Andrew Yonelinas - US grants

Recognition memory judgments can be based either on recollection of qualitative information about a previous event or on assessments of stimulus familiarity. Cognitive studies show that these two memory retrieval processes are functionally distinct. However, very little is known about the cortical substrates of these two processes, and significant gaps remain in our understanding of their functional properties. The specific aims of the current proposal are as follows. (1) Determine if hippocampal and parahippocampal regions contribute to recollection and familiarity by contrasting the recognition memory deficits of amnesic patients with hippocampal (H) and hippocampal+parahippocampal (HP) lesions. Previous studies showed that patients with HP lesions exhibited deficits in both recollection and familiarity. In order to identify whether these regions contribute differentially to these two processes it is now essential that we contrast the memory deficits of H and HP patients. By examining the cortical substrates of recollection and familiarity these studies will serve to test competing theories of recognition memory and will evaluate the functional specificity of regions within the medial temporal lobe in humans. (2) Determine if familiarity-based recognition judgments are based on conceptual implicit memory, by contrasting the effects of two experimental variables (i.e., semantic encoding and dividing attention) and medial temporal lobe lesions (i.e., H and HP lesions) on familiarity and implicit memory. The results will show whether familiarity and conceptual implicit memory exhibit similar cortical regions, and thus will provide a test of current models of recognition memory and implicit memory. 3) Determine the forgetting functions of recollection and familiarity in healthy subjects and patients with hippocampal and parahippocampal damage in order to further characterize these processes and cortical regions, and to test models that assert that hippocampal and parahippocampal regions support long-term and intermediate-term memory respectively.

prefrontal lobe /cortex; memory; neural information processing; temporal lobe /cortex; clinical research; human subject;

DESCRIPTION (provided by applicant): Recognition memory can be based on recollection of qualitative information about previous events, or on assessments of stimulus familiarity. These two processes are functionally distinct and are supported by separate sub-regions of the medial temporal lobes. The long-term goal of the proposed studies is to determine the cortical substrates and functional properties of the processes supporting recognition memory, which will provide a foundation for accurate diagnosis and rehabilitation protocols for neurological patients suffering from memory impairments. The specific aims of the current proposal are to: 1) Investigate the role of prefrontal cortex in recollection and familiarity. Although the prefrontal cortex is critical for human memory, we currently do not know how this region contributes to recollection and familiarity. The proposed studies will determine the role of the prefrontal cortex in recollection and familiarity by examining the effects of left and right lateral prefrontal lobe damage on these forms of memory in human neurological patients. The studies will characterize the mnemonic functions of the prefrontal cortex and allow direct tests of competing theories of human recognition memory. 2) Determine if conceptual implicit memory relies on regions in the temporal lobes and prefrontal cortex. It is currently debated whether familiarity reflects a form of implicit memory. Previous studies have demonstrated that familiarity and perceptual implicit memory (e.g., fragment completion) can be functionally dissociated, and that they rely on separate brain regions. It remains unknown, however, if the brain systems supporting familiarity are involved in conceptual implicit memory (e.g., exemplar generation). We will examine conceptual implicit memory in patients with damage to different temporal lobe regions and patients with damage to the lateral prefrontal cortex. The studies will be critical in determining the brain regions necessary for conceptual implicit memory and in resolving the debate about the cognitive-neural mechanisms underlying familiarity and implicit memory. 3) Determine the conditions under which familiarity can support recognition memory for novel associations. A core assumption underlying many current theories of recollection - and of hippocampal function - is that recollection is necessary for associating or binding different aspects of an event together in long-term memory. However, recent evidence indicates that familiarity can support associative learning under certain conditions. Two competing explanations for these results have been proposed: 'within-domain' theories predict that familiarity can support associative recognition only when the association is between items from the same processing domain, whereas 'unitization' theories predict that familiarity will be useful only when the associated items are encoded as a single unit. We will examine the effects of unitization and of changing processing domains on familiarity-based associative memory in healthy controls and in amnesic patients with preserved familiarity judgments (e.g., hypoxic patients) in order to determine the conditions under which familiarity can support associative learning. These studies will be essential in understanding how the brain supports learning of novel associations, and will provide the first direct test of competing theories of familiarity.

