Modeling the influence of the hippocampal memory system on the oculomotor system.

Visual exploration is related to activity in the hippocampus (HC) and/or extended medial temporal lobe system (MTL), is influenced by stored memories, and is altered in amnesic cases. An extensive set of polysynaptic connections exists both within and between the HC and oculomotor systems such that investigating how HC responses ultimately influence neural activity in the oculomotor system, and the timing by which such neural modulation could occur, is not trivial. We leveraged TheVirtualBrain, a software platform for large-scale network simulations, to model the functional dynamics that govern the interactions between the two systems in the macaque cortex. Evoked responses following the stimulation of the MTL and some, but not all, subfields of the HC resulted in observable responses in oculomotor regions, including the frontal eye fields, within the time of a gaze fixation. Modeled lesions to some MTL regions slowed the dissipation of HC signal to oculomotor regions, whereas HC lesions generally did not affect the rapid MTL activity propagation to oculomotor regions. These findings provide a framework for investigating how information represented by the HC/MTL may influence the oculomotor system during a fixation and predict how HC lesions may affect visual exploration.

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.

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.

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.

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.