseline, which models the mean and linear trend cases, with A.A. showing relatively faster speeds on both Parts A of all time steps in the series. These activation maps were then spatially and B of the Trail Making Test. transformed to Talairach space (Cox and Hyde, 1997; Talairach and Tournoux, 1988), resampled to a 2 mm3 voxel size, and spatially smoothed using a Gaussian Verbal learning and memory as assessed with stories and word filter with a full width at half-maximum value of 6.0 mm to minimize individual lists ranged from average to very superior across SDAM cases, with anatomical variability. Peak voxels of interest (VOIs) were selected from clusters the exception of minor impairments in the word list task for C.C. (free significantly activated by the comparison group, without reference to SDAM cases, recall) and B.B. (recognition). Acquisition of six simple designs on the in response to AM (collapsed across all lifetime periods) versus the control Brief Visuospatial Memory Test (BVMT) over three trials ranged from condition (po0.0001) in regions known to be important in AM (Svoboda et al., 2006). Percent BOLD signal change from these VOIs were compared between low average to superior across SDAM cases, with delayed recall of SDAM cases and comparison participants using group statistics (see below). these designs ranging from average to superior. Visual memory as D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 109 assessed by the Rey Complex Figure Test (RCFT) was the only measure 3.2.2. Autobiographical Interview (AI) in the battery in which the SDAM cases were consistently impaired. The SDAM cases' generation of internal details was significantly At immediate recall, two SDAM cases' scores were classified as reduced relative to the comparison group for the childhood and borderline impaired and one (C.C.) was severely impaired. After a teenage life periods. The SDAM cases' performance across the 30 min delay, scores for all cases were in the severely impaired range remaining time periods was variable (statistics are reported in (see Fig. 1). These results could not be accounted for by impaired Table 2; also see Fig. 3). C.C. produced an excess of details (internal visuomotor function, as two of three SDAM cases showed normal and external) for the two most recent time periods, whereas the scores on the copy trial of this task. The third, A.A., was impaired on remaining SDAM cases' internal details for these time periods the copy trial due to minor errors stemming from a poor organiza- ranged from impaired to average. There were no significant group tional strategy, evidenced by fragmentation of elements from a single differences in generation of external (non-episodic) details (see perceptual feature (e.g., the large diagonal cross; Shorr et al., 1992). Table 2 and Fig. 3) across time periods. While C.C. produced The difference between the SDAM cases' performances on the RCFT outlying scores for external details across time periods, this could and the Brief Visuospatial Memory Test (BVMT; simple design not account for the relative sparing of SDAM cases' external learning) can be accounted for by differences in test characteristics. details. Whereas the BVMT involves repeated presentation of simple designs Although reduced internal detail generation in the SDAM cases over three learning trials, the RCFT involves a single presentation of a was restricted to remote time periods at the group level, the SDAM comparatively more complex design, with points awarded for the cases' rated vividness (i.e., how clearly the event could be visualized) number of visual details reproduced. of all events was significantly reduced (see Table 2 and Fig. 3). As noted in Section 2, the AI detail classification criteria dictate that any detail that could reasonably reflect episodic re-experiencing should be classified as internal in order to avoid subjectivity in scoring, 3.2. Experimental tests of memory which may account for the SDAM cases' elevated internal details as determined quantitatively. On the other hand, scorers' composite Behavioral data are presented in Table 2 and Figs. 2 and 3.Case ratings, which allow for qualitative judgment of episodic autobio- data were compared to control participants using group-level statis- graphical specificity, were significantly reduced for the SDAM cases tics, reported in Table 2. Statistics for main effects and interactions than the comparison group for five of the six time periods (see are reported in the text; simple effects are presented in Table 2.A Table 2 and Fig. 3). SDAM cases did not significantly differ from significance threshold of p o0.05 was used for all tests (two-tailed). comparison participants when rating the amount of emotional When indicated, results were corrected for inhomogeneity of var- change from before to after the event occurred or the current iance (Satterthwaite, 1946). importance of the event; ratings were variably lower for rated importanceatthetimeoftheevent(seeTable 2).

3.2.1. Remember/know source 3.2.3. Future autobiographical events While the SDAM cases demonstrated largely intact recognition The SDAM cases produced fewer details for future imagined and cued recall (Table 2 and Fig. 2A) at both 30 min and 24 h, they events than did the comparison group but this was not statistically fi ¼ were significantly impaired relative to the comparison group on signi cant (F1,16 ¼ 2.41, p 0.14), and there was no group by detail type (i.e., internal versus external details) interaction (p¼0.79; see source recall at 24 h only (F1,16 ¼7.58, p¼0.014). A marginally Table 2). Scorers' ratings of episodic specificity were signific- significant group by source type interaction at 24 h (F1,17 ¼3.53, p¼0.079) revealed that this effect was specific for items that were antly lower in the SDAM cases relative to the comparison group ¼ ¼ initially presented visually as opposed to auditorily (Table 2 and (t16 2.46, p 0.025). Fig. 2B), corresponding to the impaired visual memory on neu- ropsychological testing as noted above. Although the interaction at 3.3. Neuroimaging 30 min was not statistically significant (p¼0.55), a similar pattern of impaired visual, but not auditory, source memory was observed 3.3.1. Structural imaging for 30 min. As expected, the cases also reported reduced re- While there were no major structural abnormalities detected experiencing of the encoding context at both 30 min and 24 h upon neuroradiological assessment of the SDAM cases' MRI scans, (i.e., “remember” responses) relative to the comparison group (see volumetric analysis of the hippocampus revealed a significant

