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HIPPOCAMPUS 26:1291–1302 (2016) 1 1,2 1,3 Maria C. D’Angelo, R. Shayna Rosenbaum, and Jennifer D. Ryan * ABSTRACT: Amnesia is associated with impairments in relational mem- ability to infer novel information indirectly from prior ory, which is critically supported by the hippocampus. By adapting the learning (Smith and Squire, 2005; Ryan et al., 2016). transitivity paradigm, we previously showed that age-related impairments Impairments in the ability to make inferential judg- in inference were mitigated when judgments could be predicated on ments in novel situations have implications for social known pairwise relations, however, such advantages were not observed in the adult-onset amnesic case D.A. Here, we replicate and extend this find- learning, as inference is a key component in problem ing in a developmental amnesic case (N.C.), who also shows impaired solving and for guiding behavior in social interactions relational learning and transitive expression. Unlike D.A., N.C.’s damage (Holyoak, 2012; Koscik and Tranel, 2012a,b). affected the extended hippocampal system and diencephalic structures, Although amnesic cases can demonstrate intact prior and does not extend to neocortical areas that are affected in D.A. Crit- knowledge of relations, it remains unclear whether ically, despite their differences in etiology and affected structures, N.C. and D.A. perform similarly on the task. N.C. showed intact pairwise such prior knowledge can be used to support novel knowledge, suggesting that he is able to use existing semantic information, inferences in amnesic cases. but this semantic knowledge was insufficient to support transitive expres- Amnesia is often characterized as a pervasive impair- sion. The present results suggest a critical role for regions connected to ment in the ability to learn novel, arbitrary relations the hippocampus and/or medial prefrontal cortex in inference beyond among individual stimuli due to damage to the hippo- learning of pairwise relations. V 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. campus and the extended hippocampal system (EHS) (Cohen and Eichenbaum, 1993; Aggleton and Brown, KEY WORDS: memory; transitivity; developmental amnesia; semantic 1999; Ryan et al., 2000; Moses and Ryan, 2006). To memory date, relational memory impairments in amnesic cases have most often been examined using tasks that test relations that had been directly studied. For example, in the transverse patterning (TP) task (Spence, 1952; Rick- INTRODUCTION ard and Grafman, 1998), individuals are typically required to learn novel relations among three stimuli Relational memory is a critical component of higher-order cognitive (A, B, C), where each stimulus wins in the context of functioning (Konkel et al., 2008; Moscovitch, 2008; Addis et al., 2011; one of the other stimuli and loses in the context of the Duff and Brown-Schmidt, 2012; Cohen, 2015) and is sensitive to neu- remaining stimulus. Amnesic cases show intact perform- rological disturbances and aging (Ryan et al., 2013; D’Angelo et al., in ance on TP when the relations were learned prior to press). Relational memory impairments can lead to impairments in the their neurological insult (Moses et al., 2008a), and are impaired on TP when the relations are arbitrary and must be learned in the confines of the experiment (Rick- ard and Grafman, 1998; Moses et al., 2008a; Ryan This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and et al., 2013; D’Angelo et al., 2015). However, these reproduction in any medium, provided the original work is properly cited impairments can be mitigated when learning of arbi- and is not used for commercial purposes. trary relations is supported by a unitization strategy Rotman Research Institute, Baycrest, 3560 Bathurst St, Toronto, (Ryan et al., 2013; D’Angelo et al., 2015). Ontario, Canada M6A 2E1; Department of Psychology, York Univer- sity, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3; Depart- Inference performance has often been studied using ment of Psychology and Department of Psychiatry, University of the transitive inference (TI) task (Dusek and Eichen- Toronto, 27 King’s College Cir, Toronto, Ontario, Canada M5S 1A1 baum, 1997), in which individuals first learn a series of Grant sponsor: Canadian Institutes of Health Research (CIHR to M.C.D); pairwise relations (e.g., A wins over B, B wins over C, C Grant sponsor: CIHR Operating Grant (to J.D.R.); Grant sponsor: Natural wins over D, D wins over E), after which they are tested Sciences and Engineering Research Council (NSERC) Discovery (to J.D.R. and R.S.R.); Grant sponsor: Ontario Ministry of Health and Long Term on novel pairs (e.g., B vs. D), which require inference of Care through the Ontario Research Coalition of Research Institutes/ a hierarchy within the stimuli (A> B> C> D> E). Centres on Health & Aging (ORC) (to M.C.D.); Grant sponsor: Tier II Prior work has demonstrated impaired TI performance Canada Research Chair Award (to J.D.R.). in human amnesic cases (Smith and Squire, 2005; *Correspondence to: Jennifer D. Ryan, Rotman Research Institute, Baycrest 3560 Bathurst St. Toronto, Ontario, Canada M6A 2E1. Smith et al., 2014) and in hippocampal lesion studies E-mail: jryan@research.baycrest.org with non-human animals (Dusek and Eichenbaum, Accepted for publication 11 May 2016. 1997). However, in TI, some stimuli are always DOI 10.1002/hipo.22606 rewarded (e.g., A), and other stimuli are never rewarded Published online 3 June 2016 in Wiley Online Library (e.g., E). As a result, the intervening stimuli can be (wileyonlinelibrary.com). V C 2016 THE AUTHORS HIPPOCAMPUS PUBLISHED BY WILEY PERIODICALS, INC. 1292 D’ANGELO ET AL. biased through the associative strength of the end stimuli (Frank (MTL), including the hippocampus, as well as damage to the right ventromedial prefrontal cortex (vmPFC) and right ante- et al., 2003), such that performance can be guided by associative rior temporal lobe (ATL) (Rosenbaum et al., 2008). Like the strength of individual stimuli rather than by relational knowledge older adults, D.A. showed impaired relational learning of novel of the hierarchy (Moses et al., 2008b; 2010a). premise pairs, but intact relational knowledge based on semantic To examine the extent to which prior knowledge can be memory. However, unlike older adults, D.A.’s inference perform- used to support inferential judgements in amnesia, we used a ance was impaired regardless if the transitive expression was based version of the transitivity task (Bunsey and Eichenbaum, 1996) on