Holistic recollection via pattern completion involves hippocampal subfield CA3

Episodic memories typically comprise multiple elements. A defining characteristic of episodic retrieval is holistic recollection, i.e., comprehensive recall of the elements a memorized event encompasses. A recent study implicated activity in the human hippocampus with holistic recollection of multi-element events based on cues (Horner et al., 2015). Here, we obtained ultra-high resolution functional neuroimaging data at 7 tesla in 30 younger adults (12 female) using the same paradigm. In accordance with anatomically inspired computational models and animal research, we found that metabolic activity in hippocampal subfield CA3 (but less pronounced in dentate gyrus) correlated with this form of mnemonic pattern completion across participants. Our study provides the first evidence in humans for a strong involvement of hippocampal subfield CA3 in holistic recollection via pattern completion.SIGNIFICANCE STATEMENT Memories of daily events usually involve multiple elements, although a single element can be sufficient to prompt recollection of the whole event. Such holistic recollection is thought to require reactivation of brain activity representing the full event from one event element ("pattern completion"). Computational and animal models suggest that mnemonic pattern completion is accomplished in a specific subregion of the hippocampus called CA3, but empirical evidence in humans was lacking. Here, we leverage the ultra-high resolution of 7 tesla neuroimaging to provide first evidence for a strong involvement of the human CA3 in holistic recollection of multi-element events via pattern completion

Feasibility of Digital Memory Assessments in an Unsupervised and Remote Study Setting

Sensitive and frequent digital remote memory assessments via mobile devices hold the promise to facilitate the detection of cognitive impairment and decline. However, in order to be successful at scale, cognitive tests need to be applicable in unsupervised settings and confounding factors need to be understood. This study explored the feasibility of completely unsupervised digital cognitive assessments using three novel memory tasks in a Citizen Science project across Germany. To that end, the study aimed to identify factors associated with stronger participant retention, to examine test-retest reliability and the extent of practice effects, as well as to investigate the influence of uncontrolled settings such as time of day, delay between sessions or screen size on memory performance. A total of 1,407 adults (aged 18-89) participated in the study for up to 12 weeks, completing weekly memory tasks in addition to short questionnaires regarding sleep duration, subjective cognitive complaints as well as cold symptoms. Participation across memory tasks was pseudorandomized such that individuals were assigned to one of three memory paradigms resulting in three otherwise identical sub-studies. One hundred thirty-eight participants contributed to two of the three paradigms. Critically, for each memory task 12 independent parallel test sets were used to minimize effects of repeated testing. First, we observed a mean participant retention time of 44 days, or 4 active test sessions, and 77.5% compliance to the study protocol in an unsupervised setting with no contact between participants and study personnel, payment or feedback. We identified subject-level factors that contributed to higher retention times. Second, we found minor practice effects associated with repeated cognitive testing, and reveal evidence for acceptable-to-good retest reliability of mobile testing. Third, we show that memory performance assessed through repeated digital assessments was strongly associated with age in all paradigms, and individuals with subjectively reported cognitive decline presented lower mnemonic discrimination accuracy compared to non-complaining participants. Finally, we identified design-related factors that need to be incorporated in future studies such as the time delay between test sessions. Our results demonstrate the feasibility of fully unsupervised digital remote memory assessments and identify critical factors to account for in future studies

A remote digital memory composite to detect cognitive impairment in memory clinic samples in unsupervised settings using mobile devices

