Hippocampal-orbitofrontal interactions in memory and reality filtering

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Thesis

Reference

Hippocampal-orbitofrontal interactions in memory and reality filtering

THÉZÉ, Raphaël

Abstract

Le filtre orbitofrontal de la réalité est un mécanisme, indépendant des fonctions médio-temporales (MTL) de la mémoir, filtrant les pensées. ORFi permet de percevoir la réalité et est associé à un marqueur électrophysiologique. Nous émettons l'hypothèse que le cortex orbitofrontal (OFC) filtre les pensées alors qu'elles sont générées dans le MTL.

Premièrement, un marqueur électrophysiologique de l'encodage de la mémoire, généré par le MTL, a été identifié (Thézé et al. 2016). Ce marqueur était associé avec une augmentation de cohérence thêta dans le MTL. Il apparaît 35 ms avant le marqueur d'ORFi (Thézé et al.

2017a). Les deux sont associés à une augmentation thêta de cohérence, l'un depuis le MTL, l'autre depuis l'OFC, chacun vers l'autre. Finalement, un groupe de patients dans le spectre des trouble de la schizophrénie ont démontré une réduction significative du marqueur ORFi, dont l'ampleur peut prédire le diagnostic. La cohérence thêta qui augmentait chez les contrôles était absence des patients dans l'OFC et le MTL et, pour ce dernier, corrélait avec les scores [...]

THÉZÉ, Raphaël. Hippocampal-orbitofrontal interactions in memory and reality filtering. Thèse de doctorat : Univ. Genève et Lausanne, 2017, no. Neur. 217

DOI : 10.13097/archive-ouverte/unige:100003 URN : urn:nbn:ch:unige-1000038

Available at:

http://archive-ouverte.unige.ch/unige:100003

Disclaimer: layout of this document may differ from the published version.

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DOCTORAT EN NEUROSCIENCES des Universités de Genève

et de Lausanne

UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES

Département des Neurosciences Cliniques FACULTÉ DE MÉDECINE

Professeur A. Schnider

Hippocampal-Orbitofrontal Interactions In Memory And Reality Filtering

THÈSE

Présentée à la Faculté de sciences de l’Université de Genève pour obtenir le grade de Docteur en Neurosciences

par

Raphaël Pierre THÉZÉ-BOISSONNET de

Montréal (Canada)

Thèse N° 217

Genève Université de Genève

2017

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3 Acknowledgment

First and foremost, a few words dedicated to those whose work, words and presence made this thesis possible by guiding and helping me along the years that have already elapsed.

I first have to thank prof. Armin Schnider, my thesis director, for his supervision. He has been dedicated and persistent in his teaching, always available in times of confusion or when in need of corrections and, mostly, enthusiastic about the scientific research.

Writing a thesis is to some extent a solipsistic process until it is finally unveiled and it comes under scrutiny of the jury’s expertise. I would like to thank prof.

Christoph Michel, prof. Stephan Kaiser, Dr. Radek Ptak and Dr. Lucas Spierer for taking over this crucial role.

This research would certainly not have been possible without the constant support, the commitment and the great friendship of Aurélie, who I warmly thank for it. Particular thanks also go to Adrian for sharing with me his expertise of the world of brain connectivity and Matlab, and for teaching it to me with the greatest patience and friendship. I gratefully thank all my colleagues and now friends, past and present, for their help, but most of all for their cheerfulness, the numerous hours of extreme sports at noon and the myriad of amazing moments I have shared with them.

A mention also goes to the neuropsychologists, the psychiatrists and other researchers who contributed to this work. A special thought goes for my participants, many of them my friends, who sacrificed their haircut for the sake of science.

Now, a thesis is not just the product of science.

I particularly thank my mother, Ariane, for being such an inspiration, and for relentlessly pushing me forward since the day I was born.

I profoundly thank Elena, my partner and my ally in most things in my life. I thank her for her joy through the best moments, for her support in harder times and for her love, always still.

At last, I wish to thank my father for encouraging me, my family members, and those who are, or were at a time, the closest during this PhD life.