Table 2). This was statistically significant at 30 min but not at 24 h interaction (group laterality; F1,10 ¼7.78, p ¼0.019), which was as this t statistic was evaluated at reduced degrees of freedom due attributable to smaller right hippocampi in the SDAM cases (M: to inhomogeneity of variance across groups (see Table 2). None- 3005.28, SD: 47.53) relative to comparison group (see Fig. 4; M: theless, as can be seen in Fig. 2A, the cases generated fewer 3259.47, SD: 319.70; t8.9 ¼2.31, p¼0.046). A comparison of the “remember” responses at 24 h than did comparison subjects, a right minus left uncorrected hippocampal volumes revealed a significant effect when tested non-parametrically (Mann–Whitney significant group difference, (t10 ¼3.39, p¼0.007) such that the U¼0.00, p¼0.007). SDAM cases showed a greater asymmetry between hippocampi

0 Control A.A. B.B. C.C. -1

-2 z-score -3

A.A. B.B. C.C. Delayed Recall

Fig. 1. Complex figure recall. Delayed complex figure recall, with a typical comparison participant (age 48; left), followed by reproductions of each SDAM case's (N¼3) delayed recall performance. Each SDAM case's z-score (derived from age-matched normative data; Meyers and Meyers, 1995) for delayed recall. 110 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118

Table 2 Descriptive data and simple effects for behavioral measures at the group level.

Test Control mean (SD) Case mean (SD) Group effect

Remember/know source Adjusted scores (30 min) tp Recognition 0.97 (0.03) 0.95 (0.06) 1.09 0.294 Recall 0.53 (0.18) 0.62 (0.11) 0.86 0.404 Remember 0.85 (0.12) 0.58 (0.23) 2.97 0.009nn Knowa 0.12 (0.11) 0.51 (0.43) 1.58 0.251 Auditory source 0.30 (0.16) 0.28 (0.06) 0.50 0.629 Visual source 0.43 (0.07) 0.35 (0.11) 1.84 0.084# Adjusted scores (24 h) Recognition 0.89 (0.06) 0.85 (0.13) 0.79 0.443 Recall 0.37 (0.15) 0.40 (0.13) 0.34 0.736 Rememberb 0.76 (0.12) 0.32 (0.28) 2.63 0.110 Knowa 0.13 (0.10) 0.34 (0.12) 2.82 0.013n Auditory source 0.24 (0.11) 0.19 (0.11) 0.63 0.540 Visual source 0.36 (0.05) 0.18 (0.02) 5.74 0.000nnn

Autobiographical Interview Internal 1 week 67.60 (22.43) 69.27 (61.15) 0.05 0.967 1 month 57.87 (17.02) 70.60 (31.75) 1.03 0.317 1 year 58.73 (16.72) 54.60 (10.55) 0.41 0.690 10 years 50.80 (18.54) 34.33 (16.63) 1.42 0.174 Teen 53.07 (14.08) 27.27 (14.58) 2.88 0.011n Child 49.40 (16.20) 22.93 (10.84) 2.68 0.017n

External 1 week 20.13 (11.69) 42.60 (48.71) 0.79 0.509 1 month 25.50 (12.68) 33.30 (33.81) 0.39 0.730 1 year 22.57 (13.80) 29.70 (25.65) 0.72 0.485 10 years 22.13 (11.02) 37.17 (20.50) 1.89 0.078# Teen 25.80 (15.91) 43.70 (33.64) 1.49 0.157 Child 27.67 (15.69) 40.27 (29.93) 1.10 0.287 Examiner ratings 1 week 19.20 (1.15) 16.10 (2.08) 3.77 0.002nn 1 month 18.37 (1.81) 17.03 (2.44) 1.11 0.283 1 year 18.23 (1.79) 15.27 (1.10) 2.73 0.015n 10 years 18.37 (1.97) 13.83 (3.33) 3.28 0.005nn Teen 18.93 (2.22) 10.63 (3.33) 5.50 0.000nnn Child 17.80 (2.60) 10.13 (2.02) 4.79 0.000nnn Participant ratings Visualize 1 week 5.37 (0.72) 1.67 (0.76) 8.07 0.000nnn 1 month 5.13 (1.16) 1.33 (0.58) 5.46 0.000nnn 1 year 4.80 (0.94) 1.17 (0.29) 6.48 0.000nnn 10 years 4.80 (1.15) 1.17 (0.29) 10.70 0.000nnn Teen 4.20 (1.21) 1.17 (0.29) 8.58 0.000nnn Child 4.00 (1.41) 1.17 (0.29) 3.38 0.004nn Emotional change 1 week 2.70 (1.25) 1.83 (0.76) 1.14 0.271 1 month 3.03 (1.11) 2.67 (1.53) 0.50 0.627 1 year 3.10 (1.26) 2.83 (2.31) 0.30 0.772 10 years 3.33 (1.21) 3.17 (0.58) 0.23 0.821 Teen 3.80 (1.47) 3.83 (1.89) 0.03 0.973 Child 3.93 (1.53) 4.83 (1.04) 0.96 0.351

