In der vorliegenden Habilitationsschrift wurde eine Serie von Studien zusammengefasst, die menschliches räumliches Arbeitsgedächtnis, den "Visuospatialen Skizzenblock", untersucht haben. Dieses Kurzzeitgedächtnissystem ist häufig im Rahmen von Erkrankungen des frontalen Kortex und seiner mit ihm verbundenen Hirnareale, z.B. dem Morbus Parkinson, dem Morbus Alzheimer oder der Schizophrenie, beeinträchtigt und für einen relevanten Teil der kognitiven Defizite dieser Patienten verantwortlich. Wir untersuchten sowohl Gesunde als auch Patienten mit fokalen Läsionen des Gehirns mit Varianten des "Gedächtnissakkaden"-Paradigmas, einem etablierten okulomotorischen Verfahren zur Untersuchung von Raumgedächtnis. Es wurden sowohl behaviorale Aspekte von Arbeitsgedächtnis als auch mögliche anatomische Substrate dieses Gedächtnissystems sowie zeitstabilerer "Langzeit"-Gedächtnissysteme untersucht. Ziel war es, klarere Korrelationen zwischen messbarem Verhalten einerseits und Anatomie/Physiologie von Raumgedächtnis andererseits zu etablieren. Wir konnten erstmals zeigen, dass menschliches räumliches Arbeitsgedächtnis selektiv für aktuelles Verhalten relevante Wahrnehmungsinhalte repräsentiert. Der Zugang verhaltensirrelevanter Rauminformationen zu räumlichem Arbeitsgedächtnis wird offenbar durch effiziente (Aufmerksamkeits-) Filtermechanismen verhindert. Für die Existenz solcher Filtermechanismen gab es bislang nur elektrophysiologische Belege im Tiermodell. Da die Speicherkapazität von Arbeitsgedächtnis gering ist, erlauben diese Filtermechanismen möglicherweise einen effizienteren Umgang mit der Fülle und Komplexität unserer Umwelt. Umgekehrt lässt die in unserem Experiment sichtbar gewordene enge Verzahnung von Arbeitsgedächtnis und Aufmerksamkeit die Hypothese zu, dass eine gestörte Arbeitsgedächtniskapazität sowohl durch eine primäre Beeinträchtigung der Speichermechanismen selbst als auch durch Störungen der attentionalen Kontrolle derselben zustande kommen kann. Des weiteren konnten wir erstmals zeigen, dass menschliches räumliches Arbeitsgedächtnis eine klare Zeitgrenze hat, die für einzelne räumliche items bei ungefähr 20 Sekunden liegt. Jenseits dieser Zeitgrenze scheint eine vom Arbeitsgedächtnis unabhängige Raumrepräsentation für menschliches Verhalten bedeutsam zu werden. Der Begriff "Arbeitsgedächtnis" sollte also für Gedächtnisaufgaben reserviert bleiben, deren Gedächtnisphase 20 Sekunden nicht überschreitet. Unsere Befunde zeigen weiterhin, dass bei ansonsten konstantem Design einer Gedächtnisaufgabe, die Dauer der Gedächtnisphase bereits wesentlich darüber entscheidet, welches Gedächtnissystem untersucht wird. Die von uns durchgeführten Läsionsstudien an Patienten und neurophysiologischen Studien an Gesunden bestätigen, dass räumliches Arbeitsgedächtnis durch ein Netzwerk kortikaler Areale kontrolliert wird, das unter anderem den Dorsolateralen Präfrontalen Kortex, den Posterioren Parietalen Kortex und das Frontale Augenfeld umfasst. Innerhalb dieses Netzwerks nehmen diese Areale jedoch klar verschiedene kognitive Partialfunktionen wahr. Der Dorsolaterale Präfrontale Kortex und der Posteriore Parietale Kortex scheinen in erster Linie der Repräsentation von Raum in perzeptuellen Koordinaten, d.h. einem räumlichen "Wahrnehmungsbild" zu dienen, mit einer nur kurzfristigen Rolle des Posterioren Parietalen Kortex und einer dominierenden Rolle des Dorsolateralen Präfrontalen Kortex während der Gedächtnisphase einer Arbeitsgedächtnisaufgabe. Das Frontale Augenfeld scheint der Repräsentation von Raum in okulomotorischen Koordinaten zu dienen, d.h. der kurzzeitigen Speicherung einer geplanten okulomotorischen Antwort auf einen räumlichen Wahrnehmungsinhalt. Schließlich sprechen unsere Ergebnisse dafür, dass es mit dem Wechsel von Arbeitsgedächtnis zu einer zeitstabileren Raumrepräsentation bei Gedächtnisphasen von mehr als 20 Sekunden Länge auch zu einem Wechsel der