Remote monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer's disease, this is particularly relevant for patients who seek medical advice due to memory problems. Here, we develop a remote digital memory composite (RDMC) score from an unsupervised remote cognitive assessment battery focused on episodic memory and long-term recall and assess its construct validity, retest reliability, and diagnostic accuracy when predicting MCI-grade impairment in a memory clinic sample and healthy controls. A total of 199 participants were recruited from three cohorts and included as healthy controls (n = 97), individuals with subjective cognitive decline (n = 59), or patients with mild cognitive impairment (n = 43). Participants performed cognitive assessments in a fully remote and unsupervised setting via a smartphone app. The derived RDMC score is significantly correlated with the PACC5 score across participants and demonstrates good retest reliability. Diagnostic accuracy for discriminating memory impairment from no impairment is high (cross-validated AUC = 0.83, 95% CI [0.66, 0.99]) with a sensitivity of 0.82 and a specificity of 0.72. Thus, unsupervised remote cognitive assessments implemented in the neotiv digital platform show good discrimination between cognitively impaired and unimpaired individuals, further demonstrating that it is feasible to complement the neuropsychological assessment of episodic memory with unsupervised and remote assessments on mobile devices. This contributes to recent efforts to implement remote assessment of episodic memory for case-finding and monitoring in large research studies and clinical care

The functional architecture of memory representations in the parahippocampal-hippocampal system

Episodic memories are inherent to our lives. We naturally remember past experiences and become unsettled when their recollection falls short. Recollection is a fascinating and complex process. A memory is not a single piece of information. A memory reflects our rich experiences and comprises many aspects of information, some item-related (e.g. objects and their features) and others contextual (e.g. the scenery). Our brain must be configured to represent and process all these aspects so that we can later access and recollect the entire experienced episode. In the brain’s medial temporal lobe lies a key assembly of regions for episodic memory, the parahippocampal-hippocampal system. The aim of this dissertation is to provide evidence and discuss characteristics of this system’s functional architecture that serve episodic memory. First, I focus on the representation and processing of experienced episodes in the parahippocampal-hippocampal system. Item and context information reach the system from largely segregated cortical processing streams. To what extent the information continues to be communicated in a segregated manner is unclear. With ultra-high field functional imaging, I provide novel empirical evidence, notably on a subregional level in humans, for two functional routes throughout the system. One route specifically processes scene information, in functionally connected parahippocampal, posterior-medial entorhinal cortices, and the distal subiculum. Another route, that connects perirhinal Area 35 and the retrosplenial cortex to anterior entorhinal subregions and the subiculum/CA1 border, shows no selectivity between scene and object processing. Additionally, I review evidence across species and conclude that the perirhinal cortex processes and integrates item-related features, irrespective of their nature, into unitized multidimensional item representations. Together, these insights suggest topographically specific routes through the human parahippocampal-hippocampal system, characterized by organized item-context convergence and unique context processing, respectively. Subsequently, I examine which part of the system is particularly involved when we recollect episodes. Computational and animal models suggest hippocampal subfield CA3 plays a crucial role in completing a cue towards a whole memory representation. With ultra-high field functional imaging, I provide the first empirical evidence in humans for the involvement of subregion CA3 in the cortical reactivation of the information that makes up an episode. This insight bridges the gap between model-based observations and human brain function. It shows the specific functionality of subregion CA3 in accessing memory representations and reinstating them in the cortex for holistic recollection. Finally, I discuss what happens to our memories when disease distorts their functional architecture. I provide a novel conceptual link between the information-specific architecture of the parahippocampal-hippocampal system, memorability, and altered memories with progressing Alzheimer’s pathology. I propose that memory representations reflect the pathological distortion of the system along information-specific routes. Certain aspects may thus withstand decline in early pathology stages, causing a profile of fragmented representations with potentially diagnostic value. My thesis advances insight into the functional architecture of memory representations in the human parahippocampal-hippocampal system at a rare level of subregional detail. I leverage ultra-high field functional imaging, translate long-held hypotheses from computational and rodent research to the human brain and incorporate insights across clinical and basic cognitive neuroscience. The findings sketch a specific representational architecture with subregional dynamics set up to keep information together that belongs together. This organizational scaffold has implications for the nature of memories and their recollection. My work contributes to insights on how cognitive functions like episodic memory emerge from the design of the human brain, and hence how we remember our past experiences

Source Data from Functional Connectivity and Information Processing in the Entorhinal-Hippocampal Circuitry

This study examined functional connectivity and information processing in subregions of the human medial temporal lobe with ultra-high field imaging at 7 Tesla. The Project contains related source data files and statistical maps

