Effects of extended practice and unitization on relational memory in older adults and neuropsychological lesion cases.

Unitization - the fusion of objects into a single unit through an action/consequence sequence - can mitigate relational memory impairments, but the circumstances under which unitization is effective are unclear. Using transverse patterning (TP), we compared unitization (and its component processes of fusion, motion, and action/consequence) with extended practice on relational learning and transfer in older adults and neuropsychological cases with lesions (to varying extents) in the medial prefrontal cortex (mPFC) or hippocampus/medial temporal lobe (HC/MTL). The latter included a person with bilateral HC lesions primarily within the dentate gyrus. For older adults, TP accuracy increased, and transfer benefits were observed, with extended practice and unitization. Broadly, the lesion cases did not benefit from either extended practice or unitization, suggesting the mPFC and dentate gyrus play important roles in relational memory and in unitization. The results suggest that personalized strategy interventions must align with the cognitive and neural profiles of the user.

The Role of the Ventromedial Prefrontal Cortex and Basal Forebrain in Relational Memory and Inference.

The ventromedial prefrontal cortex (vmPFC) is involved in diverse cognitive operations, from inhibitory control to processing of semantic schemas. When accompanied by damage to the basal forebrain, vmPFC lesions can also impair relational memory, the ability to form and recall relations among items. Impairments in establishing direct relations among items (e.g., A is related to B, B is related to C) can also hinder the transitive processing of indirect relationships (e.g., inferring that A and C are related through direct relations that each contain B). Past work has found that transitive inference improves when the direct relations are organized within an existing knowledge structure, or schema. This type of semantic support is most effective for individuals whose relational memory deficits are mild (e.g., healthy age-related decline) rather than pronounced (e.g., hippocampal amnesia, amnestic mild cognitive impairment). Given that vmPFC damage can produce both relational memory and schema processing deficits, such damage may pose a particular challenge in establishing the type of relational structure required for transitive inference, even when supported by preexisting knowledge. To examine this idea, we tested individuals with lesions to the mPFC on multiple conditions that varied in pre-experimental semantic support and explored the extent to which they could identify both previously studied (direct) and novel transitive (indirect) relations. Most of the mPFC cases showed marked transitive inference deficits and even showed impaired knowledge of preexisting, direct, semantic relations, consistent with disruptions to schema-related processes. However, one case with more dorsal mPFC damage showed preserved ability to identify direct relations and make novel inferences, particularly when pre-experimental knowledge could be used to support performance. These results suggest that damage to the mPFC and basal forebrain can impede establishment of ad hoc relational schemas upon which transitive inference is based, but that appealing to prior knowledge may still be useful for those neurological cases that have some degree of preserved relational memory.

Selective attention effects on recognition: the roles of list context and perceptual difficulty.

Two recent studies reported superior recognition memory for items that were incongruent targets than for items that were congruent targets in a prior incidental study phase (Krebs et al. in Cereb Cortex (New York, NY) 25(3):833-843, 2015; Rosner et al. in Psychol Res 79(3):411-424, 2015). The present study examined this effect further by addressing two issues. First, we examined whether this effect is sensitive to the list context in which congruent and incongruent items are presented. In Experiment 1, this issue was addressed by manipulating the relative proportions of congruent and incongruent trials in the study phase. In Experiments 2A and 2B, the same issue was examined by contrasting randomly intermixed and blocked manipulations of congruency. The results of these experiments, as well as a trial-to-trial sequence analysis, demonstrate that the recognition advantage for incongruent over congruent items is robust and remarkably insensitive to list context. Second, we examined recognition of incongruent and congruent items relative to a single word baseline condition. Incongruent (Experiment 3A) and congruent (Experiment 3B) items were both better recognized than single word items, though this effect was substantially stronger for incongruent items. These results suggest that perceptual processing difficulty, rather than interference caused by different target and distractor identities on its own, contributes to the enhanced recognition of incongruent items. Together, the results demonstrate that processes that are sensitive to perceptual processing difficulty of items but largely insensitive to list context produce heightened recognition sensitivity for incongruent targets.