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5 Abstract – english

The medial temporal lobe (MTL), and most particularly the hippocampus, holds a crucial role in the formation of new memories. Those memories are stored in the brain until they are remembered. Remembering invokes the hippocampus, which reinstates the initial memory trace. One thing that remains unclear is how the brain relates memories to the current moment and current behavior. It is suggested that a thought-filtering mechanism – called orbitofrontal reality filtering (ORFi) – separate from MTL memory functions, is enabling this perception of reality. Its failure induces reality confusion with confabulations and disorientation. It is observable from repeated runs of a continuous recognition task and is characterized in healthy subjects by an electrophysiological frontal potential at 200-300 ms originating from the orbitofrontal cortex (OFC). It is believed the OFC is filtering thoughts at the time they are being generated in the MTL through a hippocampal-orbitofrontal interaction.

Although there is an established electrophysiological marker for ORFi, there is no equivalent for MTL function. Conventional evoked potential studies may provide some insight about the underlying mechanism, but do not provide information on the neural interactions. In the studies described below, we systematically conducted a functional connectivity analysis.

In the first study (Thézé et al., 2016) we used a paradigm with visual stimuli presented twice, repeated either immediately after or following a delay of intervening stimuli. When delayed, stimuli are usually better memorized, although immediately repeated stimuli appear to trigger an electrophysiological event generated by the MTL (James et al., 2009). We could replicate this finding: we measured a positive evoked potential over frontal electrode at about 300 ms, generated by the MTL, on immediate picture repetition. Connectivity analysis further demonstrated that this potential was associated with an increase of theta-band coherence between 200-400 ms in the MTL. This increase was stronger in subjects with better memory performance after 30 min. We concluded this signal reflected a protective effect on the active memory trace.

In the second study (Thézé et al., 2017a) we combined the task from James et al.

(2009) and Thézé et al. (2016) with the original continuous recognition task testing ORFi (Schnider et al., 2002). Stimuli were again repeated twice, immediately or after a delay, in two consecutive runs. Subjects were instructed to indicate picture recurrence within an ongoing run only, which required the ability to sort out stimuli seen in the previous run that did not yet occur in the second run. It was found that the frontal potential evoked by immediately repeated stimuli, presumably reflecting encoding of the memory trace, sets in

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Raphaël Thézé Memory and Reality Filtering 19.09.2017

6 about 35 ms before the evoked potential reflecting ORFi, still both in the 200-300 ms time window. The former was associated with increased theta coherence in the MTL, similarly to Thézé et al. (2016), while the latter was associated to increased theta coherence in the OFC.

Both coherence increases were targeted at one another. We concluded that a complex interaction between the OFC and the MTL was involved in the processing of memory traces and how they pertain to the ongoing reality. As we also concluded, this interaction occurring at the time of encoding may provide an explanation for how we distinguish between memories of events that were experienced and events that were only imagined.

In the last study (Thézé et al., 2017b) we recorded a group of patients within the schizophrenic spectrum disorder with various degrees of psychosis. They were compared to a group of healthy controls while they performed the classical version of the ORFi task.

Psychosis is characterized with a difficulty in distinguishing what does not pertain to reality.

Here we explored whether the reality confusion in psychosis was also associated with disturbed ORFi. Patients, compared to controls, obtained similar performance in neuropsychological testing and performed equally well at the recognition task but displayed a significantly reduced, albeit present, frontal potential between 200-300 ms typical of ORFi.

The magnitude of this reduction was in fact predictive of the diagnosis, and was not merely due to medication. Functional connectivity analysis demonstrated that theta coherence increase from the OFC and the left HC observed in the control group was absent in the patient group. The magnitude of the coherence decrease correlated with scores of hallucination in left MTL regions but not the OFC. These findings indicate that in cognitively intact patients with schizophrenia spectrum disorder, ORFi is preserved but invokes different neural resources than in healthy subjects and is associated with abnormal cerebral connectivity.

