The Neural and Cognitive Basis of Cumulative Lifetime Familiarity Assessment

Perirhinal cortex (PrC) has been implicated as a brain region in the medial temporal lobes (MTL) that critically contributes to familiarity-based recognition memory, a process that allows for recognition to occur independently of contextual recollection. Informed by neurophysiological research in non-human primates, fMRI, as well as behavioural work in humans, the current thesis research tests the novel hypothesis that PrC cortex functioning also underlies the ability to assess cumulative lifetime familiarity with object concepts that are characterized by a lifetime of experiences. In Chapter 2, a patient (NB) with a left anterior temporal lobe (ATL) lesion that included PrC as well as an amnesic patient (HC) with a bilateral lesion to the hippocampus were tested on their ability to make lifetime familiarity judgements for object concepts (i.e., concrete nouns). Patient NB made abnormal familiarity ratings for objects concepts relative to matched controls, while patient HC produced ratings that did not differ from control participants. In Chapter 3, I tested healthy young adults on a frequency judgement task and lifetime familiarity task while they underwent fMRI. A region in the left PrC tracked both the perceived frequency of recent laboratory exposure as well as perceived lifetime familiarity. Finally, in Chapter 4, I tested whether indeed lifetime familiarity judgements are based on conceptual processing by making use of an associative priming paradigm. Associatively-related primes increased the perceived familiarity of object concepts while also reducing the latency of these judgements. Overall, the results from all three empirical chapters provides evidence that warrants an extension of PrC functioning to include the cumulative assessment of lifetime familiarity with object concepts

Emotion’s Influence on the Evaluation of Familiarity

Emotion enhances the encoding and consolidation of memory traces, leading to the salient reliving of emotional experiences. In the recognition memory literature, the induction of somatic arousal and feelings of perceptual fluency during retrieval have been associated with illusory familiarity. Understudied in this literature is an investigation into how one’s emotional state, independent of stimulus content, influences recollective and familiarity-based recognition memory retrieval. Two priming paradigms were employed in the current thesis research to contrast the effects of affective priming and identity priming on familiarity and recollection using the Remember/Know procedure. Enhanced familiarity-based discrimination was revealed using affective priming, selective to participants with low overall recognition performance. Identity-priming resulted in a response bias, indicative of an induction of erroneous feelings of familiarity. Both manipulations failed to influence recollection. These results illustrate that a heightened affective state can provide selective benefits to familiarity, dissociating from a confused sense of familiarity induced through increased perceptual fluency

Impaired Assessment of Cumulative Lifetime Familiarity for Object Concepts After Left Anterior Temporal-Lobe Resection that Includes Perirhinal Cortex but Spares the Hippocampus

The ability to recognize the prior occurrence of objects can operate effectively even in the absence of successful recollection of episodic contextual detail about a relevant past object encounter. The pertinent process, familiarity assessment, is typically probed in humans with recognition-memory tasks that include an experimentally controlled study phase for a list of items. When meaningful stimuli such as words or pictures of common objects are employed, participants must judge familiarity with reference to the recent experimental encounter rather than their lifetime of autobiographical experience, which may have involved hundreds or thousands of exposures across numerous episodic contexts. Humans can, however, also judge the cumulative familiarity of objects concepts they have encountered over their lifetime. At present, little is known about the cognitive and neural mechanisms that support this ability. Here, we tested an individual (NB) with a rare left anterior temporal-lobe lesion that included perirhinal cortex but spared the hippocampus, who had previously been found to exhibit selective impairments in familiarity assessment on verbal recognition-memory tasks. As NB exhibits normal recollection abilities, her case presents a unique opportunity to examine potential links between both types of familiarity. In Experiment 1, we demonstrated that NB\u27s impairment in making recognition judgments affects cumulative frequency judgments for exposure to concept names in a recent study episode. Experiments 2 and 3 revealed, with a task borrowed from the semantic-memory literature, that NB\u27s impairments do indeed extend to abnormalities in judging cumulative lifetime familiarity for object concepts. These abnormalities were not limited to verbal processing, and were present even when pictures were offered as additional cues. Moreover, they showed sensitivity to concept structure as reflected in semantic feature norms; we only observed them for judgments on object concepts with high feature overlap. In Experiment 4, we found that an amnesic patient (HC) with previously established deficits in autobiographical recollection, due to a selective lesion of the extended hippocampal system, does not exhibit any abnormalities in assessing lifetime familiarity. Together, these findings provide support for a functional link between the assessment of recent changes in familiarity, as probed with experimental study-test paradigms, and cumulative lifetime familiarity based on autobiographical experience accrued outside the laboratory. They argue in favor of the notion that familiarity is closely related to the representation of concept knowledge, likely through computations in perirhinal cortex