Existing semantic knowledge provides a schematic scaffold for inference in early cognitive decline, but not in amnestic MCI.

Healthy older adults show impaired relational learning, but improved transitive expression when inferences are made across pre-experimentally known premise relations. Here, we used the transitivity paradigm to ask whether the organizational structure within schemas facilitates the bridging of relations for novel inference for otherwise healthy older adults who are exhibiting early signs of cognitive decline ("at-risk" older adults), and individuals with single- or multiple-domain amnestic mild cognitive impairment (aMCI). Relational learning was impaired in the two older adult groups, but transitive expression was facilitated by prior semantic knowledge of relations. Prior semantic knowledge did not improve novel inference for aMCI individuals. Schematic scaffolding can successfully support inference in preclinical cognitive decline, but such cognitive support may no longer be useful later in the disease process when dysfunction in neural circuitry may be too severe. The findings encourage future work of semantic knowledge and inference in larger samples of aMCI cases.

Gradual learning and inflexible strategy use in amnesia: Evidence from case H.C.

The value of case studies in informing our understanding of dissociations and interactions in memory was recognized early on by Endel Tulving, whose comprehensive work with the amnesic case K.C. helped to confirm distinctions between episodic and semantic memory. Following in this tradition, we examined memory and the use of cognitive strategies in the developmental amnesic case H.C., a young woman with structural abnormalities in the extended hippocampal system (Rosenbaum et al., 2014). H.C. was tested on two tasks, transitivity and transverse patterning, that each required learning the relations among items, and for the former, also examined the ability to make inferences across sets of relations. H.C. was tested across multiple sessions and demonstrated two seemingly contradictory patterns of performance: evidence of gradual learning, yet an inability to flexibly switch to a cognitive strategy that may otherwise benefit performance. Specifically, on the transitivity task, H.C. showed gradual learning of novel relations that led to successful inferential performance. On transverse patterning, H.C. showed some gradual learning of the relations among the objects across sessions, and expressed knowledge that the task followed 'rock-paper-scissors' rules. However, H.C. did not benefit from a unitization strategy, which had shown previous success with other amnesic cases (D'Angelo et al., 2015; Ryan, Moses, Barense, & Rosenbaum, 2013). H.C.'s over-reliance on 'rock-paper-scissors' rules, even in the face of alternate strategies, is suggestive of an inability to enact cognitive flexibility. Poor performance thus may have resulted from interference from the experimentally presented strategy on her self-imposed strategy. The present findings echo work reported by Tulving in case K.C. (Tulving, Hayman, & Macdonald, 1991). Whereas neurologically intact individuals may rely on the functions of the hippocampal system to rapidly learn new information and resolve interference, some individuals with hippocampal amnesia may learn information gradually, but such learning is particularly prone to interference, resulting in an inability to flexibly adapt to changes in the learning conditions in order to optimize performance.

Object-in-place Memory Predicted by Anterolateral Entorhinal Cortex and Parahippocampal Cortex Volume in Older Adults.

