Prior knowledge contribution to declarative learning. A study in amnesia, aging and Alzheimer's disease

L'étude expérimentale de la mémoire humaine a connu deux moments historiques dans les soixante dernières années. 1957 marque la découverte du rôle du lobe temporal interne bilatéral dans l'apprentissage conscient, déclaratif. 1997 marque la découverte de deux systèmes de mémoire déclarative, épisodique et sémantique. Ces découvertes résultent d'études de cas en neuropsychologie. Cette thèse s'inscrit dans la tradition neuropsychologique: sa genèse doit tout à un patient souffrant d'une forme atypique d'amnésie développementale, le patient KA. Son point de départ est une étude de cas approfondie, avec deux résultats surprenants. Malgré une amnésie sévère, KA dispose de connaissances sémantiques exceptionnelles. Par ailleurs, il montre des capacités préservées d'apprentissage explicite, mais uniquement pour des stimuli concrets, pas abstraits. En conséquence, cette thèse a exploré deux pistes de recherche. Premièrement, nous avons caractérisé les processus préservés d'apprentissage déclaratif et l'anatomie cérébrale chez ce patient. Deuxièmement, nous avons étudié le rôle des connaissances préalables dans l'apprentissage: comment ce que l'on sait influence ce dont nous nous souvenons ? Une première série d'expériences montre chez ce patient une atteinte sévère et sélective de l'ensemble du système hippocampique, alors que les structures sous- hippocampiques (cortex entorhinal, périrhinal et parahippocampique) sont préservées. Malgré une amnésie épisodique sévère, nous montrons des connaissances sémantiques supranormales et des aptitudes d'apprentissage explicite rapide. Ces aptitudes sont toutefois restreintes aux stimuli associés à des connaissances préalables. Une seconde série d'expériences explore l'hypothèse selon laquelle les connaissances préalables facilitent l'apprentissage en mémoire déclarative, même dans les situations où le lobe temporal interne est fragilisé, comme dans le vieillissement, ou lésé, comme chez le patient KA ou dans la maladie d'Alzheimer. Nos résultats suggèrent l'existence de processus d'apprentissage rapide en mémoire déclarative, indépendants du système hippocampique et sensibles à la présence de représentations préexistantes. Ces processus semblent affectés par la maladie d'Alzheimer, et ce en lien avec un défaut d'activité des régions sous-hippocampiques antérieures. A l'inverse, les sujets âgés sains peuvent utiliser les connaissances préalables et pourraient ainsi compenser le déclin de la mémoire associative. Ce travail s'accorde avec les modèles postulant une dissociation fonctionnelle au sein du lobe temporal interne pour l'apprentissage déclaratif. Il soutient les propositions neurocognitives et computationnelles récentes, suggérant une voie d'apprentissage néocortical rapide mobilisable dans certaines circonstances. Il met en exergue la dynamique des apprentissages en mémoire déclarative et notamment l'intrication fondamentale entre "savoir" et "se souvenir". Ce que je sais a un impact profond sur ce dont je vais me souvenir. Cette thèse permet d'envisager de nouveaux outils cognitifs pour le diagnostic de la maladie d'Alzheimer. De plus, il semble que des lésions temporales internes auront un impact distinct sur l'apprentissage selon le statut des informations à mémoriser en mémoire à long terme, offrant un regard nouveau sur les effets stimulus-dépendants dans l'amnésie. Une considération approfondie des connaissances préalables associées au contenu de nos expériences, et leur caractérisation détaillée, est requise pour affiner les modèles de la mémoire déclarative. Ces résultats apportent de nouvelles pistes de recherche quant aux circonstances épargnant l'apprentissage, notamment associatif, lors du vieillissement. Plus généralement, ils contribuent à la compréhension des déterminants d'un apprentissage réussi, en mettant l'accent sur les recouvrements entre processus de récupération et d'acquisition. Des applications potentielles en découlent dans le domaine éducatif.The experimental study of human memory has had two historic moments in the last sixty years. 