Importance now 1 week 3.57 (1.71) 3.17 (0.76) 0.64 0.542 1 month 3.47 (1.71) 3.50 (0.50) 0.06 0.951 1 year 3.57 (1.37) 3.50 (2.18) 0.07 0.945 10 years 3.70 (1.63) 3.67 (1.26) 0.03 0.974 Teen 2.33 (1.50) 3.17 (1.53) 0.88 0.393 Child 2.13 (1.51) 3.67 (2.02) 1.54 0.144 Importance then 1 week 4.20 (1.49) 2.00 (0.50) 4.58 0.001nn 1 month 4.17 (1.52) 3.00 (0.87) 1.84 0.126 1 year 4.67 (0.67) 2.67 (1.26) 4.10 0.001nn 10 years 4.80 (1.11) 4.67 (1.26) 0.19 0.855 Teen 4.53 (1.60) 3.33 (2.52) 1.09 0.291 Child 4.53 (1.41) 3.50 (2.50) 1.03 0.318

Future events Fp Details 22.10 (10.66) 12.08 (6.66) 2.41 0.142 tp Examiner ratings 12.42 (1.97) 9.00 (3.36) 2.46 0.025n D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 111

Table 2 (continued )

Test Control mean (SD) Case mean (SD) Group effect

fMRI ratings 5.99 (0.99) 2.03 (0.80) 6.58 0.000nnn

Note: SD; standard deviation. n po0.05. nn po0.01. nnn po0.001. # p o0.10. a Know responses are necessarily high when remember responses are low. An estimate of familiarity can be derived under the assumption of independence between recollection and familiarity (Yonelinas and Jacoby, 1995); however, we were unable to do so due to ceiling effects in control participants. b Remember responses were significantly impaired in SDAM cases when tested non-parametrically (Mann-Whitney U¼0.00, p¼0.007; see Section 3).

1 * * 0.4

0.8 0.3 0.6

0.2 0.4

0.1 0.2 Corrected Proportion (Hits-FA) Corrected Proportion (Hits-FA) 0 0 Recognition Cued Recall Remember Auditory Visual

A.A. B.B. C.C Con

Fig. 2. Verbal cued recall, recognition, “remember” responses (i.e., self-reported recollection of encoding for correctly recognized items), and source memory at 24 h. (A) Mean recognition, cued recall, and “remember responses” for the SDAM cases (N¼3) and comparison group (N¼15). No significant group differences were observed for recognition or cued recall. “Remember” responses were significantly reduced. (B) Mean source memory stratified into visual and auditory source memory for SDAM cases and comparison participants. SDAM cases produced significantly fewer correct source responses; this deficit was specific to items presented visually. Comparison group is shown with 95% confidence intervals. SDAM cases are indicated in the legend. All scores are plotted as proportion of hits minus false alarms (FA).

(left4right; M: 225.67, SD: 37.00) than comparison participants mean for comparison participants: 1.17, SD: 0.43; mean for SDAM (M: 21.22, SD: 99.32, see Fig. 4). cases: 0.04, SD: 0.53; see Fig. 6C).

3.3.2. fMRI 4. Discussion The SDAM cases reported reduced subjective ratings of autobio- graphical recollection (i.e., vividness) during scanning (M: 2.03, SD: We report data from three healthy adults with a mnemonic 0.80) relative to comparison participants (N¼21; M: 5.99, SD: 0.99; syndrome that is confined to an inability to mentally travel back- t22¼6.58, po0.0001; see Fig. 5AandTable 2). SDAM cases also wards in time in the absence of detectable neuropathology or showed significant activation reductions in core regions in the significant daily life handicap. In accordance with similar nomencla- autobiographical network (Cabeza and St Jacques, 2007; Maguire, ture used for HSAM (LePortetal.,2012;Patihisetal.,2013), we have