arbitrary relations that had to be learned within the confines adapted for use with humans (Ryan et al., 2016). In the transi- of the experiment or was based on pre-experimentally known tivity task, participants are shown a sample stimulus (e.g., A) relations. We previously hypothesized that D.A.’s inability to use and two choice stimuli (e.g., B, X) and are asked to select the prior knowledge to mitigate his deficit may be the result of his choice stimulus that “belongs” with the sample stimulus (e.g., damage to the right ATL, an area previously implicated in the A ! B). Through training, participants learn the relations ability to use prior knowledge to scaffold new learning (Kan among pairs of stimuli that comprise two sets (e.g., A ! B, B et al., 2009) and as the hub of semantic memory processing ! C, C ! D; W ! X, X ! Y, Y ! Z). Inference can then (Patterson et al., 2007). It is therefore possible that intact transi- be tested using novel pairs containing indirect relations that tive expression can be achieved in other amnesic cases through can only be solved when knowledge from trained pairs is bridging in semantic memory if the semantic network (including bridged (e.g., A ! C?Y?, where C is the correct inference). ATL) is relatively intact. Critically, unlike TI, the problems are setup such that associa- The present study is encouraged by recent neuroimaging tive strength cannot be used to guide performance, as the asso- studies that have investigated the role of the hippocampus in ciative strength among the choice stimuli is equated (e.g., C inferring new relations. During fMRI scanning, Schlichting and Y were rewarded an equal number of times during the et al. (2015) tested participants on an inference task similar to training phase). Our adaptation of the transitivity task includes the transitivity paradigm used in the current study. The authors multiple conditions that vary in terms of whether the items found a dissociation between anterior and posterior regions and/or relations among items are known a priori from accumu- within the hippocampus, whereby anterior regions were associ- lated semantic knowledge. Critically, one condition (known ated with integration, while posterior regions were associated items/pairwise relations) allowed us to test the expression of with maintaining distinct representations (see also Shohamy novel inference in the context of previously known relations. In and Wagner, 2008; Collin et al., 2015). Using a similar task this condition, the pairwise “premise” relations in each set and MEG, Backus et al., (2016) found that hippocampal theta (e.g., A ! B, B ! C, C ! D) were comprised of relations power at encoding predicted later inference, and found known from prior knowledge [e.g., ball of yarn (A) ! knitted increased theta coherence between the hippocampus and scarf (B), knitted scarf (B) ! ice skates (C), ice skates (C) ! medial PFC. These and other recent neuroimaging studies have baseball, and glove (D)], but critically, the novel inference trials highlighted a role for the hippocampus in inference, and in were not comprised of semantically rich relations [e.g., ball of particular have highlighted how integration may occur at yarn (A) ! ice skates (C)]. This condition was contrasted with encoding and/or at test, depending on task demands (Zeitha- a condition requiring novel inference following learning of mova et al., 2012; see also Schlichting and Preston, 2015). arbitrary relations (known items/arbitrary relations). Although these neuroimaging studies provide insight into Using these conditions, we recently examined whether prior the regions and networks involved in relational learning and knowledge could support inferential judgments in older adults inference, they do not provide information regarding the criti- (Ryan et al., 2016), as older adults also show impairments on cal role of these regions/networks. In particular, the findings TP (Driscoll et al., 2003; Ostreicher et al., 2010) and TI (Ryan from neuroimaging stand in stark contrast to a recent case et al., 2009; Moses et al., 2010b). Relative to younger adults, study that reported impaired inference only in cases with older adults showed impaired relational learning of premise pairs vmPFC damage, but not in cases with unilateral hippocampal in the known items/arbitrary relations condition, but older damage, when pairwise relations were known (Koscik and Tra- adults had intact knowledge of relations that could be based on nel, 2012b). Therefore, to understand the critical role of the prior semantic knowledge (known items/pairwise relations condi- hippocampus and its extended network, case studies are tion). Critically, although older adults had impaired transitive required to test the predictions made by neuroimaging studies expression when novel inferences had to be made across pairs of (see Rosenbaum et al., 2014). Given the predictions made by relations that were learned within the confines of the experi- the fMRI work and our prior work with D.A. (Ryan et al., ment, transitive expression was intact when novel inferences 2016), the present study examined whether D.A.’s impaired were made across pairs of relations that were pre-experimentally inference in the context of known pairwise relations would be known (known items/pairwise relations condition). In sum, replicated in a case of developmental amnesia, N.C. (D’Angelo older adults showed intact inference for novel problems when et al., 2015). N.C. has damage to the EHS and diencephalic there was intact knowledge of the premise relations. regions that does not include the hippocampus and vmPFC Our prior study (Ryan et al., 2016) also examined whether but that connects these regions. If, like D.A., N.C. shows prior knowledge could support inference in an amnesic case, impaired inference in the context of known pairwise relations, D.A., who has bilateral damage to his medial temporal lobe then it would suggest that deficits in binding and inference can Hippocampus IMPAIRED INFERENCE IN AMNESIA 1293 occur when the hippocampal system is disconnected from the vmPFC, even in the absence of frank hippocampal damage. This finding would be consistent with the neuroimaging stud- ies reviewed above (Schlichting et al., 2015). It would also sug- gest that D.A.’s impaired performance in this condition was not due to his additional right ATL damage. If it had been the case that N.C. were able to perform inference in the context of known pairwise relations, then this finding would be consistent with prior patient work showing intact inference in cases with MTL