Resolving Cross-modal Semantic Interference among Object Concepts Requires Medial Temporal Lobe Cortex.

The ability to flexibly categorize object concepts is essential to semantic cognition because the features that make two objects similar in one context may be irrelevant and even constitute interference in another. Thus, adaptive behavior in complex and dynamic environments requires the resolution of feature-based interference. In the current case study, we placed visual and functional semantic features in opposition across object concepts in two categorization tasks. Successful performance required the resolution of functional interference in a visual categorization task and the resolution of visual interference in a functional categorization task. In Experiment 1, we found that patient D. A., an individual with bilateral temporal lobe lesions, was unable to categorize object concepts in a context-dependent manner. His impairment was characterized by an increased tendency to incorrectly group objects that were similar on the task-irrelevant dimension, revealing an inability to resolve cross-modal semantic interference. In Experiment 2, D. A.'s categorization accuracy was comparable to controls when lures were removed, indicating that his impairment is unique to contexts that involve cross-modal interference. In Experiment 3, he again performed as well as controls when categorizing simple concepts, suggesting that his impairment is specific to categorization of complex object concepts. These results advance our understanding of the anterior temporal lobe as a system that represents object concepts in a manner that enables flexible semantic cognition. Specifically, they reveal a dissociation between semantic representations that contribute to the resolution of cross-modal interference and those that contribute to the resolution of interference within a given modality.

A smartphone intervention that enhances real-world memory and promotes differentiation of hippocampal activity in older adults.

The act of remembering an everyday experience influences how we interpret the world, how we think about the future, and how we perceive ourselves. It also enhances long-term retention of the recalled content, increasing the likelihood that it will be recalled again. Unfortunately, the ability to recollect event-specific details and reexperience the past tends to decline with age. This decline in recollection may reflect a corresponding decrease in the distinctiveness of hippocampal memory representations. Despite these well-established changes, there are few effective cognitive behavioral interventions that target real-world episodic memory. We addressed this gap by developing a smartphone-based application called HippoCamera that allows participants to record labeled videos of everyday events and subsequently replay, high-fidelity autobiographical memory cues. In two experiments, we found that older adults were able to easily integrate this noninvasive intervention into their daily lives. Using HippoCamera to repeatedly reactivate memories for real-world events improved episodic recollection and it evoked more positive autobiographical sentiment at the time of retrieval. In both experiments, these benefits were observed shortly after the intervention and again after a 3-mo delay. Moreover, more detailed recollection was associated with more differentiated memory signals in the hippocampus. Thus, using this smartphone application to systematically reactivate memories for recent real-world experiences can help to maintain a bridge between the present and past in older adults.

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.

Integrative and distinctive coding of visual and conceptual object features in the ventral visual stream.

A significant body of research in cognitive neuroscience is aimed at understanding how object concepts are represented in the human brain. However, it remains unknown whether and where the visual and abstract conceptual features that define an object concept are integrated. We addressed this issue by comparing the neural pattern similarities among object-evoked fMRI responses with behavior-based models that independently captured the visual and conceptual similarities among these stimuli. Our results revealed evidence for distinctive coding of visual features in lateral occipital cortex, and conceptual features in the temporal pole and parahippocampal cortex. By contrast, we found evidence for integrative coding of visual and conceptual object features in perirhinal cortex. The neuroanatomical specificity of this effect was highlighted by results from a searchlight analysis. Taken together, our findings suggest that perirhinal cortex uniquely supports the representation of fully specified object concepts through the integration of their visual and conceptual features.

Dissociable contributions of thalamic nuclei to recognition memory: novel evidence from a case of medial dorsal thalamic damage.

The thalamic nuclei are thought to play a critical role in recognition memory. Specifically, the anterior thalamic nuclei and medial dorsal nuclei may serve as critical output structures in distinct hippocampal and perirhinal cortex systems, respectively. Existing evidence indicates that damage to the anterior thalamic nuclei leads to impairments in hippocampal-dependent tasks. However, evidence for the opposite pattern following medial dorsal nuclei damage has not yet been identified. In the present study, we investigated recognition memory in NC, a patient with relatively selective medial dorsal nuclei damage, using two object recognition tests with similar foils: a yes/no (YN) test that requires the hippocampus, and a forced choice corresponding test (FCC) that is supported by perirhinal cortex. NC performed normally in the YN test, but was impaired in the FCC test. Critically, FCC performance was impaired only when the study-test delay period was filled with interference. We interpret these results in the context of the representational-hierarchical model, which predicts that memory deficits following damage to the perirhinal system arise due to increased vulnerability to interference. These data provide the first evidence for selective deficits in a task that relies on perirhinal output following damage to the medial dorsal nuclei, providing critical evidence for dissociable thalamic contributions to recognition memory.