The lateral portion of the entorhinal cortex is one of the first brain regions affected by tau pathology, an important biomarker for Alzheimer disease. Improving our understanding of this region's cognitive role may help identify better cognitive tests for early detection of Alzheimer disease. Based on its functional connections, we tested the idea that the human anterolateral entorhinal cortex (alERC) may play a role in integrating spatial information into object representations. We recently demonstrated that the volume of the alERC was related to processing the spatial relationships of the features within an object [Yeung, L. K., Olsen, R. K., Bild-Enkin, H. E. P., D'Angelo, M. C., Kacollja, A., McQuiggan, D. A., et al. Anterolateral entorhinal cortex volume predicted by altered intra-item configural processing. Journal of Neuroscience, 37, 5527-5538, 2017]. In this study, we investigated whether the human alERC might also play a role in processing the spatial relationships between an object and its environment using an eye-tracking task that assessed visual fixations to a critical object within a scene. Guided by rodent work, we measured both object-in-place memory, the association of an object with a given context [Wilson, D. I., Langston, R. F., Schlesiger, M. I., Wagner, M., Watanabe, S., & Ainge, J. A. Lateral entorhinal cortex is critical for novel object-context recognition. Hippocampus, 23, 352-366, 2013], and object-trace memory, the memory for the former location of objects [Tsao, A., Moser, M. B., & Moser, E. I. Traces of experience in the lateral entorhinal cortex. Current Biology, 23, 399-405, 2013]. In a group of older adults with varying stages of brain atrophy and cognitive decline, we found that the volume of the alERC and the volume of the parahippocampal cortex selectively predicted object-in-place memory, but not object-trace memory. These results provide support for the notion that the alERC may integrate spatial information into object representations.

Remembering "primed" words: A counter-intuitive effect of repetition on recognition memory.

The present study examines the effect of immediate repetition on recognition memory. In a series of 4 experiments, the study phase task was to name aloud a word that was immediately preceded by either the same word (repeated trials) or a different word (not-repeated trials). Across experiments, performance in the study phase demonstrated the anticipated benefit in naming times for repeated trials. More important, performance in the test phase revealed greater sensitivity for not-repeated than repeated trials. This effect was observed even when repetitions at study were separated by an unrelated word (Experiment 3), and was eliminated only when participants named both words in succession at study (Experiment 4). These findings fit nicely with the desirable difficulty principle (R. A. Bjork, 1994), as they demonstrate that items more easily processed at study (i.e., repeated items) are not as well-encoded as items that are more difficult to process at study (i.e., not-repeated items). Furthermore, the current study points to the possibility that attentional orienting in response to processing difficulty may constitute a broadly important cognitive control adaptation that impacts memory encoding. (PsycINFO Database Record

Breaking down unitization: Is the whole greater than the sum of its parts?

Memory impairments are often observed in aging. Specifically, older adults have difficulty binding together disparate elements (relational memory). We have recently shown that a cognitive strategy known as unitization can mitigate impaired relational learning in the transverse patterning task (TP) in both amnesia and healthy aging. This strategy allows items to be fused together through an interaction such that one item acts upon another. In the context of TP, unitization is comprised of three component processes: (1) fusion, (2) motion, and (3) semantic comprehension of action/consequence sequences. Here, we examine which of these components are sufficient to mitigate age-related impairments. Four groups of older adults were given either the full unitization strategy or one of the three component strategies. Each group of older adults showed impairments in memory for the relations among items under standard training instructions relative to a threshold that marks learning of a winner-take-all rule (elemental threshold). However, participants who were given either the full unitization strategy or the action/consequence-only strategy showed improved performance, which was maintained following the 1-hour delay. Therefore, semantically rich action/consequence interactions are sufficient to mitigate age-related relational memory impairments.

Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis.

We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimer's disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total gray/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging scans, whereas hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume-the same region in which Alzheimer's pathology originates-was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in undiagnosed community-dwelling older adults.

Anterolateral Entorhinal Cortex Volume Predicted by Altered Intra-Item Configural Processing.