damage when the pairwise relations are known (Koscik and Tranel, 2012b). This study was further motivated by the fact that N.C. is a developmental amnesic case, and thus there may be a greater chance of reorganization due to the early onset of the amnesia. Like other developmental amnesic cases, N.C. shows a dissocia- tion of impaired episodic memory in the context of relatively spared semantic memory (Vargha-Khadem et al., 1997; D’Angelo et al., 2015), which stands in contrast to adult- acquired cases who typically show impaired semantic memory for learning that occurs after the onset of their amnesia (O’Kane et al., 2004; Bayley et al., 2008). One caveat is that the semantic learning observed in developmental amnesia occurs gradually over time and is typically not equivalent to the rapid learning observed in healthy adults (Gardiner et al., 2008) who can benefit from episodic encoding. Despite slowed semantic learning in developmental amnesia, there is some evi- dence that semantic knowledge can support other cognitive functions typically reliant on the hippocampal system, as the developmental amnesic case Jon was able to use semantic infor- mation to support “episodic” recall (Brandt et al., 2006). Jon’s ability to use semantic learning to support other cognitive functions may be the result of plasticity and reorganization FIGURE 1. A. T1 weighted MRI scans of N.C., with arrow that can occur in developmental amnesia due to the early age pointing to his right thalamic lesion. B. T1 weighted and T2 of injury (Vargha-Khadem et al., 2003). weighted MRI scans (left and right, respectively) showing that In sum, the present study examined whether the findings of N.C.’s lesion shows slightly hypointense on the T1-weighted image impaired inference observed in D.A. would also apply to a devel- and hyperintense on the coronal T2-weighted image. Figure from opmental amnesic person who has a greater chance for semantic D’Angelo et al. (2015). reorganization. N.C.’s particular pattern of damage would also inform whether anteromedial thalamic damage is sufficient to lead to a similar pattern of impairment as observed in D.A., and of education, including high school and 1 yr of technical col- whether the hippocampus and EHS are critical for inference. If lege. He was aged 20 at the time of testing. N.C. experienced N.C. shows impaired TI in the context of semantic pairwise a thalamic stroke shortly after birth, which primarily affected knowledge, it would suggest that inference requires hippocampal the right mediodorsal nucleus, and partially affected the left binding even when pairwise knowledge is supported by existing mediodorsal nucleus and right anterior nucleus. N.C. also has semantic memory. The results of this study will further our reductions to his right fornix and his mammillary bodies, espe- understanding of the conditions under which strategies based on cially on the right. N.C.’s left lateral ventricle is larger than the semantic knowledge can support other cognitive functions in right. He has white matter changes along the left lateral ventri- amnesia. Moreover, the results of the present study would con- cle and also in the left temporal lobe, with the inferior longitu- tribute to our understanding of the nature of inference itself. dinal fasciculus most involved. See Figure 1 for MR scans highlighting N.C.’s damage. METHODS Neuropsychological Tests & Results The results of an updated neuropsychological evaluation per- Amnesic Case formed when NC was 20-yr old are shown in Table 1. As N.C. has previously been described in D’Angelo et al. described in D’Angelo et al. (2015), these results confirmed (2015). Briefly, N.C. is a young, right-handed man with 14 yr that in the context of average intelligence, N.C. was severely Hippocampus 1294 D’ANGELO ET AL. TABLE 1. impaired on tests of delayed recall. N.C. also performed below expected levels on tests of working memory and more complex Neuropsychological Profile of N.C aspects of visuospatial processing (e.g., recognizing faces, inte- grating details into a complex figure). In contrast, his perform- Test Normed score ance was largely intact on standard measures of semantic knowledge, language, processing speed, and executive function General Intelligence WAIS-IV: Full Scale IQ (standard score) 94 (see Table 1). Verbal Comprehension Index 101 Perceptual Reasoning Index 106 Apparatus and Stimuli Working Memory Index 76 Processing Speed Index 91 The apparatus and stimuli were identical to those used in Semantic Knowledge our prior work (Ryan et al., 2016). The experiment was pro- WAIS-IV Vocabulary (scaled score) 10 grammed and run on a desktop computer connected to a 19- Language Production inch monitor using E-prime 1.1. N.C. responded using the Boston Naming Test (percentile) 39th Semantic Fluency (animals) (z-score) 1.47 keys “Q” and “P” on a standard keyboard. Each of the four Anterograde Memory stimulus conditions consisted of eight colored stimuli divided WMS-IV Logical Memory into two sets (see Fig. 2). The four stimulus conditions differed Logical Memory I: Immediate recall (scaled score) 7 b based on whether the objects and their relations were known Logical Memory II: Delayed recall (scaled score) 2 before the experimental session. Logical Memory II: Recognition (percentile) 3–9th California Verbal Learning Test-II Total trials 1–5 (t score) 29 Known items/semantic relations (K-S) Short delay free recall (z-score) 22.5 Short delay cued recall (z-score) 21.5 The K-S condition consisted of two groups of known Long delay free recall (z-score) 22.5 objects, whose relations within each group were also known Long delay cued recall (z-score) 23 before the experimental session. In this condition, one group Learning (z-score) 21.5 e b of objects (A, B, C, and D) were all items typically found in a Total intrusions (z-score) 5 e b kitchen, while the other group of objects (W, X, Y, and Z) Total repetitions (z-score) 1.5 Recognition (Hits) (z-score) 0.5 were all items used for gardening. Recognition (False Positives) (z-score) 3 Discrimination 21.5 Known items/pairwise relations (K-P) Rey-Osterrieth complex figure (t score) Immediate recall < 20 The K-P condition consisted of two groups of known Delayed recall < 20 objects where the relations among all of the items within each Test Normed Score group were not known a priori, but in which consecutive pairs Processing Speed of items in each group had meaningful relations. For example WASI-IV Coding 7 WASI-IV Symbol Search 10 in the first set of objects (A, B, C, and D), the yarn (object A) Visuospatial