Pattern completion and the medial temporal lobe memory system

Pattern completion is a mechanism that allows us to infer a whole unit based on partial information. Memory theorists have posited that hippocampal pattern completion underlies recollection of episodic memories. To provide an introduction to hippocampal pattern completion and to illustrate the current state of research, we first address its psychological conceptualization for recollection and then outline the neuroanatomy and computational models of the hippocampal circuitry relevant for pattern completion. We further review neurophysiological investigations in rodents and studies on hippocampal pattern completion in humans. Finally, we discuss unresolved conceptual issues and open questions regarding the role of hippocampal pattern completion within and beyond episodic memory

Transversal functional connectivity and scene-specific processing in the human entorhinal-hippocampal circuitry

Scene and object information reach the entorhinal-hippocampal circuitry in partly segregated cortical processing streams. Converging evidence suggests that such information-specific streams organize the cortical – entorhinal interaction and the circuitry’s inner communication along the transversal axis of hippocampal subiculum and CA1. Here, we leveraged ultra-high field functional imaging and advance Maass, Berron et al. (2015) who report two functional routes segregating the entorhinal cortex (EC) and the subiculum. We identify entorhinal subregions based on preferential functional connectivity with perirhinal Area 35 and 36, parahippocampal and retrosplenial cortical sources (referred to as ECArea35-based, ECArea36-based, ECPHC-based, ECRSC-based, respectively). Our data show specific scene processing in the functionally connected ECPHC-based and distal subiculum. Another route, that functionally connects the ECArea35-based and a newly identified ECRSC-based with the subiculum/CA1 border, however, shows no selectivity between object and scene conditions. Our results are consistent with transversal information-specific pathways in the human entorhinal-hippocampal circuitry, with anatomically organized convergence of cortical processing streams and a unique route for scene information. Our study thus further characterizes the functional organization of this circuitry and its information-specific role in memory function

Content-specific vulnerability of recent episodic memories in Alzheimer's disease

Endel Tulving's episodic memory framework emphasizes the multifaceted re-experiencing of personal events. Indeed, decades of research focused on the experiential nature of episodic memories, usually treating recent episodic memory as a coherent experiential quality. However, recent insights into the functional architecture of the medial temporal lobe show that different types of mnemonic information are segregated into distinct neural pathways in brain circuits empirically associated with episodic memory. Moreover, recent memories do not fade as a whole under conditions of progressive neurodegeneration in these brain circuits, notably in Alzheimer's disease. Instead, certain memory content seem particularly vulnerable from the moment of their encoding while other content can remain memorable consistently across individuals and contexts. We propose that these observations are related to the content-specific functional architecture of the medial temporal lobe and consequently to a content-specific impairment of memory at different stages of the neurodegeneration. To develop Endel Tulving's inspirational legacy further and to advance our understanding of how memory function is affected by neurodegenerative conditions such as Alzheimer's disease, we postulate that it is compelling to focus on the representational content of recent episodic memories

Forecasting memory function in aging : pattern-completion ability and hippocampal activity relate to visuospatial functioning over 25 years

Heterogeneity in episodic memory functioning in aging was assessed with a pattern-completion functional magnetic resonance imaging task that required reactivation of well-consolidated face-name memory traces from fragmented (partial) or morphed (noisy) face cues. About half of the examined individuals (N = 101) showed impaired (chance) performance on fragmented faces despite intact performance on complete and morphed faces, and they did not show a pattern-completion response in hippocampus or the examined subfields (CA1, CA23, DGCA4). This apparent pattern-completion deficit could not be explained by differential hippocampal atrophy. Instead, the impaired group displayed lower cortical volumes, accelerated reduction in mini-mental state examination scores, and lower general cognitive function as defined by longitudinal measures of visuospatial functioning and speed-of-processing. In the full sample, inter-individual differences in visuospatial functioning predicted performance on fragmented faces and hippocampal CA23 subfield activity over 25 years. These findings suggest that visuospatial functioning in middle age can forecast pattern-completion deficits in aging.