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7 Abstract – français

Le lobe médio-temporal (MTL), et plus particulièrement l’hippocampe, tiennent un rôle crucial dans la création de nouveaux souvenirs. Ceux-ci sont alors entreposés dans le cerveau jusqu’à ce qu’ils soient évoqués. Se remémorer un souvenir active de nouveau l’hippocampe, ce qui restore la trace de mémoire initiale. Une chose cependant reste absconse : comment le cerveau rapporte-t-il les souvenirs avec l’instant présent et le comportement présent. Il est suggéré qu’un mécanisme de filtrage des pensées – appelé le filtre orbitofrontal de la réalité (ORFi) – indépendant des fonctions de mémoire du MTL, permet cette perception de la réalité. Un manquement de ce mécanisme produit une confusion de la réalité, avec des confabulations et une désorientation. On peut l’observer lors de la répétition de passages avec une tâche de reconnaissance continue, qui se caractérise chez les sujets sains par un potentiel electrophysiologique frontal à 200-300 ms qui est émis par le cortex orbitofrontal (OFC). Il est proposé que l’OFC filtre les pensées au moment où elles sont générées dans le MTL à travers une interaction hippocampo-orbitofrontal. Bien qu’il existe un marqueur électrophysiologique de l’ORFi, il n’en existe pas d’équivalent pour les fonctions du MTL. Les études traditionnelles de potentiels évoquées permettent d’envisager les mécanismes sous-jacents, mais ne permettent aucune interprétation quant aux interactions neurales. Dans les études présentées ci-dessous, une analyse de connectivité fonctionnelle a systématiquement été appliquée.

Dans la première étude (Thézé et al., 2016) nous avons utilisé un paradigme dans lequel des stimuli visuels sont présentés à deux reprises, soit immédiatement après la première présentation, soit après la présentation intermédiaire d’autres stimuli. Lorsqu’ils sont espacés, les stimuli sont généralement mieux mémorisés, bien que les stimuli immédiatement répétés déclenche une activation électrophysiologique dans le MTL (James et al., 2009). Nous avons pu répliquer ces résultats : un potentiel évoqué positif aux électrodes frontales à environ 300 ms, et généré par le MTL, lors des répétitions immédiates. Les analyses de connectivité ont par ailleurs démontré que ce potentiel était associé avec une augmentation de la cohérence dans la fréquence thêta dans le MTL entre 200 et 400 ms. Cette augmentation était plus prononcée chez les sujets faisant preuve d’une meilleure mémorisation après 30 minutes.

Nous avons conclu que ce signal reflète un effet protecteur sur l’activation de la trace de mémoire.

Dans la deuxième étude (Thézé et al., 2017a) nous avons combiné la tâche décrite par James et al (2009) avec la tâche de reconnaissance continue développée par Schnider et al.

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8 (2002) pour tester l’ORFi. Les stimuli étaient là encore répétés deux fois, immédiatement ou après un délai, lors de deux passages consécutifs. Les sujets étaient instruits d’indiquer la récurrence d’une image lors d’un même passage, les obligeant à identifier les stimuli aperçus lors du premier passage qui n’étaient pas encore apparus dans le second. Il a été démontré que le potentiel frontal évoqué par les stimuli immédiatement répétés, et supposé refléter l’encodage de la trace de mémoire, apparait environ 35 ms avant le potentiel évoqué reflétant ORFi, tous deux dans la période de 200 à 300 ms. Le premier a été associé à une augmentation de cohérence thêta dans le MTL, semblable à Thézé et al. (2016) alors que le second a été associé à une augmentation de la cohérence thêta dans l’OFC. Les deux augmentations de cohérences étaient dirigées l’une vers l’autre. Nous avons conclu qu’une interaction complexe entre l’OFC et le MTL étaient impliquée dans le traitement des traces de mémoires en rapport avec la réalité en cours. De plus, nous avons conclu que cette interaction au moment de l’encodage de la trace pourrait expliquer comment nous différencions le souvenir de ce qui a été vécu avec le souvenir de ce qui a été seulement imaginé.

Dans la dernière étude (Thézé et al., 2017b) nous avons enregistré un groupe de patients dans le spectre des troubles de la schizophrénie présentant divers degrés de psychose.

Nous les avons comparés à un groupe de sujets sains contrôles alors qu’ils participaient à une version classique de la tâche de l’ORFi. La psychose est caractérisée avec une difficulté à distinguer ce qui n’appartient pas à la réalité. Nous avons exploré si la confusion de réalité dans la psychose était aussi associée avec une perturbation de l’ORFi. Les patients, comparés aux contrôles, ont performé de manière similaire lors des évaluations neuropsychologiques ainsi que lors de la tâche de reconnaissance continue, malgré la présence réduite du potentiel frontal évoqué entre 200 et 300 ms qui est caractéristique de l’ORFi. La magnitude de cette réduction était prédictive du diagnostic, et par conséquent n’était pas le résultat d’une prise de médicaments. Les analyses de connectivité fonctionnelle ont démontré que la cohérence thêta, augmentée entre l’OFC et l’hippocampe gauche chez les contrôles, était absente dans le groupe de patients. L’amplitude de cette cohérence corrélait avec les scores d’hallucination dans les régions MTL gauche, mais pas l’OFC. Ces résultats indiquent que les patients avec des troubles du spectre de la schizophrénie mais cognitivement préservés démontrent un ORFi fonctionnel, bien qu’ils semblent recruter des ressources neurales différentes des sujets contrôles afin de compenser une connectivité fonctionnelle anormale.