Examining the Role of the Human Hippocampus in Approach-Avoidance Decision Making Using a Novel Conflict Paradigm and Multivariate Functional Magnetic Resonance Imaging.

Rodent models of anxiety have implicated the ventral hippocampus in approach-avoidance conflict processing. Few studies have, however, examined whether the human hippocampus plays a similar role. We developed a novel decision-making paradigm to examine neural activity when participants made approach/avoidance decisions under conditions of high or absent approach-avoidance conflict. Critically, our task required participants to learn the associated reward/punishment values of previously neutral stimuli and controlled for mnemonic and spatial processing demands, both important issues given approach-avoidance behavior in humans is less tied to predation and foraging compared to rodents. Participants played a points-based game where they first attempted to maximize their score by determining which of a series of previously neutral image pairs should be approached or avoided. During functional magnetic resonance imaging, participants were then presented with novel pairings of these images. These pairings consisted of images of congruent or opposing learned valences, the latter creating conditions of high approach-avoidance conflict. A data-driven partial least squares multivariate analysis revealed two reliable patterns of activity, each revealing differential activity in the anterior hippocampus, the homolog of the rodent ventral hippocampus. The first was associated with greater hippocampal involvement during trials with high as opposed to no approach-avoidance conflict, regardless of approach or avoidance behavior. The second pattern encompassed greater hippocampal activity in a more anterior aspect during approach compared to avoid responses, for conflict and no-conflict conditions. Multivoxel pattern classification analyses yielded converging findings, underlining a role of the anterior hippocampus in approach-avoidance conflict decision making. SIGNIFICANCE STATEMENT: Approach-avoidance conflict has been linked to anxiety and occurs when a stimulus or situation is associated with reward and punishment. Although rodent work has implicated the hippocampus in approach-avoidance conflict processing, there is limited data on whether this role applies to learned, as opposed to innate, incentive values, and whether the human hippocampus plays a similar role. Using functional neuroimaging with a novel decision-making task that controlled for perceptual and mnemonic processing, we found that the human hippocampus was significantly active when approach-avoidance conflict was present for stimuli with learned incentive values. These findings demonstrate a role for the human hippocampus in approach-avoidance decision making that cannot be explained easily by hippocampal-dependent long-term memory or spatial cognition.

A retroactive spatial cue improved VSTM capacity in mild cognitive impairment and medial temporal lobe amnesia but not in healthy older adults.

Visual short-term memory (VSTM) is a vital cognitive ability, connecting visual input with conscious awareness. VSTM performance declines with mild cognitive impairment (MCI) and medial temporal lobe (MTL) amnesia. Many studies have shown that providing a spatial retrospective cue ("retrocue") improves VSTM capacity estimates for healthy young adults. However, one study has demonstrated that older adults are unable to use a retrocue to inhibit irrelevant items from memory. It is unknown whether patients with MCI and MTL amnesia will be able to use a retrocue to benefit their memory. We administered a retrocue and a baseline (simultaneous cue, "simucue") task to young adults, older adults, MCI patients, and MTL cases. Consistent with previous findings, young adults showed a retrocue benefit, whereas healthy older adults did not. In contrast, both MCI patients and MTL cases showed a retrocue benefit--the use of a retrocue brought patient performance up to the level of age-matched controls. We speculate that the patients were able to use the spatial information from the retrocue to reduce interference and facilitate binding items to their locations.

Neural correlates of cognitive decline in older adults at-risk for developing MCI: evidence from the CDA and P300.

Improving the ability to detect Alzheimer's disease (AD) at the earliest stages is essential to effectively treat afflicted individuals. Electrophysiological signatures are a promising avenue for earlier diagnosis. In the present study, we investigated an ERP component associated with visual working memory capacity, the contralateral delay activity (CDA). Our participants were undiagnosed and supposedly healthy members of the community, but were defined to be at-risk for Mild Cognitive Impairment (MCI) based on performance from a brief, standardized neuropsychological test. We found that older adults at-risk for MCI had a reduced visual working memory capacity and reduced differentiation of the CDA. In a second experiment, we found that the P300, a well-characterized ERP component shown to be useful in determining conversion from MCI to AD, showed reduced amplitude in our at-risk group. Together, these findings suggest that electrophysiological signatures may be especially sensitive markers of the very earliest stages of AD.

Retrospective attention enhances visual working memory in the young but not the old: an ERP study.