1957 marks the discovery of the role of the medial temporal lobes in conscious learning. 1997 marks the discovery of two systems of declarative memory, namely episodic and semantic memories. These major breakthroughs are owed to clinical case studies in neuropsychology. This thesis follows on from the neuropsychological tradition: its genesis owes everything to a patient suffering from an atypical form of developmental amnesia, the patient KA. The starting point of this work was a thorough neuropsychological study of this patient. Two striking findings shortly arose. First, despite lifelong amnesia, KA had acquired exceptional levels of knowledge about the world. Second, remaining explicit learning abilities were restricted to meaningful, not meaningless, memoranda. As a consequence, we have investigated two research pathways in that thesis. First, we aimed at better characterizing preserved learning abilities and brain structure of the patient KA. Second, our goal was to explore how prior knowledge affects new declarative learning or, put simply, how do we learn what we know? In a first series of behavioural and neuroimaging experiments, we have shown in this patient a severe and selective damage of the whole extended hippocampal system, but preserved subhippocampal structures (entorhinal, perirhinal and parahippocampal cortex). The patient suffers from severe episodic amnesia, but we bring striking evidence for supranormal semantic knowledge as well as normal explicit learning skills. These skills were, however, restricted to familiar stimuli, that is, stimuli carrying pre-experimental knowledge. In a second series of behavioural and neuroimaging experiments, we explored the hypothesis that prior knowledge can facilitate new learning in declarative memory, even in aging or in situations where structures of the medial temporal lobe are or injured, as in amnesia or Alzheimer's disease. Our results suggest the existence of processes allowing fast learning in declarative memory, independently of the hippocampal system, and that are sensitive to the presence of pre-existing representations in long-term memory. Such learning processes appear to be selectively affected by Alzheimer's disease at the pre-dementia stage, in relation to a lack of activation of subhippocampal regions. In contrast, healthy elderly were able to rely on these learning processes to compensate for the decline in associative memory associated with aging. This work lends support to the models postulating a functional dissociation with respect to learning in declarative memory. It indeed strengthens recent neurocognitive and computational accounts that suggest a rapid neocortical learning path under certain circumstances. It highlights the dynamics of learning in declarative memory and in particular the fundamental entanglement between "knowing" and "remembering". What I know profoundly impacts what I will remember. The present thesis points towards new cognitive tools for the diagnosis of Alzheimer's disease. It further brings evidence that medial temporal lesions differentially impact learning depending on the status of the memoranda in long-term memory, which sheds a new light on material-specific effects in amnesia. Our work speaks for a thorough consideration of whether the contents of events have prior representations within long-term memory, and to further better characterize their nature if we are to better understand learning mechanisms. It also brings additional clues for a deeper understanding of how learning and memory can be preserved in aging. More generally, it contributes to a better understanding of the factors determining successful learning, with a focus on how retrieval and acquisition processes overlap during learning. Such findings have potential applications in the educational field