anatomischen Substrate von Raumgedächtnis kommt. Die von uns durchgeführten Läsionsstudien zeigen, dass jenseits der Zeitgrenzen von räumlichem Arbeitsgedächtnis neokortikale Areale des Medialen Temporallappens eine aktive Rolle für Raumgedächtnis spielen. Hier konnten wir erstmals zeigen, dass der menschliche Parahippokampale Kortex eigenständige und vom Hippokampus unabhängige Raumgedächtnisfunktionen wahrnimmt. Möglicherweise ist diese Region das Substrat eines intermediären Gedächtnissystems zwischen räumlichem Arbeitsgedächtnis und Hippokampus-abhängigem Langzeitgedächtnis. Es wird ferner deutlich, dass in einer Gedächtnisaufgabe allein durch die Wahl verschiedener Dauern der Gedächtnisphase verschiedene anatomische Substrate von Gedächtnis untersucht werden können. Die in dieser Habilitationsschrift zusammengefassten Studien zeigen am Beispiel des räumlichen Arbeitsgedächtnisses, dass es möglich ist, mit einfachen physiologischen Paradigmen Gedächtnissysteme am Menschen zu untersuchen. Bestimmte mnestische Subfunktionen lassen sich mit den hier verwandten Paradigmen präzise quantifizieren und bestimmten Hirnregionen zuordnen. Wir glauben, dass dieser methodische Ansatz sowohl eine präzisere Diagnostik von kognitiven Defiziten bei Hirnerkrankungen erlaubt, als auch die Möglichkeit eröffnet, die Therapie von Gedächtnisstörungen effektiv zu kontrollieren. / This publication summarizes a series of experimental studies examining spatial working memory, the "visuospatial scratch pad", in humans. This short-term memory system is frequently affected in disorders involving the frontal cortex and connected subcortical structures, e.g. in Parkinson's disease, Alzheimer's disease or schizophrenia. Healthy human subjects and patients with focal cerebral lesions were tested with a series of "memory-guided saccade" paradigms, i.e. oculomotor spatial memory tasks. We examined both behavioural aspects and possible anatomical substrates of spatial working memory and more stable "long-term" memory systems. Our aim was to clarify the relationship between behavioural measures of spatial memory and its neuronal substrates. In a first experiment, we were able to show that visuospatial working memory selectively represents behaviourally relevant information. Access of irrelevant visuospatial information to working memory appears to be prevented by efficient attentional filters. Facing the limited storage capacity of spatial working memory, these filters may allow for successful behaviour in perceptually complex environments. Furthermore, the tight coupling of spatial attention and spatial working memory allows for the conclusion, that spatial working memory deficits in patients may likewise result from deficient storage systems and deficient attentional control. In a second experiment, we were able to demonstrate a clear temporal limit of about 20 seconds for spatial working memory. Beyond this temporal limit, an independent and more stable spatial memory system, less susceptible to the passage of time, becomes behaviourally relevant. Thus, the term "working memory" should be confined to spatial memory tasks where the memory delay does not exceed 20 seconds. In addition, these results show that selection of a certain memory delay in a given spatial memory task is a decisive factor when examining spatial memory systems. A third series of lesion studies in patients and neurophysiological experiments in healthy subjects confirmed that cortical control of spatial working memory involves dorsolateral prefrontal cortex, posterior parietal cortex and frontal eye field. Within this network, the dorsolateral prefrontal cortex and posterior parietal cortex appear to store spatial information in perceptual coordinates, with a transient role of the posterior parietal cortex at the very beginning of the memory delay and a dominating role of the dorsolateral prefrontal cortex for most of the delay. By