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9 List of abbreviations

In order of appearance

HC Hippocampus

MTL Medial temporal lobe

EC Entorhinal cortex

OFC Orbitofrontal cortex

fMRI Functional magnetic resonance imaging ORFi Orbitofrontal reality filtering

ms Milliseconds

EEG Electroencephalography WWM Working with memory MMN Mismatch negativity ERP Event-related potential ACC Anterior cingluate cortex LHC Left hippocampus

LFG Left fusiform gyrus

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11 Table of content

Acknowledgment 3

Abstract 5

Abbreviations 9

I. Introduction 13

1.1. Learning and Memory 14

1.1.1. Memory Systems 14

1.1.2. Anatomy of Memory 16

1.1.3. Memory consolidation 17

1.1.4. Spacing Effect 19

1.1.5. False Memories 19

1.1.6. Research Question 20

1.2. Reality Confusion and Reality Filtering 20

1.2.1. Confabulations 21

1.2.2. Orbitofrontal Reality Filtering 22

1.2.2.1. Task 22

1.2.2.2. Electrophysiological and anatomical correlates 23

1.2.3. Orbitofrontal Cortex 24

1.2.3.1. Anatomy 24

1.2.3.2. Functions 25

1.2.4. Model of ORFi 26

1.2.5. Other Theories 27

1.3. Schizophrenia and Reality Confusion 30

1.3.1. Hallucinations and confabulations 30

1.3.2. Anatomy of Schizophrenia 32

1.3.2.1. Electrophysiology 32

1.3.2.2. Structural Anatomy 33

1.3.2.3.Functional Anatomy 34

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12

II. Methodology 37

III. Studies from the thesis 41

3.1. Rapid Memory Stabilization by Transient Theta Coherence in the 41 Human Medial Temporal Lobe

3.2. Simultaneous Reality Filtering and Encoding of Thoughts: The Substrate 42 for Distinguishing between Memories of Real Events and Imaginations?

3.3. Neural Correlates of Reality Filtering is Schizophrenia Spectrum 43 Disorder

IV. Discussion 45

4.1. Encoding of the memory trace 45

4.2. Memory encoding and orbitofrontal reality filtering 48 4.3. Orbitofrontal reality filtering and schizophrenia spectrum disorder 51

V. Conclusion 57

5.1. Perspectives and limitations 58

VI. References 61

VII. Articles 85

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Chapter One Introduction

Like the steps one leaves in the sand, a memory is the reminiscence of our passage through time. From a cognitive perspective, it is the ability to use or revive information that was previously encoded or processed. Most of the time, we are not aware of its influence because it is never directly observed. Its existence is thus inferred from certain behaviors (e.g., a certain change in level of performance).

Memory can be characterized with three main features (Squire, 1986). First, it is not a static process, but instead it is highly dynamic and subject to constant changes. Second, memory is not a unitary process and there is no such thing as one memory area with all the memories catalogued like books on shelves. A given memory is distributed across specialized brain areas processing very specific types of knowledge and integrating information into higher order cognitive functions. Finally, memory implies a temporal component, meaning we remember things over time. The Canadian researcher Tulving referred to it as mental time travel (Tulving, 1985b), implying that the act of remembering something from the past is experiencing that past all over again in the present.

Because of the temporal dimension we live in, we differentiate a memory, which is the representation of past events, from perception, representing the present, or imagination of a future event. The three percepts however are believed to share the same fundamental mechanisms (Schacter et al., 2012), which raises a major question. Indeed, imagination is an object of memory, which itself is a present perception of the past. Then, how can we relate back to a memory and not experience it as our current perception? Aristotle (Ross, 1906) already began to answer the question by suggesting that when a perception is turned into a memory, it is then regarded by the soul as a copy of that perception. Remembering is thus reenacting a perception we had, but knowing it is only a copy of it. If that failed, we would perceive our memories as a real perception instead, such as the unfortunate Antipheron of Oreus¹, as reported by Aristotle, who took “what is not a representation as though it were one […] and said to remember the occurrence”.