Behavioral evidence from the young suggests spatial cues that orient attention toward task-relevant items in visual working memory (VWM) enhance memory capacity. Whether older adults can also use retrospective cues ("retro-cues") to enhance VWM capacity is unknown. In the current event-related potential (ERP) study, young and old adults performed a VWM task in which spatially informative retro-cues were presented during maintenance. Young but not older adults' VWM capacity benefited from retro-cueing. The contralateral delay activity (CDA) ERP index of VWM maintenance was attenuated after the retro-cue, which effectively reduced the impact of memory load. CDA amplitudes were reduced prior to retro-cue onset in the old only. Despite a preserved ability to delete items from VWM, older adults may be less able to use retrospective attention to enhance memory capacity when expectancy of impending spatial cues disrupts effective VWM maintenance.

Reducing perceptual interference improves visual discrimination in mild cognitive impairment: implications for a model of perirhinal cortex function.

Memory loss resulting from damage to the medial temporal lobes (MTL) is traditionally considered to reflect damage to a dedicated, exclusive memory system. Recent work, however, has suggested that damage to one MTL structure, the perirhinal cortex (PRC), compromises complex object representations that are necessary for both memory and perception. These representations are thought to be critical in shielding against the interference caused by a stream of visually similar input. In this study, we administered a complex object discrimination task to two memory-impaired populations thought to have brain damage that includes the PRC [patients diagnosed with amnestic mild cognitive impairment (MCI), and older adults at risk for MCI], as well as age-matched controls. Importantly, we carefully manipulated the level of interference: in the High Interference condition, participants completed a block of consecutive perceptually similar complex object discriminations, whereas in the Low Interference condition, we interspersed perceptually dissimilar objects such that there was less buildup of visual interference. We found that both memory-impaired populations were impaired on the High Interference condition compared with controls, but critically, by reducing the degree of perceptual interference, we were largely able to improve their performance. These findings, when taken together with convergent evidence from animals with selective PRC lesions and amnesic patients with focal damage to the PRC, provide support for a representational-hierarchical model of PRC function and suggest that memory loss following PRC damage may reflect a heightened vulnerability to perceptual interference.

The effects of aging on emotion-induced modulations of source retrieval ERPs: evidence for valence biases.

Many behavioral studies have shown that memory is enhanced for emotionally salient events across the lifespan. It has been suggested that this mnemonic boost may be observed for both age groups, particularly the old, in part because emotional information is retrieved with less effort than neutral information. Neuroimaging evidence suggests that inefficient retrieval processing (temporally delayed and attenuated) may contribute to age-related impairments in episodic memory for neutral events. It is not entirely clear whether emotional salience may reduce these age-related changes in neural activity associated with episodic retrieval for neutral events. Here, we investigated these ideas using event-related potentials (ERPs) to assess the neural correlates of successful source memory retrieval ("old-new effects") for neutral and emotional (negative and positive) images. Behavioral results showed that older adults demonstrated source memory impairments compared to the young but that both groups showed reduced source memory accuracy for negative compared to positive and neutral images; most likely due to an arousal-induced memory tradeoff for the negative images, which were subjectively more arousing than both positive and neutral images. ERP results showed that early onsetting old-new effects, between 100 and 300 ms, were observed for emotional but not neutral images in both age groups. Interestingly, these early effects were observed for negative items in the young and for positive items in the old. These ERP findings offer support for the idea that emotional events may be retrieved more automatically than neutral events across the lifespan. Furthermore, we suggest that very early retrieval mechanisms, possibly perceptual priming or familiarity, may underlie the negativity and positivity effects sometimes observed in the young and old, respectively, for various behavioral measures of attention and memory.

The effects of aging on ERP correlates of source memory retrieval for self-referential information.

Numerous behavioral studies have suggested that normal aging negatively affects source memory accuracy for various kinds of associations. Neuroimaging evidence suggests that less efficient retrieval processing (temporally delayed and attenuated) may contribute to these impairments. Previous aging studies have not compared source memory accuracy and corresponding neural activity for different kinds of source details; namely, those that have been encoded via a more or less effective strategy. Thus, it is not yet known whether encoding source details in a self-referential manner, a strategy suggested to promote successful memory in the young and old, may enhance source memory accuracy and reduce the commonly observed age-related changes in neural activity associated with source memory retrieval. Here, we investigated these issues by using event-related potentials (ERPs) to measure the effects of aging on the neural correlates of successful source memory retrieval ("old-new effects") for objects encoded either self-referentially or self-externally. Behavioral results showed that both young and older adults demonstrated better source memory accuracy for objects encoded self-referentially. ERP results showed that old-new effects onsetted earlier for self-referentially encoded items in both groups and that age-related differences in the onset latency of these effects were reduced for self-referentially, compared to self-externally, encoded items. These results suggest that the implementation of an effective encoding strategy, like self-referential processing, may lead to more efficient retrieval, which in turn may improve source memory accuracy in both young and older adults.