Recent functional imaging studies have proposed that the human entorhinal cortex (ERC) is subdivided into functionally distinct anterolateral (alERC) and posteromedial (pmERC) subregions. The alERC overlaps with regions that are affected earliest by Alzheimer's disease pathology, yet its cognitive function remains poorly understood. Previous human fMRI studies have focused on its role in object memory, but rodent studies on the putatively homologous lateral entorhinal cortex suggest that it also plays an important role in representing spatial properties of objects. To investigate the cognitive effects of human alERC volume differences, we developed an eye-tracking-based task to evaluate intra-item configural processing (i.e., processing the arrangement of an object's features) and used manual segmentation based on a recently developed protocol to delineate the alERC/pmERC and other medial temporal lobe (MTL) subregions. In a group of older adult men and women at varying stages of brain atrophy and cognitive decline, we found that intra-item configural processing, regardless of an object's novelty, was strongly predicted by alERC volume, but not by the volume of any other MTL subregion. These results provide the first evidence that the human alERC plays a role in supporting a distinct aspect of object processing, namely attending to the arrangement of an object's component features.SIGNIFICANCE STATEMENT Alzheimer's disease pathology appears earliest in brain regions that overlap with the anterolateral entorhinal cortex (alERC). However, the cognitive role of the alERC is poorly understood. Previous human studies treat the alERC as an extension of the neighboring perirhinal cortex, supporting object memory. Animal studies suggest that the alERC may support the spatial properties of objects. In a group of older adult humans at the earliest stages of cognitive decline, we show here that alERC volume selectively predicted configural processing (attention to the spatial arrangement of an object's parts). This is the first study to demonstrate a cognitive role related to alERC volume in humans. This task can be adapted to serve as an early detection method for Alzheimer's disease pathology.

Impaired inference in a case of developmental amnesia.

Amnesia is associated with impairments in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm, we previously showed that age-related impairments in inference were mitigated when judgments could be predicated on known pairwise relations, however, such advantages were not observed in the adult-onset amnesic case D.A. Here, we replicate and extend this finding in a developmental amnesic case (N.C.), who also shows impaired relational learning and transitive expression. Unlike D.A., N.C.'s damage affected the extended hippocampal system and diencephalic structures, and does not extend to neocortical areas that are affected in D.A. Critically, despite their differences in etiology and affected structures, N.C. and D.A. perform similarly on the task. N.C. showed intact pairwise knowledge, suggesting that he is able to use existing semantic information, but this semantic knowledge was insufficient to support transitive expression. The present results suggest a critical role for regions connected to the hippocampus and/or medial prefrontal cortex in inference beyond learning of pairwise relations. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Negative priming 1985 to 2015: a measure of inhibition, the emergence of alternative accounts, and the multiple process challenge.

In this article, three generations of authors describe the background to the original article; the subsequent emergence of vigorous debates concerning what negative priming actually reflects, where radically different accounts based on memory retrieval were proposed; and a re-casting of the conceptual issues underlying studies of negative priming. What started as a simple observation (slowed reaction times) and mechanism (distractor inhibition) appears now to be best explained by a multiple mechanism account involving both episodic binding and retrieval processes as well as an inhibitory process. Emerging evidence from converging techniques such as functional magnetic resonance imaging (fMRI), and especially electroencephalography (EEG), is beginning to identify these different processes. The past 30 years of negative priming experiments has revealed the dynamic and complex cognitive processes that mediate what appear to be apparently simple behavioural effects.

The effectiveness of unitization in mitigating age-related relational learning impairments depends on existing cognitive status.

Binding relations among items in the transverse patterning (TP) task is dependent on the integrity of the hippocampus and its extended network. Older adults have impaired TP learning, corresponding to age-related reductions in hippocampal volumes. Unitization is a training strategy that can mitigate TP impairments in amnesia by reducing reliance on hippocampal-dependent relational binding and increasing reliance on fused representations. Here we examined whether healthy older adults and those showing early signs of cognitive decline would also benefit from unitization. Although both groups of older adults had neuropsychological performance within the healthy range, their TP learning differed both under standard and unitized training conditions. Healthy older adults with impaired TP learning under standard training benefited from unitized training. Older adults who failed the Montreal Cognitive Assessment (MoCA) showed greater impairments under standard conditions, and showed no evidence of improvement with unitization. These individuals' failures to benefit from unitization may be a consequence of early deficits not seen in older adults who pass the MoCA.

Relational learning and transitive expression in aging and amnesia.