1 Besides its mentioning by Aristotle in De Memoria, there is no record of this Antipheron. Oreus however is located on the island of Euboia (Bloch, 2007)

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14 Let’s take a more pragmatic example. Every morning you go to work driving a car that you will park somewhere in the vicinity of your work. When you do, you will form a memory of that location which you will store in your mind and will eventually retrieve later when you go back to it. Over the course of the week, chances are you will not use the same parking spot every day. You will then be faced with multiple memories relating to that information, and it raises the question: how could you know which one relates to today’s experience? This is very similar to questioning how can we differentiate a perception from hallucination. The answer a priori is you can’t, because you may believe very strongly something is real if that is how it is represented in your mind, and that would be subjectively as real as anything else. Hence, how is the brain dealing between memory and reality?

1.1. Learning and Memory

Before understanding how a memory relates to the present moment, it is crucial to understand what memory is and what are its building blocks: encoding, maintenance and retrieval. Once our eyes fall upon an unknown item for the very first time, it triggers a cascade of events leading to the memorization of the information regarding this item. This process involves an encoding phase upon which memories undergo consolidation, that is, they stabilize over time (Battaglia et al., 2011). Memories will remain encoded and unaltered in a complex network of neural connections distributed across specialized areas of the brain (Squire, 1986). Eventually the distributed neocortical regions that were collectively engaged at the time of encoding will be reactivated and coordinated (Mishkin, 1982; Squire, 1987;

Damasio, 1989; Kahn et al., 2004; Wheeler et al., 2006) to reconstruct in a thought the components of the initial perception (Squire and Kandel, 2000).

1.1.1. Memory systems

The Atkinson-Shiffrin model of memory (1968) originally proposed three main components of memory (figure 1), each reflecting different purposes, mechanisms and structures. Although it’s been much criticized and reviewed since then, it laid the building blocks of our understanding of memory. The first type of memory is the sensory information being stored. The second category, called short-term memory, is associated with retention over seconds to minutes. It is today still debated whether it should be dissociated from working memory (Cowan, 2008), which also illustrates a short-term memory storage but in a

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15 very limited capacity store for performing mental operations on its content. This content can either originate from sensory inputs or could be retrieved from long-term memory. For this reason, it’s been suggested to be a multi-component process embracing both short and long- term memory (Ericsson and Kintsch, 1995). The latter, long-term memory, is measured in days or years and is further divided into two categories, declarative and non-declarative.

Declarative memory refers to knowledge we can access consciously, including personal experiences and world general knowledge, while its counterpart is knowledge without conscious access, such as motor or cognitive skills (Squire, 1992).

Tulving (1972) proposed a two-part separation of declarative memory (figure 1):

episodic memory, the memory of personal events in our lives that were generally personally experienced (i.e. last winter I went to Montreal) and semantic memory, which is factual knowledge about facts of the world in general (i.e. Montreal is a city of Canada). Episodic memories are characterized with a spatio-temporal signature; they contain knowledge about the context, place and time in which the memory occurred. Semantic knowledge does not contain information about the episode in which it was acquired.

Once a memory has been acquired it must be retrieved to serve its purpose. This can happen spontaneously (i.e. we just think of something) or upon a stimulus (i.e. something we perceive activates the memory). The latter is recognition memory and consists of two mechanisms. The first, familiarity, is considered to be context free and the item recognized just feels familiar based on the memory strength (Mandler, 1980). The second, recollection, is context dependent (i.e. when and where) and involves remembering qualitative information (Baddeley, 1982). Tulving (1985a) later turned subjective recognition into the main tool of

Figure 1. Schematic organization of memory components after Atkinson-Shiffrin’s (1968) and Tulving’s (1972) models.

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16 memory research with the remember/know procedure. Participants are asked to decide if a given item was previously seen, and if so if they could recollect it occurring or if they just had a feeling that it did (Yonelinas and Jacoby, 1995).