DESCRIPTION (provided by applicant): The ability to successfully form memories for arbitrary associations is essential for most acts of daily living. Numerous studies have shown that the hippocampus plays a critical role in associative memory. Recent work indicates that the perirhinal cortex (PRc) is also involved, but its functional role in associative memory is poorly understood. This research program will use functional magnetic resonance imaging (FMRI) and novel behavioral paradigms to test three theories of how the PRc contributes to associative recognition: (1) Unitization theory asserts that the PRc can support familiarity-based recognition of novel associations if the paired items are encoded as a single unit, but that the hippocampus is required for recollection of relations between items that are encoded as separate units. Novel FMRI experiments are proposed to test whether the PRc specifically contributes to recognition of associations between pairs of items that were encoded as a single unit. Parallel behavioral studies will test whether unitization influences indices of familiarity. (2) Domain theory asserts that the PRc supports familiarity-based recognition for associations between items from the same processing domain, but that the hippocampus is required to support recollection for associations between items from different processing domains. Novel FMRI studies are proposed to test whether the PRc supports associations between items from the same processing domains, but not associations between items from different domains. In addition, behavioral studies will test whether within-domain, but not across-domain associations influence the behavioral indices of familiarity. (3) Binding of items and contexts (BIC) theory asserts that the PRc represents item information, the PHc represents context information, and that this information is bound by the hippocampus. FMRI experiments are proposed to test whether recall of item information will be associated with PRc activity, whereas the recall of contextual information will lead to PHc activity. By testing the three theories, this proposal can provide the foundation for the development of a comprehensive theory of MTL function that can incorporate the influences of encoding processing, stimulus domain, and retrieval processing. Several psychiatric (e.g., schizophrenia) and neurological (e.g., Alzheimer's disease and traumatic brain injury) disorders are associated with memory impairments and with medial temporal lobe dysfunction. The proposed research may lead to improved diagnostic and therapeutic approaches to these disorders. PUBLIC HEALTH RELEVANCE Basic research on the mnemonic functions of the medial temporal lobe region is critically important because several psychiatric (e.g., schizophrenia) and neurological (e.g., Alzheimer's disease and traumatic brain injury) disorders are associated with memory impairments and MTL dysfunction. Such memory disorders can have a devastating effect on patients'quality of life. Research clarifying the basic neural mechanisms of memory can lead to improved diagnosis and treatment of these disorders.

? DESCRIPTION (provided by applicant): It is well established that vision depends on a complex network of brain regions. Although visual processing has been extensively studied in a range of subcortical and neocortical regions, little is known about visual processing in higher-order, multimodal areas of the medial temporal lobes (MTL). Recent work has indicated that specific MTL subregions (e.g., the hippocampus and perirhinal cortex)-which are traditionally associated with memory processes- play a critical role in online visual processing. For instance, our recent studies have demonstrated that MTL damage can impair processes that support scene perception and visual short-term memory. These surprising findings have opened up many important questions about which visual processes are supported by the MTL, about the roles of different MTL subregions in visual cognition, and about how different memory and visual processes interact. The central idea behind this application is to address these fundamental questions with a combination of studies examining patients with focal lesions to specific MTL subregions, high-resolution functional magnetic resonance imaging (fMRI), and model-based analyses of results obtained with novel psychophysical paradigms. The studies aim to determine the role of the MTL in complex visual perception and visual short-term memory, and to determine how the processes involved in perception and visual short-term memory tasks interact with episodic memory. The application uses a unique 'parallel lesion/fMRI approach' in which studies of MTL lesion patients and high-resolution neuroimaging studies of healthy subjects allows conclusions about the involvement of different regions in healthy subjects, and about whether such regions play a necessary causal role in these behaviors. In addition, the proposed studies will be the first to utilize high-resolution imaging of the MTL in perception and short-term memory tasks and will utilize a novel combination of parametric psychophysical methods with neuroimaging methods, and so promise to provide novel insights into the visual processes supported by substructures of the MTL not previously possible. The proposed studies are significant because they challenge current models to explain MTL involvement across perception and memory paradigms, and thus will provide richer and more theoretically constraining results than previously possible. In addition, the studies have important translational implications because they will provide a more complete characterization of the cognitive deficits associated with temporal lobe damage suffered by various psychiatric and neurological populations. By identifying the cognitive processes supported by these regions, the proposed studies can lead to the development of targeted rehabilitation strategies that better capitalize on both the disrupted and the spared functions in such patients.

Project Abstract Lesions to the human medial temporal result in striking and often long-lasting deficits in delayed verbal memory, termed medial temporal lobe amnesia. While models of medial temporal lobe function, such as declarative memory theory, hypothesize a restricted role for the medial temporal lobe in memory function, a growing consensus in cognitive neuroscience suggests that such deficits also include impairments in representations important to other areas of cognition, such as perception, attention, working memory, language, and spatial navigation. Here, we propose a novel model to better account for the range of cognitive deficits that accompany medial temporal lobe lesions. Our model hypothesizes that human medial temporal lobe function can best be described as involving both representational precision and binding, predicting increasing deficits as task-demands increase along these two critical dimensions. Experiments in Aim 1 test our model with a particular focus on testing representational precision in the context of memory and navigation to allow us to compare the outcomes from these experiments against those predicted by declarative memory theory. Experiments will include testing with bilateral medial temporal lobe patients, including those with lesions primarily restricted to the hippocampus, and high-resolution fMRI studies in healthy participants to better determine the mechanistic basis of hippocampal contributions to precision and binding. Aim 2 will determine the predictive capacity of our model, in conjunction with fMRI-based network modeling, to explain deficits accompanying unilateral medial temporal lesions that occur as a result of surgical resections during treatment of pharmacologically intractable epilepsy. The anticipated outcomes from the proposal are: 1) a more complete account of the consequences of medial temporal lobe lesions, particularly to the hippocampus, on cognition than can be provided by neuropsychological measures alone 2) a more complete predictive model of the effects of unilateral temporal lobe resection on cognitive outcomes post-resection, possibly allowing greater flexibility in determining which patients should undergo responsive neurostimulation (RNS) vs. resection 3) modeling whether and how extra-medial temporal lobe cortical networks can compensate for lost function following resection 4) potentially, inspiration for novel therapies involving cognitive interventions or neurostimulation targeting intact cortical tissue in patients with amnestic-like symptoms.