2001; Svoboda et al., 2006), F1,22 ¼8.26, p¼0.009, particularly in the labeled this as “severely deficient autobiographical memory” (SDAM). midline anterior regions (left medial prefrontal cortex; mPFC) Their subjective reports were investigated with a variety of neural associated with the mental projection of the self through time and and behavioral measures of recollection. In accord with their intact themidlineposteriorregions(rightprecuneus)associatedwith daily life function, neuropsychological test performance was largely visual memory (Fletcher et al., 1995; Gilboa et al., 2004; Northoff intact. With the exception of complex figure recall, standard neu- et al., 2006;seeFig. 5BandC;seealsoTable 3 for the full list of ropsychological measures of recognition, cued recall, and free recall regions). were normal and even superior in some of the SDAM cases. Cued recall of novel verbal paired associates, even following a 24-h delay, was intact. 3.3.3. ERP The SDAM cases' profile of laboratory memory test scores was Recognition performance (i.e., hits-FA) in the SDAM cases was notable for impaired recovery of visual information. Their delayed similar to that of comparison participants (N¼9, t10 ¼0.86, p¼0.41; complex figure recall was uniformly poor. Whereas comparison 64% corrected hits (SD: 0.19) versus 70% (SD: 0.09), respectively; see subjects tended to be more accurate at identifying the visual than Fig. 6D).Asexpected,inthecomparisongrouptherewasarobust auditory presentation modality of verbal paired associates, all of the LPC in the 500–700 ms window over left parietal sites at 500 ms SDAM cases showed the opposite pattern, with impairment for post-stimulus for correctly recognized items (F1,8 ¼19.06, p¼0.002), visually presented items, particularly after 24 h. These deficits could with a laterality effect (F1,8 ¼7.30, p¼0.03; for the left side; F1,8 ¼ not be accounted for by perceptual impairments. Recollection of 68.11, po0.001; see Fig. 6A). This effect was absent in the SDAM visual material is inherent to autobiographical re-experiencing cases (F1,2 ¼0.85, p¼0.45; see Fig. 6B). A direct comparison of hits-CR (Conway and Pleydell-Pearce, 2000; Greenberg and Knowlton, in SDAM cases versus the comparison group revealed a significant 2014; Rubin et al., 2003). Our data suggest that the SDAM cases' reduction in SDAM cases relative to controls (t10 ¼4.07, p¼0.002; recollection deficits may reflect a failure of relational binding of 112 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118

Internal Details External Details

140 140 120 120 100 100 80 * * 80 60 60 40 40 20 20 0 0 1 wk 1 mo 1 yr 10 yr Teen Child 1 wk 1 mo 1 yr 10 yr Teen Child

Examiner Ratings Participant Ratings

* * * * 6 * * * * * * 20 5 15 4

10 3 2 5 1 0 0 1 wk 1 mo 1 yr 10 yr Teen Child 1 wk 1 mo 1 yr 10 yr Teen Child

A.A. B.B. C.C Con

Fig. 3. Autobiographical Interview. The top panel shows the number of internal (left) and external (right) details, while the bottom panel shows examiner (left) and participant (right) ratings from the Autobiographical Interview (Levine et al., 2002) for SDAM cases (N¼3) and comparison participants (N¼15) across six time periods. Generation of internal (episodic) details was significantly reduced relative to the comparison group for remote time periods only. SDAM cases did not differ from the comparison group in the number of external details generated. SDAM cases differed from the comparison group on examiner ratings for five out of six time periods, while their own ratings were significantly reduced for all six time periods. Error bars indicate 95% confidence intervals for the comparison group.

Hippocampal Volume Hippocampal Asymmetry

3500 * 100 3400 50 * 3300 0 3200 -50 3100 -100 3000 -150 2900 -200 2800 -250 Right Hippocampus Left Hippocampus -300

A.A. B.B. C.C Con

Fig. 4. Hippocampal volume. Hippocampal volumes following correction for intracranial volume (Arndt et al., 1991) are plotted with 95% confidence intervals in comparison participants (N¼9). Corrected volumes for each case (N¼3) are plotted separately as indicated in the legend. The panel on the left shows that SDAM cases had lower right hippocampal volumes relative to the comparison group. The panel on the right shows that SDAM cases had a greater asymmetry between right and left uncorrected hippocampi relative to the comparison group. visual details to event information at the time of encoding or an In spite of the deficit in recollection, the SDAM cases showed inability to link visual information to event cues at retrieval. As normal recognition memory and cued recall even for items discussed in more detail below, the neuroimaging findings were presented visually at encoding. One explanation for these findings consistent with a visual mnemonic deficit. Greenberg and Knowlton is that the SDAM cases compensated for their recollection deficit (2014) recently reported two healthy individuals with a self-reported by using familiarity-based processes to achieve normal perfor- profound, lifelong impairment in visual imagery and low subjective mance; for example, for cued recall, the SDAM cases may have ratings of re-experiencing autobiographical memories evoked by cue encoded the semantic content of the items. Anecdotally, the SDAM words. Neuropsychological data (available for one of the two cases describe using a verbal rehearsal strategy to help remember individuals) was consistent with the presently reported data in that details from the past from their daily lives. An alternative but there was isolated visual memory impairment, including low scores related possibility is that when study items were presented on the Rey–Osterreith Complex Figure Test. visually, the SDAM cases encoded the information auditorily (i.e., D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 113

8.0 7.0 * 6.0 ii 5.0 4.0 i 3.0 2.0

Vividness Ratings Vividness 1.0 0.0

1.00 * 0.60 * A.A. 0.60 B.B. 0.40 C.C. 0.20 Con 0.20 -0.20 % Signal Change -0.60 0.00 L. Medial R. Precuneus Prefrontal Cortex