Function is meaningfully related to the scarf (object B), the scarf is WAIS-IV Block Design 13 related to the ice skates (object C), and the skates are related Rey-Osterrieth Complex Design—Copy (percentile) 11–16th to the baseball glove (object D). However, there are no pre- Judgment of Line Orientation (percentile) 72nd existing, commonly used, meaningful relations among the non- Benton Facial Recognition Test Borderline Working Memory consecutive items (A–C, A–D, B–D), such as between the yarn WAIS-IV Letter-Number Sequencing 6 and the baseball glove, the yarn and the skates, or the scarf and a b WAIS-IV Digit Span 5 the baseball glove. Similarly, in the second set (W, X, Y, Z), Attention and Executive Function f the construction hat (object W) is meaningfully related to the Trail Making Test (z-score) nails (object X), the nails are related to the picture frame Part A (sec) 20.74 Part B (sec) 20.95 (object Y), and the picture frame is related to the camera Phonemic Fluency (FAS) (z-score) 0.31 (object Z). Once again, although these pairwise relations exist WAIS-IV Similarities (scaled score) 10 among the consecutive items, there are no meaningful relations WAIS-IV Matrix Reasoning (scaled score) 11 among nonconsecutive items (W–Y, W–Z, X–Z; the construc- tion hat and the picture frame, the construction hat and the WAIS-IV, Wechsler Adult Intelligence Scale–IV; WMS-IV, Wechsler Memory Scale–IV. camera, or the nails and the camera). Canadian Norms. Borderline/impaired performance. Known items/arbitrary relations (K-A) In house norms. Tombaugh et al., 1999. The K-A condition consisted of two sets of known objects, Lower scores indicate better performance; whose relations within each group were not known prior to the Tombaugh, 2004. experimental session, and for which no overall or pairwise rela- tions were known prior to training. For example, in one set Hippocampus IMPAIRED INFERENCE IN AMNESIA 1295 FIGURE 2. Stimuli used for the ABCD and WXYZ stimulus sets across the four experi- mental conditions. Figure taken from Ryan et al. (2016). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] the relations among an umbrella (object A), a set of keys exception that he was not given the test phase for condition N-A, (object B), a brush (object C), and a flashlight (object D) were due to low performance in the training phase. In Session 5, N.C. learned and were separate from the relations among an arm- was trained and tested on all four conditions. chair (object W), a hanger (object X), a wrench (object Y), and a barbeque (object Z). All objects in the known item condi- Training phase tions were common, nameable objects selected from the Hem- era 3.01 database. On every trial, N.C. was shown a problem set containing three items (see Fig. 3). A sample object was presented centrally Novel items/arbitrary relations (N-A) on the upper half of the screen for 2 s on its own, after which two choice items appeared on the lower half of the screen, one The N-A condition was identical to the known items/arbi- on the left and one on the right. N.C. was instructed to pick trary relations condition, with the exception that eight novel, the choice object that made a correct pairing with the sample abstract objects were used as the stimuli. These objects were created using Corel Draw v.12. TABLE 2. Procedure Overview of Conditions Completed by N.C. in Each Session Each condition consisted of three training blocks followed by a Known items/ Known items/ Known items/ Novel items/ no-feedback test block, described below. N.C. was trained and tested Semantic Pairwise Arbitrary Arbitrary on the four conditions over five separate sessions (see Table 2). The Session relations relations relations relations conditions were always administered in the following order: K-S, K-P, K-A, and N-A to ensure understanding of the task require- 1 – ments. In Session 1, N.C. did not complete the test phase for the 2 3 – K-A condition due to low performance in the training phase. Given his poor performance in the K-A, the N-A condition was not admin- istered in Session 1. In Session 2, N.C. was trained and tested on all conditions. In Session 3, N.C. completed all conditions with the 5 Training and test phases completed. exception of N-A, which was excluded due to time constraints. In 5 Failed training phase, test phase not administered. Session 4, N.C. was trained and tested on all conditions, with the –5 Condition not administered. Hippocampus 1296 D’ANGELO ET AL. FIGURE 3. Depiction of the training and test sequences in the novel relations that had to be inferred across pairs of previously stud- transitivity task. Trials were self-paced and feedback was provided in ied relations (novel probe pairs). Novel probe pairs include pairs in the training phase only. The sample stimulus was presented at the which the sample was separated from the choice items by one (1- top of the screen, and the two choice stimuli were presented along away), two (2-away) or a mixture of one and two intervening items the bottom of the screen. Participants were required to select one of and their respective relations (mixed). Figure adapted from Ryan the two choice stimuli that ‘belonged’ with the sample stimulus. Test et al.(2016). [Color figurecan be viewed in theonlineissue, which trials could depict previously studied relations (studied trials), or is available at wileyonlinelibrary.com.] object, using the left and right response keys to pick the left procedures used in animal work (Bunsey and Eichenbaum, and right choice items, respectively. A happy cartoon face and 1996). the phrase “Correct!” was presented following correct responses, Training blocks advanced only if the criterion of 70% accu- and an angry cartoon face and the phrase “Wrong!” was racy was achieved. If accuracy was less than 70%, the block presented following incorrect responses. N.C. was required to repeated. Testing within a condition was terminated if a study learn the relations among the items through trial and error. block was repeated six times without criterion being reached. The training phase consisted of three blocks in which N.C. was trained on the relations among consecutive pairs of items Test phase in each set. In the first block, all of the samples were drawn The test phase was identical to the training phase with the from the first set of stimuli (A, B, C, D—see Fig. 1). Each following exceptions. The test phase included four trial types: problem set was presented consecutively and this sequence was studied, one-away, two-away, and mixed. Studied trials were repeated four times