contrast, the frontal eye field appears to store spatial information in oculomotor coordinates, i.e. to maintain a prepared eye movement to a remembered target location across a delay. A fourth series of lesion studies in patients showed that spatial memory for delays longer than 20 seconds is controlled by anatomical substrates distinct from those controlling spatial working memory. Beyond the temporal limits of spatial working memory, neocortical regions of the medial temporal lobe appear to contribute significantly to spatial memory. Within these neocortical regions, the parahippocampal cortex may carry spatial memory functions independent of the hippocampal formation and distinct from spatial working memory. We propose that this region is the neuronal substrate of an intermediate memory system, linking spatial working memory and spatial long-term memory both functionally and anatomically. Moreover, these results show that selection of a certain memory delay in a given spatial memory task is a decisive factor when examining neuronal substrates of spatial memory. Taken together, our experiments show that human memory can effectively be investigated with simple physiological paradigms. Spatial memory functions can precisely be quantified with oculomotor paradigms and related to defined anatomical substrates. This approach may allow for precise diagnosis of cognitive deficits and efficient monitoring of treatment of memory disorders.

Recent proposals have attributed a key role to novelty in the formation of new episodic memories. These proposals are based on evidence of enhanced memory and greater metabolic activity in the hippocampus in response to novel relative to familiar materials. However, such novelty effects are incongruous with long-standing observations that familiar items and lists are associated with better memory than novel ones. In four experiments, I explored possible reasons for this apparent discrepancy. In Experiment 1, I directly tested whether previously observed novelty effects were the result of novelty, discrimination demands, or both. I used linguistic materials (proverbs) to replicate the novelty effect but found it occurred only when familiar items were subject to source confusion. In Experiment 2, to examine better how novelty influences episodic memory, I used experimentally familiar, pre-experimentally familiar, and novel proverbs in a paradigm designed to overcome discrimination demand confounds. Memory was better for both types of familiar proverbs. These cognitive results indicate that familiarity, not novelty, leads to better episodic memory for studied items, regardless of whether familiarity is experimentally induced or based on prior knowledge. I also conducted two fMRI experiments to evaluate the neural correlates of the encoding of novel and familiar forms of information. In Experiment 3, I compared the neural encoding correlates of source memory for novel and familiar visual scenes using fMRI. Replicating previous neuroimaging studies, I observed an anterior novelty-sensitive region of the hippocampus specialized in novelty encoding. Unlike past studies, I also probed for familiarity-encoding regions and identified such regions in the posterior hippocampus. I replicated this pattern in Experiment 4 using proverbs as stimuli. As in Experiment 2, I found the effect held whether familiarity was based on prior knowledge or experimental induction. In both fMRI experiments, anterior and posterior hippocampal regions were functionally connected with different large-scale networks, helping to explain local variation in hippocampal functional specialization in terms of different neural contexts. Together, these experiments show that stimulus familiarity enhances episodic memory for materials, and that novelty is processed differently, not preferentially, in the hippocampus. A new model of hippocampal novelty processing is proposed.