Fig. 5. Autobiographical memory and fMRI. (A) Ratings of vividness during fMRI AM study; SDAM cases (N¼3) reported reduced recollection relative to comparison participants (N¼21). (B) Activation maps demonstrating (i) left medial prefrontal cortex and (ii) right precuneus peaks in the autobiographical versus control (odd-number detection) contrast in comparison participants (po0.0001). As a group, SDAM cases showed reduced activation across selected VOIs (see Section 2 and Table 3), specifically in the anterior and posterior midline, medial temporal, middle temporal, and thalamic regions. (C) Mean activation for SDAM cases and comparison participants for left medial prefrontal cortex and right precuneus peaks. Means are plotted with 95% confidence intervals in comparison participants with each case plotted separately as indicated in the legend. L: left; R: right.

Table 3 Full list of brain regions selected for VOI analysis from the comparison group.

Region Cluster size (μL) BA xyzControl mean (SD) Case mean (SD) Group effect

tp

L. sup frontal gyr 2976 10 4 66 24 0.39 (0.34) 0.17 (0.21) 1.10 0.282 L. med frontal gyr 37720 10 2 58 4 0.71 (0.63) 0.29 (0.23) 2.70 0.013n L. inf frontal gyr 9760 45 54 24 2 0.38 (0.37) 0.00 (0.22) 1.68 0.107 L. mid temporal gyr 1544 21 60 4 10 0.37 (0.28) 0.11 (0.37) 1.45 0.160 R. mid temporal gyr 1336 21 58 4 14 0.28 (0.22) 0.01 (0.14) 2.13 0.045n L. parahipocampus 9924 28 22 22 8 0.56 (0.29) 0.11 (0.31) 2.48 0.021n R. parahipocampus 4664 28 20 22 8 0.45 (0.33) 0.20 (0.27) 1.24 0.227 L. thalamus (ant nuclei) 4864 4 2 14 0.40 (0.32) 0.00 (0.04) 5.43 0.000nnn L. post cingulate gyr 38632 29 4 48 10 1.22 (0.75) 0.76 (0.75) 0.99 0.333 R. precuneus 3816 19 38 78 40 0.42 (0.39) 0.11 (0.12) 2.81 0.018n R. cerebellar tonsil 2184 6 50 42 0.45 (0.31) 0.17 (0.21) 1.46 0.157 R. cerebellar declive 7072 30 76 22 0.50 (0.52) 0.44 (0.29) 0.18 0.863

Note: Standardized space (Talairach and Tournoux, 1988), BA: Brodmann's area; L: left; R: right; sup: superior; inf: inferior med: medial; mid: middle; ant: anterior; post: posterior; gyr: gyrus; and SD: standard deviation. Cluster size is in reference to the cluster in the comparison participants from which the VOI was extracted. n po0.05. nnn po0.001. 114 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118

Fig. 6. Recognition memory and ERPs. Scalp maps and ERP waveforms for parietal clusters for hits and correct rejections (CR). Recognition performance in the SDAM cases (N¼3) was similar to that of comparison participants (N¼9). (A) Hits elicited significantly more positive ERPs than CR for comparison participants on the left side. (B) There was no such effect in the SDAM cases, where ERPs for hits versus false alarms (FA) were significantly less positive than comparison participants in the 500–700 ms temporal window (highlighted in the translucent overlay). (C) Mean ERP amplitude for hits-CR for each individual case and the comparison group. (D) Behavioral performance for SDAM cases versus controls for hits minus FA. Means are plotted with 95% confidence intervals in comparison participants with each case plotted separately as indicated in the legend. by mentally sounding out the words). Yet for strictly visual stimuli ratings of re-experiencing and reduced activation of key areas of the (e.g., the complex figure) this strategy may not be possible. AM network on fMRI (Levine et al., 2009). The SDAM cases reported The SDAM cases' production of internal details (i.e., details specific here have a lifetime of practice in compensating for their lack of first- in time and place) on the AI was significantly different from com- person, autonoetic connection to their own past with non-episodic parison participants for the teenage and childhood time periods only. processes (supported by, for example, rehearsing events and review- There were no differences for external details. Contrary to expecta- ing photographs). Patient H.C., a well-characterized developmental tion, generation of internal details for recent time periods did not amnesic patient, also reported using frequent rehearsal and photo- differ from that of controls. These findings raise the question of how graph viewing to compensate for her memory impairment (Rabin et the SDAM cases generated a normal quantity of internal details for al., 2013). We speculate that such processes enabled the production recent events in the absence of subjective re-experiencing (as of internal episodic-like details for recent events. Such compensation indicated by the SDAM cases' own ratings of their memories). In fact, may have not been possible for the more remote time periods, which there is precedent for such an effect. Cermak and O'Connor (1983, p. occurred prior to the SDAM cases' realization that their memory was 230) reported that a patient with severe amnesia due to herpes qualitatively different from other individuals (all SDAM cases simplex encephalitis could elaborate on past events “with a clarity reported realizing their memory was different from other people in bewildering to those cognizant of his memory deficiencies” even early adulthood). though further examination revealed that he had no episodic AM; In devising the Autobiographical Interview scoring method, we details were produced on the basis of intact semantic memory. found that it was impossible to reliably distinguish truly episodic As noted in Section 2,theAIdetailclassification criteria dictate from episodic-like details. Indeed, we assume that episodic-like that any detail that could reasonably reflect episodic re-experiencing details occur in all autobiographical protocols, albeit to a lesser should be classifiedasinternal.Thisavoidssubjectivejudgmentsin extent than in the SDAM cases. This is why scorers' ratings (an scoring and produces the expected effects in patients with episodic accepted standard method for scoring AM; Kopelman et al., 1989) autobiographical amnesia due to brain disease with impoverished provide useful adjunctive information as the rating criteria take access to first-person AM (Irish et al., 2011; McKinnon et al., 2008; into consideration qualitative information as well as detail quan- Milton et al., 2010; Murphy et al., 2008),yetitcanoverestimatere- tity. Using these ratings, the SDAM cases' episodic deficit broa- experiencing in those who can generate a large number of “episodic- dened to include 5 out of 6 time periods. like” details on the basis of non-episodic processes. For example, we Using a procedure based on the AI (Addis et al., 2008), we also found that patient M.L., who had episodic autobiographical amnesia found that SDAM cases produced relatively impoverished protocols due to traumatic frontotemporal disconnection, was only marginally for episodes projected to take place in the future, although this impaired for internal detail production in spite of grossly impaired finding was statistically significant for observer ratings only. These D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 115