Perirhinal Cortex Tracks Degree of Recent as well as Cumulative Lifetime Experience with Object Concepts

Evidence from numerous sources indicates that recognition of the prior occurrence of objects requires computations of perirhinal cortex (PrC) in the medial temporal lobe (MTL). Extant research has primarily probed recognition memory based on item exposure in a recent experimental study episode. Outside the laboratory, however, familiarity for objects typically accrues gradually with learning across many different episodic contexts, which can be distributed over a lifetime of experience. It is currently unknown whether PrC also tracks this cumulative lifetime experience with object concepts. To address this issue, we con- ducted a functional magnetic resonance imaging (fMRI) experiment in healthy individuals in which we compared judgments of the perceived lifetime familiarity with object concepts, a task that has previously been employed in many normative studies on concept knowledge, with frequency judgments for recent laboratory exposure in a study phase. Guided by neurophysiological data showing that neurons in primate PrC signal prior object exposure at multiple time scales, we predicted that PrC responses would track perceived prior experience in both types of judgments. Left PrC and a number of cortical regions that are often co- activated as part of the default-mode network showed an increase in Blood-Oxygen-Level Dependent (BOLD) response in relation to increases in the perceived cumulative lifetime familiarity of object concepts. These regions included the left hippocampus, left mid-lateral temporal cortex, as well as anterior and posterior cortical midline structures. Critically, left PrC was found to be the only region that showed this response in combination with the typically observed decrease in signal for perceived recent exposure in the experimental study phase. These findings provide, to our knowledge, the first evidence that ties signals in human PrC to variations in cumulative lifetime experience with object concepts. They offer a new link between the role of PrC in recognition memory and its broader role in conceptual processing

Abnormal Semantic Knowledge in a Case of Developmental Amnesia

An important theory holds that semantic knowledge can develop independently of episodic memory. One strong source of evidence supporting this independence comes from the observation that individuals with early hippocampal damage leading to developmental amnesia generally perform normally on standard tests of semantic memory, despite their profound impairment in episodic memory. However, one aspect of semantic memory that has not been explored is conceptual structure. We built on the theoretically important distinction between intrinsic features of object concepts (e.g., shape, colour, parts) and extrinsic features (e.g., how something is used, where it is typically located). The accrual of extrinsic feature knowledge that is important for concepts such as chair or spoon may depend on binding mechanisms in the hippocampus. We tested HC, an individual with developmental amnesia due to a well-characterized lesion of the hippocampus, on her ability to generate semantic features for object concepts. HC generated fewer extrinsic features than controls, but a similar number of intrinsic features than controls. We also tested her on typicality ratings. Her typicality ratings were abnormal for nonliving things (which more strongly depend on extrinsic features), but normal for living things (which more strongly depend on intrinsic features). In contrast, NB, who has MTL but not hippocampal damage due to surgery, showed no impairments in either task. These results suggest that episodic and semantic memory are not entirely independent, and that the hippocampus is important for learning some aspects of conceptual knowledge

Listeria-based vaccination against the pericyte antigen RGS5 elicits anti-vascular effects and colon cancer protection

ABSTRACTColorectal cancer (CRC) remains a leading cause of cancer-related mortality despite efforts to improve standard interventions. As CRC patients can benefit from immunotherapeutic strategies that incite effector T cell action, cancer vaccines represent a safe and promising therapeutic approach to elicit protective and durable immune responses against components of the tumor microenvironment (TME). In this study, we investigate the pre-clinical potential of a Listeria monocytogenes (Lm)-based vaccine targeting the CRC-associated vasculature. CRC survival and progression are reliant on functioning blood vessels to effectively mediate various metabolic processes and oxygenate underlying tissues. We, therefore, advance the strategy of initiating immunity in syngeneic mouse models against the endogenous pericyte antigen RGS5, which is a critical mediator of pathological vascularization. Overall, Lm-based vaccination safely induced potent anti-tumor effects that consisted of recruiting functional Type-1-associated T cells into the TME and reducing tumor blood vessel content. This study underscores the promising clinical potential of targeting RGS5 against vascularized tumors like CRC