There is more to memory than recollection and familiarity.

Theoretical models of memory retrieval have focused on processes of recollection and familiarity. Research suggests that there are still other processes involved in memory reconstruction, leading to experiences of knowing and inferring the past. Understanding these experiences, and the cognitive processes that give rise to them, seems likely to further expand our understanding of the neural substrates of memory

Names and their meanings: A dual-process account of proper-name encoding and retrieval

The ability to pick out a unique entity with a proper name is an important component of human language. It has been a primary focus of research in the philosophy of language since the nineteenth century. Brain-based evidence has shed new light on this capacity, and an extensive literature indicates the involvement of distinct fronto-temporal and temporo-occipito-parietal association cortices in proper-name retrieval. However, comparatively few efforts have sought to explain how memory encoding processes lead to the later recruitment of these distinct regions at retrieval. Here, we provide a unified account of proper-name encoding and retrieval, reviewing evidence that socio-emotional and unitized encoding subserve the retrieval of proper names via anterior-temporal-prefrontal activations. Meanwhile, non-unitized item-item and item-context encoding support subsequent retrieval, largely dependent on the temporo-occipito-parietal cortex. We contend that this well-established divergence in encoding systems can explain how proper names are later retrieved from distinct neural structures. Furthermore, we explore how evidence reviewed here can inform a century-and-a-half-old debate about proper names and the meanings they pick out

Memory for fearful faces across development: specialization of amygdala nuclei and medial temporal lobe structures

International audienceEnhanced memory for emotional faces is a significant component of adaptive social interactions, but little is known on its neural developmental correlates. We explored the role of amygdaloid complex (AC) and medial temporal lobe (MTL) in emotional memory recognition across development, by comparing fMRI activations of successful memory encoding of fearful and neutral faces in children (n = 12; 8–12 years) and adolescents (n = 12; 13–17 years). Memory for fearful faces was enhanced compared with neutral ones in adolescents, as opposed to children. In adolescents, activations associated with successful encoding of fearful faces were centered on baso-lateral AC nuclei, hippocampus, enthorhinal and parahippocampal cortices. In children, successful encoding of fearful faces relied on activations of centro-mesial AC nuclei, which was not accompanied by functional activation of MTL memory structures. Successful encoding of neutral faces depended on activations in anterior MTL region (hippocampal head and body) in adolescents, but more posterior ones (hippocampal tail and parahippocampal cortex) in children. In conclusion, two distinct functional specializations emerge from childhood to adolescence and result in the enhancement of memory for these particular stimuli: the specialization of baso-lateral AC nuclei, which is associated with the expertise in processing emotional facial expression, and which is intimately related to the specialization of MTL memory network. How the interplay between specialization of AC nuclei and of MTL memory structures is fundamental for the edification of social interactions remains to be elucidated

Relationship between hippocampal structure and memory function in elderly humans

With progressing age, the ability to recollect personal events declines, whereas familiarity-based memory remains relatively intact. It has been hypothesized that age-related hippocampal atrophy may contribute to this pattern because of its critical role for recollection in younger humans and after acute injury. Here, we show that hippocampal volume loss in healthy older persons correlates with gray matter loss (estimated with voxel-based morphometry) of the entire limbic system and shows no correlation with an electrophysiological (event-related potential [ERP]) index of recollection. Instead, it covaries with more substantial and less specific electrophysiological changes of stimulus processing. Age-related changes in another complementary structural measure, hippocampal diffusion, on the other hand, seemed to be more regionally selective and showed the expected correlation with the ERP index of recollection. Thus, hippocampal atrophy in older persons accompanies limbic atrophy, and its functional impact on memory is more fundamental than merely affecting recollection

Reconciling the object and spatial processing views of the perirhinal cortex through task-relevant unitization

The perirhinal cortex is situated on the border between sensory association cortex and the hippocampal formation. It serves an important function as a transition area between the sensory neocortex and the medial temporal lobe. While the perirhinal cortex has traditionally been associated with object coding and the "what" pathway of the temporal lobe, current evidence suggests a broader function of the perirhinal cortex in solving feature ambiguity and processing complex stimuli. Besides fulfilling functions in object coding, recent neurophysiological findings in freely moving rodents indicate that the perirhinal cortex also contributes to spatial and contextual processing beyond individual sensory modalities. Here, we address how these two opposing views on perirhinal cortex-the object-centered and spatial-contextual processing hypotheses-may be reconciled. The perirhinal cortex is consistently recruited when different features can be merged perceptually or conceptually into a single entity. Features that are unitized in these entities include object information from multiple sensory domains, reward associations, semantic features and spatial/contextual associations. We propose that the same perirhinal network circuits can be flexibly deployed for multiple cognitive functions, such that the perirhinal cortex performs similar unitization operations on different types of information, depending on behavioral demands and ranging from the object-related domain to spatial, contextual and semantic information