for a total of 12 trials (i.e., [A ! B vs. X; identical to those presented during training and tested the rela- B ! C vs. Y; C ! D vs. Z] x 4). The second block was iden- tions among consecutive items within each set. The remaining tical to the first block with the exception that all of the samples trial types tested N.C.’s ability to derive the relations among were drawn from the second set of stimuli (W, X, Y, Z). In the nonconsecutive items within each set. These novel probe trials third block, samples were drawn from both stimulus sets. Each problem set the two sets of stimuli were presented six times in included problem sets in which the sample was separated from the choice items by one (one-away: A ! C vs. Y, B ! D vs. the third block (i.e., six presentations of Set 1: [A ! B vs. X; Z, W ! C vs. Y, X ! D vs. Z), two (two-away: A ! D vs. B ! C vs. Y; C ! D vs. Z] and Set 2: [W ! X vs. A; X ! Y vs. C; Y ! Z vs. D]). Within each of the six presentations, Z, W ! D vs. Z), or a mixture of one and two intervening the sequential order of the problem sets was maintained, but items and their respective relations (mixed: A ! C vs. Z, A ! the order of Set 1 or Set 2 first was randomly selected. There- D vs. Y, W ! C vs. Z, W ! D vs. Y). Each instance of each fore, learning always followed the same sequence, analogous to trial type presented six times (e.g., A ! B vs. X was presented Hippocampus IMPAIRED INFERENCE IN AMNESIA 1297 six times) for a total of 96 trials in the test phase. No feedback was given in the test phase. In both the training and test phases the correct choice stim- ulus was counterbalanced such that it appeared an equal num- ber of times on the left and right sides of the screen. Healthy Controls N.C.’s performance was contrasted with performance of the 36 healthy younger adults described in our prior work (Ryan et al., 2016). Briefly, 36 healthy younger adults (mean age5 23.1, SE5 0.5, range: 18–28) with no known pathology were recruited from the volunteer participant pool at the Rot- man Research Institute at Baycrest. All participants gave informed written consent and participated in exchange for monetary compensation. This experiment received ethics approval from the Toronto Academic Health Science Council. FIGURE 4. Mean accuracy in the training phase for healthy con- The procedure for the healthy controls was identical to the trols (from Ryan et al., 2016) and N.C. as a function of the four stimu- lus conditions. Error bars represent the 95% confidence interval (CI) procedure for N.C. with the following exceptions. The first dif- of the mean accuracy in the healthy controls. The dotted line here and ference concerned whether the sample and choice stimuli were in all graphs represents chance performance (0.50). presented together during training and/or test. Twelve of the healthy controls completed the task with identical stimuli pre- variance, which included stimulus condition and trial type (stud- sentation as N.C.: the sample and choice stimuli were pre- ied, one-away, two-away, vs. mixed pairs) as within-subject fac- sented together both during training and test, as outlined tors. To simplify the presentation of results, experiment version above (sample alone for 2 s, after which the two choice stimuli (onset, onset1 delay, and delay) and stimulus condition pre- were presented along with the sample until a response was sented first (K-S, K-P, K-A, and N-A) were not included in the made). This is the experiment version referred to as onset in present set of analyses. N.C. was not given either of these our prior study. Twelve healthy controls saw the sample stimu- manipulations, and we found no consistent interactions of these lus separately from the choice stimuli for both the training and variables with stimulus condition or trial type in our prior analy- test phases. In both phases, these participants were shown the ses (Ryan et al., 2016). The inclusion of these two variables in sample stimulus presented alone for 2 s, followed by a blank the present set of analyses showed the same pattern of results screen for 3 s, and finally the two choice stimuli were pre- and the results of these analyses are available on request. N.C.’s sented until a response was made. This is the experiment ver- performance was examined relative to healthy controls by con- sion to as delay in our prior work. The remaining twelve trasting his performance against the 95% confidence interval healthy controls were shown the choice stimuli along with the (CI) of healthy controls, as done in our prior work (Moses sample stimulus during the training phase (as in the onset con- et al., 2008a; Ryan et al., 2013). dition), but in the test phase the choice stimuli were presented separately from the sample stimulus (as in the delay condition). This is the experiment version referred to as onset1 delay in our prior work. The sample and choice stimuli were presented RESULTS together or separately during training and/or test to examine the role for the hippocampus in bridging information across Training Phase—Healthy Controls time (Wallenstein et al., 1998; Bangasser et al., 2006). In our Accuracy in the training phase for the healthy controls and prior work, we found no consistent differences across the dif- N.C. is plotted in Figure 4. The analysis of accuracy in the ferent experiment versions (Ryan et al., 2016), therefore N.C. training phase revealed a main effect of stimulus condition was only trained on the onset condition. (F(3,105)5 21.2, P< 0.001, e5 0.70, h 5 0.38). As expected, Order of stimulus conditions and experiment version were accuracy was highest in the two conditions with semantic rela- counterbalanced across conditions in the healthy controls. N.C. tions (M5 0.97, SE5 0.01 for both the K-S and K-P condi- was always given the task in the same order (K-S, K-P, K-A, N-A) in an effort to support his understanding of the task demands. tions), followed by the K-A condition (M5 0.92, SE5 0.01) and was lowest in the N-A condition (M5 0.89, SE5 0.02). Analysis Training Phase—N.C Training accuracy was analyzed using a mixed-effects repeated measures analysis of variance, where stimulus condition (K-S, K- N.C. performed similarly to healthy controls on the condi- P, K-A, and N-A) was included as a within-subjects factor. Test tions when prior knowledge supported performance (K-S: accuracy was analyzed using a repeated measures analysis of M5 0.99; K-P: M5 0.98). In contrast to his high Hippocampus 1298 D’ANGELO ET AL. FIGURE 5. Mean accuracy in the test phase healthy controls (from Ryan et al., 2016) and