Recent proposals have attributed a key role to novelty in the formation of new episodic memories. These proposals are based on evidence of enhanced memory and greater metabolic activity in the hippocampus in response to novel relative to familiar materials. However, such novelty effects are incongruous with long-standing observations that familiar items and lists are associated with better memory than novel ones. In four experiments, I explored possible reasons for this apparent discrepancy. In Experiment 1, I directly tested whether previously observed novelty effects were the result of novelty, discrimination demands, or both. I used linguistic materials (proverbs) to replicate the novelty effect but found it occurred only when familiar items were subject to source confusion. In Experiment 2, to examine better how novelty influences episodic memory, I used experimentally familiar, pre-experimentally familiar, and novel proverbs in a paradigm designed to overcome discrimination demand confounds. Memory was better for both types of familiar proverbs. These cognitive results indicate that familiarity, not novelty, leads to better episodic memory for studied items, regardless of whether familiarity is experimentally induced or based on prior knowledge. I also conducted two fMRI experiments to evaluate the neural correlates of the encoding of novel and familiar forms of information. In Experiment 3, I compared the neural encoding correlates of source memory for novel and familiar visual scenes using fMRI. Replicating previous neuroimaging studies, I observed an anterior novelty-sensitive region of the hippocampus specialized in novelty encoding. Unlike past studies, I also probed for familiarity-encoding regions and identified such regions in the posterior hippocampus. I replicated this pattern in Experiment 4 using proverbs as stimuli. As in Experiment 2, I found the effect held whether familiarity was based on prior knowledge or experimental induction. In both fMRI experiments, anterior and posterior hippocampal regions were functionally connected with different large-scale networks, helping to explain local variation in hippocampal functional specialization in terms of different neural contexts. Together, these experiments show that stimulus familiarity enhances episodic memory for materials, and that novelty is processed differently, not preferentially, in the hippocampus. A new model of hippocampal novelty processing is proposed.

Recollection, the process by which an item provokes the retrieval of associated information stored in the brain, is a key component of recognition memory. It is explored in this thesis through the use of a paradigm designed to allow the neural correlates of amount recalled to be identified through parametric fMRI analysis. A series of experiments were carried out during the development and optimisation of this paradigm in order to ensure that the various demands of this analysis were met. Subsequently this paradigm was applied during an fMRI experiment which provided data from both the encoding and retrieval stages of recollection.Whilst the development work was chiefly concerned with producing a suitable task design for the parametric fMRI analysis, these experiments provided some interesting results in their own right. The task design, which required participants to associate multiple item types within a story context, showed that there are significant differences in the frequency with which different stimuli are recollected. Participants were found to be particularly poor at recollecting faces whilst words were also shown to be recollected less frequently than either object or animal picture stimuli. A possible explanation for these differences may be related to the picture superiority effect although eye-tracking data collected from these experiments demonstrates large differences in viewing behaviour between different target stimulus types which is not correlated with later recall success. The amount of time participants spend engaging with the highly contextual scene item does predict later recall success.The fMRI analysis (Chapter 5) carried out during the encoding and retrieval stages of recollection found a variety of regions exhibiting a positive linear relationship with recollection at both these stages. This result provides support for the cortical reinstatement hypothesis of recollection despite the fact that the hippocampus only showed parametric modulation of activity during retrieval. It is proposed that parahippocampal activity during encoding and retrieval supports the recollection of contextual information whilst the same pattern of activity in parietal regions related to recollection may reflect the reinstatement of the global image of the story created during the encoding task.