Aging has been associated with a decline in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm (Bunsey and Eichenbaum (1996) Nature 379:255-257), which traditionally has been used in nonhuman animal research, this work examined the extent to which aging is accompanied by deficits in relational learning and flexible expression of relational information. Older adults' performance was additionally contrasted with that of amnesic case DA to understand the critical contributions of the medial temporal lobe, and specifically, the hippocampus, which endures structural and functional changes in healthy aging. Participants were required to select the correct choice item (B versus Y) based on the presented sample item (e.g., A). Pairwise relations must be learned (A->B, B->C, C->D) so that ultimately, the correct relations can be inferred when presented with a novel probe item (A->C?Z?). Participants completed four conditions of transitivity that varied in terms of the degree to which the stimuli and the relations among them were known pre-experimentally. Younger adults, older adults, and DA performed similarly when the condition employed all pre-experimentally known, semantic, relations. Older adults and DA were less accurate than younger adults when all to-be-learned relations were arbitrary. However, accuracy improved for older adults when they could use pre-experimentally known pairwise relations to express understanding of arbitrary relations as indexed through inference judgments. DA could not learn arbitrary relations nor use existing knowledge to support novel inferences. These results suggest that while aging has often been associated with an emerging decline in hippocampal function, prior knowledge can be used to support novel inferences. However, in case DA, significant damage to the hippocampus likely impaired his ability to learn novel relations, while additional damage to ventromedial prefrontal and anterior temporal regions may have resulted in an inability to use prior knowledge to flexibly express indirect relational knowledge.

Unitization supports lasting performance and generalization on a relational memory task: Evidence from a previously undocumented developmental amnesic case.

Recently, the amnesic case D.A. was shown to circumvent his relational memory impairments, as observed in the transverse patterning (TP) task, using a self-generated unitization strategy, and such performance benefits were maintained over extended delays (Ryan et al., 2013). "Unitization" encourages fusing of distinct items, through an action, into a single unit from which the relations among the items may then be derived. Here, we provide the first documentation of the developmental amnesic case, N.C., who presents with relatively circumscribed lesions to the extended hippocampal system, and with impaired episodic memory. Despite impairments on standard versions of TP, N.C. benefited from unitization, showed evidence of transfer to novel stimuli, and maintained his performance over extended delays. These findings suggest that self-generation is not a requirement for the successful implementation of unitization, and further provides the first evidence of rapid transfer and long-lasting success of a learning strategy in a human amnesic case.

Tip-of-the-tongue states reoccur because of implicit learning, but resolving them helps.

In six experiments, we elicited tip-of-the-tongue (TOT) states, to investigate the novel finding that TOTs on particular words tend to recur for speakers, and examine whether this effect can be attributed to implicit learning of the incorrect mapping from a lemma to phonology for that word. We elicited TOTs by asking participants to supply the word that fit a given definition, and then retested participants on those same definitions in a second test. In Experiments 1-3 we investigated the time course of learning that occurs during TOTs, and found that TOTs are likely to recur with a five-minute test-retest interval, that this error learning can still be measured following a one-week interval, and that they recur for both monolingual and bilingual speakers. We also report the novel finding that error learning can be corrected when individuals resolve their TOT, making them less likely to re-experience a TOT for that word on a later test. In Experiment 4 we showed that these learning effects are not modulated by a priori knowledge of future tests. In Experiments 5a and 5b we show that orthographic cues can help individuals resolve their TOTs, and that these cued-resolutions lead to corrective learning in much the same way as self-resolutions. In Experiment 6 we demonstrate that effortful retrieval is critical to finding differences in error learning when manipulating the duration of unresolved TOTs. We conclude that the error-repetition effect is highly robust, and is best explained by implicit learning of the erroneous state. These findings reinforce the notion that the language production system is dynamic, and continually learning from experience, even when that experience is errorful.

Selective attention and recognition: effects of congruency on episodic learning.