N.C. as a function of the four stimulus conditions and four trial types. Error bars represent the 95% CI of the mean accuracy in the healthy controls. performance in the two conditions supported by prior knowl- significant main effect of stimulus condition (F(3,105)5 7.48, edge, N.C. was impaired on the conditions where arbitrary P< 0.001, e5 0.87, h 5 0.18). As expected, accuracy was highest in the conditions with semantic (K-S: M5 0.97, relations had to be learned (K-A: M5 0.64; N-A: M5 0.61). SE5 0.01), or pairwise relations (K-P: M5 0.91, SE5 0.02), N.C.’s pattern of performance in the study phase replicates what was found with amnesic case D.A. (Ryan et al., 2016), as and was lowest in the two conditions that test pre- well as prior work showing impaired learning of arbitrary rela- experimentally arbitrary relations (K-A: M5 0.86, SE5 0.03; N-A: M5 0.86, SE5 0.03). tions in amnesic cases, but intact processing of relations known The analysis revealed a significant main effect of trial type prior to neurological insult (Moses et al., 2008a; Ostreicher (F(3,105)5 7.47, P< 0.001, e5 0.87, h 5 0.18). Participants et al., 2010; Ryan et al., 2013; D’Angelo et al., 2015). Impor- had higher accuracy for the previously studied pairs (M5 0.92, tantly, N.C.’s intact performance on the conditions supported SE5 0.02) than for the inference pairs (range5 0.88–0.89 for by prior knowledge is consistent with prior work showing evi- one-away, two-away, and mixed pairs). dence for the prior and ongoing acquisition of semantic knowl- Trial type also interacted with stimulus condition edge in developmental amnesia (Vargha-Khadem et al., 1997; (F(9,315)5 3.02, P5 0.002, e5 0.56, h 5 0.08). The general Gardiner et al., 2008). p pattern of higher accuracy for studied pairs relative to inference pairs was found for all conditions; however, the range of accu- No-Feedback Test Phase—Healthy Controls racies across trial types was exaggerated in the K-P condition Accuracy in the no-feedback test phase for the healthy con- (range5 0.86–0.96). As discussed in our prior work (Ryan trols and N.C. is plotted in Figure 5. Similar to the analysis of et al., 2016), this exaggerated range of performance is not sur- the training phase, the analysis of the test phase revealed a prising, as the studied trials tested relations known prior to the Hippocampus IMPAIRED INFERENCE IN AMNESIA 1299 experiment, while the inference trial types (one-away, two- indicating that anteromedial thalamic damage affecting hippocampal-vmPFC connectivity is sufficient to produce gen- away, and mixed) tested relations that had to be indirectly eral impairments in relational learning and inference, even in expressed based on knowledge of the premise pairs. In contrast, the context of intact ATL and semantic knowledge. trial types in the other conditions either required the expression During training, N.C. showed impaired relational learning of pre-experimentally known relations (K-S condition) or novel relative to healthy controls in conditions where arbitrary rela- relations that had to be acquired within the experimental ses- tions had to be learned in the absence of prior knowledge sion (K-A and N-A conditions). (known items/arbitrary relations and novel items/arbitrary rela- tions conditions). This result is consistent with prior work No-Feedback Test Phase—N.C examining impaired relational learning in amnesia (Ryan et al., N.C.’s accuracy on the studied trials in the test phase mir- 2000; Moses et al., 2008a; D’Angelo et al., 2015) and repli- rors his performance from the training phase. N.C.’s accuracy cates what we previously observed in D.A. using this paradigm was similar to controls on the two conditions for which the (Ryan et al., 2016). N.C. showed intact performance when the relations were known pre-experimentally (K-S and K-P). N.C. relations among premise pairs were known pre-experimentally was markedly impaired on the conditions where novel relations (known items/semantic relations and known items/pairwise had to be learned (K-A and N-A), falling outside the 95% CI relations conditions). N.C.’s intact expression of pre-existing of controls’ performance on studied trials for the two condi- relational knowledge is consistent with previous work in adult- tions, and with mean performance below chance in the N-A acquired amnesia (Moses et al., 2008a; Ryan et al., 2013; condition. D’Angelo et al., 2015) and developmental amnesia (Vargha- N.C. performed within the 95% CI of controls on the infer- Khadem et al., 1997), and is consistent with D.A.’s perform- ence trials in the K-S condition, where performance was still ance on this same task (Ryan et al., 2016). supported by pre-experimentally known relations. Although N.C. showed impaired relational memory and transitive N.C. demonstrated intact performance on the studied pairs for expression relative to controls in the test phase when perform- the K-P condition, he was unable to express novel inference ance could not be supported by prior knowledge (known with respect to these semantically rich premise relations, as items/arbitrary relations and novel items/arbitrary relations demonstrated by his poor performance on the inference pairs. conditions). This finding is perhaps unsurprising given his Therefore, although prior knowledge supported performance impaired relational learning during training. When all possible for the studied pairs, this pre-existing knowledge was unable to relations among items in a set were supported by prior knowl- support the expression of inference across intervening levels of edge (known items/semantic relations), N.C.’s performance did relational distance. not differ from that of controls: he was able to express his rela- N.C. also showed impaired performance with accuracy out- tional knowledge. Critically, when only pairwise relations side the 95% CI of controls on the inference trials in the K-A among items in a set were supported by prior knowledge and N-A conditions. Note that although N.C.’s accuracy on (known items/pairwise relations), N.C. showed intact knowl- the inference trials appears to be higher in the N-A relative to edge of the premise pairs, but showed impaired transitive K-A condition, he only completed two test phases in the N-A expression. In fact, N.C.’s performance was numerically below condition and thus his performance may not be reliable. chance on all inference trials in this condition. N.C.’s below- chance performance reflects an inability to overcome biases in responding based on weak relational information from prior knowledge (e.g., construction