findings are consistent with the notion that similar component be a consequence of a lifetime of impaired recollection. Likewise, processes are necessary for memory and prospection (Addis et al., anatomical analyses in HSAM participants (LePort et al., 2012)show 2007; Spreng et al., 2009), although more detailed measurement of structural differences in a number of brain areas previously implicated elements of prospection in SDAM is required (Szpunar et al., 2014). in AM processes (Cabeza and St Jacques, 2007; Maguire, 2001; The AI protocol provides an in-depth assessment of episodic Svoboda et al., 2006), including increased gray and white matter in versus non-episodic AM details for events that have already been the parahippocampal gyrus and lateral temporal lobes. We focused on identified prior to testing. This is in contrast with methods that hippocampal volumes due to the high reliability of these measure- include event generation in the test protocol, such as the Autobio- ments given the small sample size. Exploration of volumetric changes graphical Memory Test (AMT; Williams and Broadbent, 1986). Anec- in other cortical regions would require a larger sample of SDAM dotally, the SDAM cases reported difficulty in generating AMs for the participants. AI; indeed, their primary presenting complaint was an inability to One limitation of the fMRI AM paradigm is that the SDAM cases, retrieve autobiographical memories. To the extent that all participants as expected, did not recollect events to the same extent as compar- are permitted to use a planner/calendar or query their significant ison subjects (as indicated by reduced ratings of re-experiencing), other to generate specific AMs, it is expected that the SDAM cases although they are presumed to have exerted a similar effort as in the would be impaired in generating as many AMs as controls if asked to AI, where overall detail production was comparable to controls. do so without aids, although we did not test this empirically. These data can thus only provide information about how the SDAM Turning to the imaging findings, the mnemonic profile described cases' pattern of brain activity differs from comparison subjects when here was associated with structural and functional differences in they fail to recollect an autobiographical event. To understand the medial temporal and neocortical regions normally associated with nature of their brain activity during performance of a memory task recollection of both laboratory and real-life episodes. The neuroima- that they actually can perform, we turned to an established labora- ging data provide key information in support of the existence of this tory task of recognition memory where, consistent with their neurocognitive mnemonic syndrome in that such measures are performance on other laboratory tasks, the SDAM cases' performance insensitive to demand characteristics (relative to the behavioral was intact relative to the comparison subjects. In accordance with measures). During retrieval of personally relevant episodic memories, data from developmental amnesia (Düzel et al., 2001b) and adult the SDAM cases showed reduced activation in midline regions as cases (Addante et al., 2012), all three SDAM cases showed attenuation measured with fMRI, particularly in midline anterior and posterior in an ERP index of recollection (Düzel et al., 2001b; Rugg and Curran, regions previously associated with episodic AM. The mPFC is a key 2007). The lack of LPC effect in the SDAM cases supports the region in the AM network (Svoboda et al., 2006)thatplaysa hypothesis that the SDAM cases accomplish intact recognition with- prominent role in processes related to the self (Northoff et al., out the contribution of episodic processes. This capacity to learn and 2006), which is essential to the mental time travel inherent to retain information in the absence of episodic processes in turn episodic memory (Tulving, 2002). Accordingly, the mPFC is prefer- suggests a mechanism by which they accomplish everyday tasks entially active for episodic over semantic AM (Levine et al., 2004). reliant on mnemonic processes, although we were unable to identify The SDAM cases also showed reduced activation in the right the neural correlates of this mechanism through enhancement of precuneus, an important region in the AM network (Svoboda et al., other ERP components in our paradigm (e.g., the N400 component). 2006), with connections to both mPFC and posteromedial regions As noted in Section 1, we considered the possibility that the (Cavanna and Trimble, 2006). The precuneus has been associated SDAM cases' profile of behavioral and neuroimaging findings reflects with a number of higher order cognitive functions important for atypical neurodevelopment, namely developmental amnesia. mnemonic processes, including visuospatial imagery, familiarity and Patients with developmental amnesia, like our cases, show a selective self-referential processes (Cavanna and Trimble, 2006; Fletcher et al., deficit in their ability to recollect personal experiences, with relative 1995). It has been suggested that the precuneus mediates recall of sparing of semantic memory and a sense of familiarity, which likely visual spatial imagery associated with past events and links them to supports their ability to recognize their autobiographical experiences mental representations of the self (Andreasen et al., 1995). Reduced without actually re-experiencing them. However, there was no activation was also observed in other signature AM regions (Maguire, historical evidence to support such a diagnosis in the present cases. 