Recent research on cognitive control has focused on the learning consequences of high selective attention demands in selective attention tasks (e.g., Botvinick, Cognit Affect Behav Neurosci 7(4):356-366, 2007; Verguts and Notebaert, Psychol Rev 115(2):518-525, 2008). The current study extends these ideas by examining the influence of selective attention demands on remembering. In Experiment 1, participants read aloud the red word in a pair of red and green spatially interleaved words. Half of the items were congruent (the interleaved words had the same identity), and the other half were incongruent (the interleaved words had different identities). Following the naming phase, participants completed a surprise recognition memory test. In this test phase, recognition memory was better for incongruent than for congruent items. In Experiment 2, context was only partially reinstated at test, and again recognition memory was better for incongruent than for congruent items. In Experiment 3, all of the items contained two different words, but in one condition the words were presented close together and interleaved, while in the other condition the two words were spatially separated. Recognition memory was better for the interleaved than for the separated items. This result rules out an interpretation of the congruency effects on recognition in Experiments 1 and 2 that hinges on stronger relational encoding for items that have two different words. Together, the results support the view that selective attention demands for incongruent items lead to encoding that improves recognition.

Re-examining the role of context in implicit sequence learning.

Implicit sequence learning typically develops gradually, is often expressed quite rigidly, and is heavily reliant on contextual features. Recently we reported results pointing to the role of context-specific processes in the acquisition and expression of implicit sequence knowledge (D'Angelo, Milliken, Jiménez, & Lupiáñez, 2013). Here we examined further the role of context in learning of first-order conditional sequences, and whether context also plays a role in learning second-order conditional structures. Across five experiments we show that the role of context in first-order conditional sequences may not be as clear as we had previously reported, while at the same time we find evidence for the role of context in learning second-order conditional sequences. Together the results suggest that temporal context may be sufficient to learn complementary first-order conditional sequences, but that additional contextual information is necessary to concurrently learn higher-order sequential structures.

Implementing flexibility in automaticity: evidence from context-specific implicit sequence learning.

Attention is often dichotomized into controlled vs. automatic processing, where controlled processing is slow, flexible, and intentional, and automatic processing is fast, inflexible, and unintentional. In contrast to this strict dichotomy, there is mounting evidence for context-specific processes that are engaged rapidly yet are also flexible. In the present study we extend this idea to the domain of implicit learning to examine whether flexibility in automatic processes can be implemented through the reliance on contextual features. Across three experiments we show that participants can learn implicitly two complementary sequences that are associated with distinct contexts, and that transfer of learning when the two contexts are randomly intermixed depends on the distinctiveness of the two contexts. Our results point to the role of context-specific processes in the acquisition and expression of implicit sequence knowledge, and also suggest that episodic details can be represented in sequence knowledge.

On the specificity of sequential congruency effects in implicit learning of motor and perceptual sequences.

Individuals experience less interference from conflicting information following events that contain conflicting information. Recently, Jiménez, Lupiáñez, and Vaquero (2009) demonstrated that such adaptations to conflict occur even when the source of conflict arises from implicit knowledge of sequences. There is accumulating evidence that momentary changes in adaptations made in response to conflicting information are conflict-type specific (e.g., Funes, Lupiáñez, & Humphreys, 2010a), suggesting that there are multiple modes of control. The current study examined whether conflict-specific sequential congruency effects occur when the 2 sources of conflict are implicitly learned. Participants implicitly learned a motor sequence while simultaneously learning a perceptual sequence. In a first experiment, after learning the 2 orthogonal sequences, participants expressed knowledge of the 2 sequences independently of each other in a transfer phase. In Experiments 2 and 3, within each sequence, the presence of a single control trial disrupted the expression of this specific type of learning on the following trial. There was no evidence of cross-conflict modulations in the expression of sequence learning. The results suggest that the mechanisms involved in transient shifts in conflict-specific control, as reflected in sequential congruency effects, are also engaged when the source of conflict is implicit.