Avec l’avancée en âge, l’efficience de l’ensemble des fonctions cognitives, en particulier la mémoire épisodique, tend à diminuer. L’étude des effets Dm et old/new et des résultats de la méthode sLORETA a permis de caractériser sur un plan neurofonctionnel deux types de vieillissement non pathologique chez les seniors. D’une part, le vieillissement cognitif stable se traduit par des processus d’encodage identiques à ceux observés chez des sujets jeunes alors que les processus de récupération nécessitent un recrutement bilatéral des lobes temporaux médians, cette activation étant unilatérale chez les sujets jeunes. Ces résultats vont dans le sens du modèle HAROLD qui suggère une réduction de l’asymétrie hémisphérique avec l’âge. D’autre part, le vieillissement cognitif altéré proviendrait d’une altération des réseaux cérébraux dès la phase d’encodage. La baisse d'activité au niveau du cortex préfrontal gauche, siège des fonctions exécutives, suggèrerait une difficulté de mise en œuvre de stratégies d'encodage efficaces et aurait un impact direct sur l'activité observée au niveau du lobe temporal médian de façon bilatérale ce qui pourrait donc expliquer une difficulté de stockage de l'information. / With advancing age, the efficiency of all cognitive functions, especially episodic memory, tends to decrease. The study of Dm and old/new effects and of the results of the sLORETA method allowed to characterize, on a neurofunctionnal level, two types of non-pathological aging among seniors. On the one hand, stable cognitive aging results in encoding processes similar to those observed in young subjects while the retrieval processes require a bilateral recruitment of the medial temporal lobes, this activation being unilateral in young subjects. These results are in line with the HAROLD model, suggesting a reduction of hemispheric asymmetry with age. On the other hand, the altered cognitive aging might come from an alteration of brain networks at the early stage of the encoding phase. The decline of activity in the left prefrontal cortex, seat of executive functions, would suggest a difficult implementation of effective encoding strategies and have a direct impact on the activity observed in the medial temporal lobe bilaterally which could therefore explain information storage difficulties.

Un nombre croissant de travaux chez l’animal et chez l’homme suggèrent que les différentes structures composant le lobe temporal interne (LTI) contribuent de manière différentielle à la mémoire déclarative. Chez l’homme, deux réseaux neuraux impliquant le LTI sont décrits : un réseau mésiotemporal antérieur, constitué de structures pour lesquelles les études chez les patients cérébro-lésés indiquent qu’elles contribueraient à la mémoire décontextualisée (mémoire des objets et mémoire sémantique ou mémoire du « quoi ») ; un réseau mésiotemporal postérieur, constitué d’autres structures pour lesquelles ces études suggèrent plutôt une implication dans la mémoire contextualisée (mémoire spatiale, épisodique ou mémoire du «où » et du « quand»). Dans la Maladie d’Alzheimer (MA), les dégénérescences neurofibrillaires, dont la distribution topographique est corrélée à la nature des déficits cognitifs, se développent initialement dans les cortex sous-hippocampiques - transentorhinal et entorhinal - qui sont des composants du réseau mésiotemporal antérieur, avant de s’étendre à l’hippocampe. Les éventuels déficits cognitifs en relation avec l’atteinte de cette région ne sont pas clairement identifiés dans la MA. Les travaux présentés dans ce mémoire sont centrés sur l’étude des cortex sous-hippocampiques avec les méthodes de la neuropsychologie et la neuroimagerie. Ils suggèrent que la MA aux stades les plus précoces pourrait représenter un « modèle » d’étude privilégié des systèmes mnésiques auxquels contribue le LTI. Ces résultats sont en faveur de l’utilité de l’évaluation de la mémoire décontextualisée dans le diagnostic de la MA débutante. / There is increasing evidence from experiments in rodents and non-human primates, as well as from human studies, to suggest that the different structures within the medial temporal lobe (MTL) differentially contribute to declarative memory. In the human brain, two neural networks implicating MTL structures have been described: an anterior MTL network that includes brain areas that contribute to context-free memory (object memory and semantic memory or memory for « what ») and a posterior MTL network that contributes to context-rich memory (spatial memory, episodic memory or memory for “where” and “when”). In Alzheimer’s disease (AD), neurofibrillary tangles (NFT), associated with cognitive signs, initially appear in the sub-hippocampal (transentorhinal and entorhinal) cortex, which are part of the anterior MTL network, before reaching the hippocampus. Potential cognitive deficits related to the dysfunction of this brain area in AD are not clearly identified. In the presented studies, the emphasis is placed on the investigation of sub-hippocampal corteces using a neuropsychological approach and neuroimaging techniques. Our findings suggest that the very earliest stages of AD could represent a “model” leading to a better understanding of memory systems that involve the MTL. They also provide evidence that evaluating context-free memory may be useful in the diagnosis of early AD.