2001; Svoboda et al., 2006), including the right middle temporal Moreover, their anatomical profile does not resemble that of devel- gyrus, the left medial temporal lobe (i.e., parahippocampal gyrus), opmental amnesia. Considering hippocampal volume, we observed a and left thalamus (i.e., anterior nuclei), regions that are critical for unilateral right reduction on the order of 10%ineachcase,whereas episodic memory formation via anatomical connectivity to the developmental amnesics typically have bilateral hippocampal reduc- hippocampus (Aggleton and Brown, 1999). tion of 30–50% (Isaacs et al., 2003; Olsen et al., 2013; Picard et al., Reduced activation of the AM network in the SDAM cases may be 2012; Vargha-Khadem et al., 1997, 2003). Indeed Isaacs et al. (2003) mediated by altered hippocampal-neocortical connectivity (Söderlund propose that bilateral atrophy on the order of 20–30% is a prerequi- et al., 2012), although we did not observe reduced hippocampal site for the profile observed in developmental amnesia. Given their activity per se (possibly due to volumetric differences). Yet, structural level of educational and occupational attainment and day-to-day neuroimage analysis revealed a subtle reduction in right hippocampal functioning, which is higher than what is typically seen in develop- volume in the SDAM cases relative to comparison participants. The mental amnesia (Gadian et al., 2000; Staniloiu et al., 2013)andthe hippocampus is classically involved in recollection (Eichenbaum et al., lack of gross abnormalities on structural neuroimaging, it is likely 2007; Kinsbourne and Wood, 1975), with the right hippocampus that a neurodevelopmental syndrome, if present, is qualitatively specifically associated with processing of non-verbal or visuospatial different from that accounting for reported cases of developmental information (Bohbot et al., 1998), corresponding to the SDAM cases' amnesia. deficit in the recovery of visual information from memory. An Although depression is associated with altered AM (Palombo et interesting possibility is that the SDAM cases' deficit reflects a al., 2012; Söderlund et al., 2014; Williams et al., 2007), the pattern disruption in connectivity between the right hippocampus and right of findings described here cannot be accounted for by depression. precuneus. However, the directionality of the association between None of the SDAM cases were depressed at the time of assessment, hippocampal volume and behavior is unknown; hippocampal volume although two of the three SDAM cases had a history of depression, may reflect a mechanism of impaired recollection, or may alternatively both involved a single remote episode. AM in depression is 116 D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 characterized by capture and rumination on negative memories, first person (i.e., observer perspective). There is evidence that first avoidance of specific details, impaired executive control functions person memories are associated with more vivid recollection (e.g., to guide autobiographical search (Dalgleish et al., 2007; Williams Nigro and Neisser, 1983) but the directionality of this relationship is et al., 2007), and a subtle but significant and temporally-extensive unknown. Ancillary analyses to assess the type of internal details (e.g., reduction of internal details on the AI (Söderlund et al., 2014). event, spatial, temporal, perceptual, or emotion/thought) affected were Patients with depression do not complain of an inability to re- uninformative, possibly due to lower reliability of these measures experience past events. On the contrary, they suffer from excessive relative to the internal detail composite at the individual subject level. rumination that is characterized by vivid recollection of episodic Our goal was to describe the SDAM cases' cognitive syndrome details from negative events (Thomsen et al., 2011). In the present and associated neuroimaging findings in as much detail as possible cases, rumination (according to self-report) was conspicuously in order to stimulate further research on the nature of individual absent due to an inability to re-experience past events, and differences in episodic AM, yet the use of a small sample and a performance on neuropsychological tests of executive function large number of statistical comparisons means the present find- was intact. Nonetheless, given that two of the three SDAM cases ings should be interpreted cautiously. Moreover, there are many had a history of depressive symptoms, mood changes cannot be unanswered questions about SDAM. There is no evidence to ruled out as either a cause or effect of SDAM. Future studies on support a neurological or psychiatric explanation for our findings. larger samples of individuals with such unusual mnemonic pro- Although SDAM appears to be developmental in nature, neither files should incorporate systematic assessments of mood. the history nor the neuroimaging findings are consistent with a Healthy adults differ on numerous cognitive capacities, such as classic developmental amnesia syndrome. A crucial question for linguistic processing and mathematics. These differences have future research pertains to whether these findings reflect an implications for specific mental operations, show associations extreme on a continuum of ability in episodic autobiographical with brain