helmet going with ice skates, or GENERAL DISCUSSION construction helmet going with baseball and glove). Although N.C. made responses based on weak relational information The present study examined whether prior knowledge can during the test phase, his postexperiment explicit responses did support inference in a developmental amnesic case, N.C., who not always map onto these task responses. For example, he has diencephalic damage and atrophy within the EHS and only explicitly grouped the construction helmet with the ice associated episodic memory impairment. Despite N.C.’s early skates in Session 4, and never explicitly grouped the construc- amnesia, he shows evidence of semantic knowledge acquisition. tion helmet with the baseball and glove. We examined whether N.C. was able to use this knowledge to N.C.’s impaired inference in the context of known pairwise support inference, as there is some evidence that developmental relations suggests that he is unable to flexibly bridge across amnesic cases can use semantic information to support other existing relations in semantic knowledge. This inability to flexi- cognitive functions (Brandt et al., 2006), perhaps due to reor- bly bridge across existing relations is likely due to deficits in ganization that occurs during development (Vargha-Khadem relational binding. We hypothesize that bridging across rela- et al., 2003). N.C. was unable to use his existing semantic tions is critically dependent on the hippocampus, but that defi- knowledge to support novel inference, a finding that resembles cits can also occur when the hippocampal system is that seen in the older, adult-onset, amnesic case, D.A., who has disconnected from the vmPFC, as may be the case in N.C. damage to the MTL bilaterally and right vmPFC and ATL Our interpretation is also consistent with prior work with two (Ryan et al., 2016). The results in N.C. extend this finding by other developmental amnesic cases (Gardiner et al., 2008; Hippocampus 1300 D’ANGELO ET AL. Rosenbaum et al., 2015). For instance, although developmental damage to the EHS nonetheless impairs inference, thus demon- amnesic case Jon has intact semantic memory for pre- strating a critical role for the hippocampal system in inference. experimentally known facts, he was impaired and had slowed The present work contributes to our understanding of what learning relative to controls when learning novel facts (Gardiner inference is by showing that inference involves the ability to et al., 2008). Likewise, developmental amnesic case H.C. showed flexibly bridge existing relations in memory, which likely entails intact spatial knowledge of her neighborhood and downtown the creation of new relations, a process that is critically depend- area of her hometown, but showed impaired performance on ent on the hippocampus. Based on prior neuroimaging work tasks where she was asked to describe alternate routes to avoid (Schlichting et al., 2015), we suggest that a level of stability of blocked roads or barriers (Rosenbaum et al., 2015). Her impair- the premise relations may be required before bridging or inte- ments suggested that she could not use her existing knowledge gration can take place. This explanation is consistent with the with the same flexibility expressed in typically developing con- results of our prior study (Ryan et al., 2016), where we found trols. This prior work shows that the relatively intact semantic that older adults were impaired in establishing premise rela- knowledge that is often observed in developmental amnesia is tions and performing inference in the arbitrary conditions, but qualitatively different from semantic knowledge observed in con- were able to perform inference when the pairwise relations trols. The results from this prior work highlight the role of the were pre-experimentally known and stable (i.e., well-established hippocampus and its extended system in the development of during encoding/training phases). Depending on task demands semantic knowledge, as has been previously described (Cohen and/or the stability of the premise relations, bridging (or inte- and Eichenbaum, 1993; Squire, 2004). gration) can occur at encoding, particularly for already stable Despite the many differences between D.A. and N.C. in premise relations, and/or at test, when memory and inference terms of their pattern of damage, age, and the etiology of their are probed. Critically, the present work also shows that deficits amnesia, both cases were unable to perform inference in the in binding and inference can occur in the absence of hippo- context of premise pairs that contained relations known pre- campal damage, when the hippocampal system is disconnected experimentally. Although N.C.’s hippocampi are volumetrically from the vmPFC. Deficits in inference can occur despite the normal, the damage to his EHS (Aggleton and Brown, 1999), existence of seemingly stable premise relations (i.e., intact per- including bilateral anteromedial thalamic damage, appears to formance on the premise relations during the training phase). have disrupted his relational learning and transitive expression. In prior work, we suggested the possibility that D.A.’s inability Within the thalamus, N.C. has volume reduction primarily to use prior knowledge to mitigate his deficit was due to damage within the right mediodorsal nucleus of the thalamus, with an to neocortical areas including the right ATL, which has been additional lesion but no volume reduction within the left implicated in the ability to use prior knowledge to scaffold new mediodorsal nucleus (Rosenbaum et al., in prep). The medio- learning (Kan et al., 2009), and the right vmPFC, which has been dorsal nucleus forms part of a network between cortical MTL implicated in inference (Koscik and Tranel, 2012b) and in rapid areas, including perirhinal and entorhinal cortices, and both retrieval of relevant schemas to support flexible inference (Gilboa medial and lateral PFC (Ketz et al., 2015). N.C. also has a et al., 2009). While N.C. does not have damage to the ATL or lesion (but no significant volume reduction) within the right vmPFC, suggesting that these regions may not be critical to sup- anterior nucleus as well as an atrophied right fornix and small porting inference in the pairwise condition, N.C. does have a mammillary bodies, which may be of relevance for the present lesion to the anterior nucleus of the thalamus and degradation of findings. These structures form part of a circuit connecting the the right fornix and mammillary bodies, which may impact how hippocampus to medial PFC (Ketz et al., 2015). It is possible information is relayed to the vmPFC (Aggleton et al., 2011; Per- that N.C.’s impaired ability to bridge across existing relations gola and Suchan, 2013; Ketz et al., 2015). Therefore, it remains may reflect a critical disruption to this network. However, unknown whether N.C.’s performance is the result of damage to research involving additional cases is needed to test this this pathway, which would be consistent with a prior study show- hypothesis, in particular cases who have isolated deficits in one ing impaired inference despite intact pairwise learning in cases or another circuit. with vmPFC damage (Koscik and Tranel, 2012b). Although The present set of findings add to prior work with non- more work is needed to clarify the roles of the EHS and the human animals with lesions to the hippocampus that has iden- vmPFC in inference, the present findings highlight a potential tified a role for the hippocampus in TI in the context of suc- critical role for the EHS in inference. cessful learning of premise pairs (Bunsey and Eichenbaum, The hippocampus and its extended system may support 1996). N.C.’s impaired inference despite successful expression inference in two ways. First, the bridging and expression of of relational knowledge of premise pairs is also consistent with known relations in the known relations/pairwise condition may prior work showing a role for the hippocampus in inference require storage of new relational knowledge representing indi- that extends beyond mere relational learning of the premise rect relations, which may be mediated by the hippocampus pairs (Myers et al., 2003; Preston et al., 2004; Shohamy and (Kumaran and McClelland, 2012). In our prior work, we Wagner, 2008; Zeithamova and Preston, 2010; Collin et al., speculated that healthy older adults likely had sufficient resid- 2015; Schlichting et al., 2015; Backus et al., 2016). The pres- ual hippocampal function to support this storage, but that ent work critically extends this prior work by showing that D.A. did not (Ryan et al., 2016). Although N.C. does not even when pairwise relations are pre-experimentally known, have hippocampal damage, it is likely that the damage to his Hippocampus IMPAIRED INFERENCE IN AMNESIA 1301 anteromedial thalamus and reductions in his mammillary Aggleton JP, Brown MW. 1999. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci 22:425–444, bodies and right fornix were sufficient to impair either the stor- discussion 444–489. age or retrieval of new relational information (Aggleton and Aggleton JP, Dumont JR, Warburton EC. 2011. Unraveling the con- Brown, 1999), at either training or test. tributions of the diencephalon to recognition memory: A review. Second, evidence points to a role for hippocampal-neocortical Learn Mem 18:384–400. interactions in the assimilation of new knowledge into existing Backus AR, Schoffelen J-M, Szeb enyi S, Hanslmayr S, Doeller CF. 2016. Hippocampal-prefrontal theta oscillations support memory schemas (Tse et al., 2007, 2011). Tse and colleagues have demon- integration. Curr Biol 26:450–457. strated a critical role for the rat mPFC and hippocampus in the Bangasser DA, Waxler DE, Santollo J, Shors TJ. 2006. Trace condi- integration of new information into previously stored knowledge. tioning and the hippocampus: The importance of contiguity. Although the homolog to the rat mPFC is under debate (Kesner, J Neurosci 26:8702–8706. 2000; Farovik et al., 2008), the vmPFC has been suggested to Bayley PJ, O’Reilly RC, Curran T, Squire LR. 2008. New semantic learning in patients with large medial temporal lobe lesions. Hip- play a role in allowing rapid retrieval of relevant schemas to sup- pocampus 18:575–583. port flexible inference in humans (Gilboa et al., 2009; Kan et al., Brandt KR, Gardiner JM, Vargha-Khadem F, Baddeley AD, Mishkin 2009). Recent work has also shown that when new information is M. 2006. Using semantic memory to boost “episodic” recall in a learned, vmPFC activity increases with increasing congruency case of developmental amnesia. NeuroReport 17:1057–1060. between the new information and existing knowledge, while hip- Bunsey M, Eichenbaum H. 1996. Conservation of hippocampal mem- ory function in rats and humans. Nature 379:255–257. pocampal activity shows the opposite pattern, showing increasing Cohen NJ. 2015. Navigating life. Hippocampus 25:704–708. activity with decreasing congruency (van Kesteren et al., 2013). Cohen NJ, Eichenbaum H. 1993. Memory, Amnesia, and the Hippo- These findings are consistent with a recent proposal that the campal System. Cambridge: MIT Press. vmPFC engages in evaluative processing, whereby the vmPFC Collin SHP, Milivojevic B, Doeller CF. 2015. Memory hierarchies drives the hippocampus to make new relations when needed, map onto the hippocampal long axis in humans. Nat Neurosci 18: such as in the case of decreasing congruency (Liu et al., 2016). 1562–1564. D’Angelo MC, Kacollja A, Rabin JS, Rosenbaum RS, Ryan JD. 2015. Therefore, although N.C. was able to express knowledge for exist- Unitization supports lasting performance and generalization on a ing semantic information, his impaired inference in the pairwise relational memory task: Evidence from a previously undocumented condition may thus reflect an inability to reorganize the schema developmental amnesic case. Neuropsychologia 77:185–200. structure to reflect the incorporation of new, indirect relations, D’Angelo MC, Smith VM, Kacollja A, Zhang F, Binns MA, Barense MD, potentially because of disrupted hippocampal-neocortical interac- Ryan JD. 2016. The effectiveness of unitization in mitigating age- related relational learning impairments depends on existing cognitive tions (Wang and Morris, 2010; McKenzie and Eichenbaum, status Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, doi: 2011). 10.1080/13825585.2016.1158235. In conclusion, the results from the present study confirm that Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM, relational learning and transitive expression in the context of arbi- Baumgartner RN, Sutherland RJ. 2003. The aging hippocampus: Cogni- trary relations are impaired in a case of developmental amnesia, tive, biochemical and structural findings. Cereb Cortex 13:1344–1351. Duff MC, Brown-Schmidt S. 2012. The hippocampus and the flexible who has damage limited to the EHS. Importantly, the present use and processing of language. Front Hum Neurosci 6:69. results reveal intact semantic knowledge but show impaired infer- Dusek JA, Eichenbaum H. 1997. 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