Electrophysiological evidence for memory schemas in the rat hippocampus

According to Piaget and Bartlett, learning involves both assimilation of new memories into networks of preexisting knowledge and alteration of existing networks to accommodate new information into existing schemas. Recent evidence suggests that the hippocampus integrates related memories into schemas that link representations of separately acquired experiences. In this thesis, I first review models for how memories of individual experiences become consolidated into the structure of world knowledge. Disruption of consolidated memories can occur during related learning, which suggests that consolidation of new information is the reconsolidation of related memories. The accepted role of the hippocampus during memory consolidation and reconsolidation suggests that it is also involved in modifying appropriate schemas during learning. To study schema development, I trained rats to retrieve rewards at different loci on a maze while recording hippocampal calls. About a quarter of cells were active at multiple goal sites, though the ensemble as a whole distinguished goal loci from one another. When new goals were introduced, cells that had been active at old goal locations began firing at the new locations. This initial generalization decreased in the days after learning. Learning also caused changes in firing patterns at well-learned goal locations. These results suggest that learning was supported by modification of an active schema of spatially related reward loci. In another experiment, I extended these findings to explore a schema of object and place associations. Ensemble activity was influenced by a hierarchy of task dimensions which included: experimental context, rat's spatial location, the reward potential and the identity of sampled objects. As rats learned about new objects, the cells that had previously fired for particular object-place conjunctions generalized their firing patterns to new conjunctions that similarly predicted reward. In both experiments, I observed highly structured representations for a set of related experiences. This organization of hippocampal activity counters key assumptions in standard models of hippocampal function that predict relative independence between memory traces. Instead, these findings reveal neural mechanisms for how the hippocampus develops a relational organization of memories that could support novel, inferential judgments between indirectly related events

Integrating incremental learning and episodic memory models of the hippocampal region.

By integrating previous computational models of corticohippocampal function, the authors develop and test a unified theory of the neural substrates of familiarity, recollection, and classical conditioning. This approach integrates models from 2 traditions of hippocampal modeling, those of episodic memory and incremental learning, by drawing on an earlier mathematical model of conditioning, SOP (A. Wagner, 1981). The model describes how a familiarity signal may arise from parahippocampal cortices, giving a novel explanation for the finding that the neural response to a stimulus in these regions decreases with increasing stimulus familiarity. Recollection is ascribed to the hippocampus proper. It is shown how the properties of episodic representations in the neocortex, parahippocampal gyrus, and hippocampus proper may explain phenomena in classical conditioning. The model reproduces the effects of hippocampal, septal, and broad hippocampal region lesions on contextual modulation of classical conditioning, blocking, learned irrelevance, and latent inhibition

Which way do I go? Neural activation in response to feedback and spatial processing in a virtual T-maze

In 2 human event-related brain potential (ERP) experiments, we examined the feedback error-related negativity (fERN), an ERP component associated with reward processing by the midbrain dopamine system, and the N170, an ERP component thought to be generated by the medial temporal lobe (MTL), to investigate the contributions of these neural systems toward learning to find rewards in a "virtual T-maze" environment. We found that feedback indicating the absence versus presence of a reward differentially modulated fERN amplitude, but only when the outcome was not predicted by an earlier stimulus. By contrast, when a cue predicted the reward outcome, then the predictive cue (and not the feedback) differentially modulated fERN amplitude. We further found that the spatial location of the feedback stimuli elicited a large N170 at electrode sites sensitive to right MTL activation and that the latency of this component was sensitive to the spatial location of the reward, occurring slightly earlier for rewards following a right versus left turn in the maze. Taken together, these results confirm a fundamental prediction of a dopamine theory of the fERN and suggest that the dopamine and MTL systems may interact in navigational learning tasks