structure and function, and have a genetic basis (Hart recollection, or, they may be qualitatively set apart from the et al., 2010, 2009; Haworth et al., 2009) although they need not be normal distribution of mnemonic capacities. A similar question associated with low daily life function or generalized cognitive can be posed for the HSAM cases (Ally et al., 2013; LePort et al., impairment. Within memory, individual differences as assessed in 2012; Parker et al., 2006; Patihis et al., 2013). Contrasting these the laboratory have been shown to have behavioral and neural two sets of extreme AM cases in larger sample sizes and at earlier biomarkers (Kirchhoff and Buckner, 2006; Miller et al., 2002; developmental stages would advance knowledge concerning the Papassotiropoulos et al., 2006; Rudebeck et al., 2009), yet indivi- behavioral and neural correlates of normal variation in AM in the dual differences have not heretofore been well documented for general population and provide a unique window of opportunity AM, which is the naturalistic expression of fundamental human to explore the mechanisms of human memory. Furthermore, mnemonic function. characterization of more typical variation in naturalistic mnemo- The SDAM cases described here subjectively report a dense nic capacities could provide valuable information concerning episodic autobiographical impairment in the context of preserva- memory disorders and dementia and the relationship of real-life tion of other cognitive and mnemonic capacities (with the excep- memory capacities to other traits (such as personality traits) and tion of visual memory). Their subjective reports were confirmed susceptibility to psychiatric disorders, such as depression and with multiple behavioral measures using both laboratory and post-traumatic stress disorder which are associated with altered naturalistic methods. Although episodic detail counts on the AI AM processing (McKinnon et al., 2014; Palombo et al., 2012; were higher than expected for recent time periods, examiner Söderlund et al., 2014; Williams et al., 2007) and may even ratings were significantly reduced for all but one very recent time mediate the development and maintenance of these disorders, period. We suggest that these SDAM cases are capable of produ- particularly in PTSD (American Psychiatric Association, 2013). cing episodic-like details for recent time periods in the absence of Moreover, given the importance of AM to the ability to plan and recollection, as has been shown in other cases of amnesia (Levine predict future outcomes (e.g., Race et al., 2011; Sheldon et al., et al., 2009; Cermak and O'Connor, 1983). While the behavioral 2011), this research may open up a window of opportunity to data are confirmatory, the neuroimaging data are less affected by examine how AM affects other facets of socialization, such as demand characteristics and provide insights into a possible interpersonal relationships (for anecdotal reports of these effects mechanism for these SDAM cases' subjective findings. As expected in HSAM, see LePort et al., 2012 and Parker et al., 2006). However, given the lack of episodic recollection, the SDAM cases failed to future research is needed to determine more systematically how engage the network of brain regions that is strongly associated variability in AM impacts social experiences, daily function and with AM recollection during fMRI scanning. Most importantly, the quality of life. marked absence of a late positive ERP in the presence of intact recognition supports our hypothesis that these SDAM cases' intact learning and memory is accomplished without recollection. Given the SDAM cases' uniform impairment on memory for a complex Acknowledgments figure and visual source recall, and the importance of visual processes to AM (Rubin et al., 2003; Rubin and Umanath, We thank Drs. Endel Tulving and Asaf Gilboa for their comments 2015), we suggest that the observed impairment is mainly on earlier versions of this manuscript. We thank Dr. Emrah Düzel for attributed to processing of visual information within AM (see stimuli for the ERP paradigm and Dan Schilensky, Fuqiang Gao, and Dr. also Greenberg and Knowlton, 2014). The SDAM cases' subtle Sandra E. Black for assistance with hippocampal volumetrics. Namita reduction in right hippocampal volumes is consistent with this Kumar, Aggie Bacopulos, Leann Lapp, and Allison Mackey are thanked notion, although the causal direction of this anatomical variant is for assistance with data collection. This work was supported by grants indeterminate. from the Canadian Institutes of Health Research (MOP–84347) and the It is unknown whether this deficit in AM is secondary to more National Institute of Mental Health (R01 MH076067) to B.L. and a basic impairments in visual imagery or a deficit in self-referential Natural Sciences and Engineering Research Council of Canada gradu- processing, both of which are integral component processes in AM ate award granted to D.J.P. This research formed part of D.J.P.'s processing. Although we did not systematically query whether a given graduate work. Initials of the SDAM cases have been changed. Finally, AM was constructed from an observer versus a field perspective, we thank the SDAM cases for participating in the experiments subjectively the SDAM cases report difficulty envisioning an event in reported here. D.J. Palombo et al. / Neuropsychologia 72 (2015) 105–118 117

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