1.1.2. Anatomy of memory

Our society stresses the importance of having a “good memory”, although its absence is as much important. Memory deficits are referred to as amnesia and often result from traumas, brain lesions or degeneration. It may involve the inability to learn new things (i.e.

encoding) or the loss of previous memories (i.e. maintenance) and it can affect any type of memory previously described. In counterpart, the study of these deficits has permitted to measure an intangible phenomenon and, mainly, to map an anatomy of memory.

The most famous case in the literature of memory is without doubt the one of Henry Molaison (Corkin, 2002), known as H.M. In 1953, he underwent bilateral resection of the medial temporal lobes, originally to treat his epilepsy, and as a result developed an amnesia so severe that he remained oblivious to anything that occurred after that day or during the months preceding the surgery itself (Scoville and Milner, 1957). He was unfortunate to lose the capacity to make a new memory for the entirety of his life, but he provided the most significant insight in the field of memory, the crucial role of the medial temporal lobe, and notably the hippocampus (HC), to rapidly encode new information (Davachi, 2006).

The medial temporal lobe (MTL) memory system includes the amygdala, the HC, and the surrounding entorhinal (EC), perirhinal and parahippocampus cortices (Squire and Zola- Morgan, 1991). According to Scoville and Milner (1957), H.M. had bilateral HC removal. As it was later demonstrated with post-mortem examination (Annese et al., 2014), the anterior part of the hippocampi was removed, but most of the EC and parts of the amygdala were also resected, with small lesions to the left prefrontal cortex, due to surgical procedures.

The HC became one of the most intensively studied structures in humans but also monkeys and rats and is now anatomically precisely described (Insausti et al., 1987; Suzuki and Amaral, 1994; Burwell et al., 1995; Lavenex and Amaral, 2000). The HC consists of four cornu ammonis fields, the dentate gyrus and the subicular complex. It is at the core of a highly hierarchical processing, with the particularity of forming a loop on itself. The entorhinal cortex is its principal gateway, receiving most of the input aimed at the HC from multiple cortical areas – such as the orbitofrontal cortex (OFC), nucleus accumbens, cingulate cortex or visual cortex – as well as perirhinal and parahippocampal cortices and projecting back to

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17 them (Squire et al., 2004). Accordingly, H.M. memory impairment could be attributed to the EC removal as much, if not more, as the hippocampal ablation (Annese et al., 2014).

Bilateral damage to HC causes dense anterograde and, regarding certain aspects, temporally graded retrograde amnesia (Nadel and Moscovitch, 1997). It is involved in many aspects of explicit memory (predominantly spatial, contextual, episodic) (Squire et al., 2004), but it is generally understood as a region that allows binding contextual features of events to create unitary representation of experiences (Baddeley, 2010). Typically recollection will be relying on the HC while familiarity on the perirhinal cortex (Ranganath et al., 2004; Bowles et al., 2007). Recollection may also require the frontal cortex (Squire et al., 2004). A patient known as R.B. had restricted lesion to the first cornu ammonis field (CA1) of the HC and developed pure anterograde amnesia with little retrograde amnesia over 1-2 years (Zola- Morgan et al., 1986). This kind of observation supports the theory that HC is critical for encoding new memories but is not involved in their long-term storage, since older memories were intact. The presence of some retrograde amnesia (i.e. 1-2 years) however is also suggesting a role of the HC in the storage or access of recent memories. Lesions to the rest of the MTL are associated to retrograde amnesia covering more years in the past (Frankland and Bontempi, 2005).

Wernicke-Korsakoff patients have similar amnesia problems, due to alcohol consumption, but without damage to the medial temporal lobes. Alcohol consumption in this case leads to a deficiency in thiamine (i.e. vitamin B1), which in turn destroys the diencephalic structures (mammillary bodies and fornix mostly), and all the connections to cortical structures such as frontal and temporal lobes (Kopelman et al., 2009). Those observations have strong implications on understanding memory function, and it implies that monitoring of the memory trace is just as critical as encoding or storage. Indeed, Nahum et al.

(2015b) could demonstrate with 4 Wernicke-Korsakoff patients performing a simple continuous recognition task that, as opposed to healthy control and non-amnesic alcoholic patients, they would lack electrophysiological activity emanating from the medial-temporal.

Their findings were associated with bilateral damage of the fornix, which is a major output of the HC to the mammillary bodies and indirectly to the frontal cortex.

1.1.3. Memory consolidation

Following the encoding of information, memory must be consolidated. Consolidation is a process where long-term memory is being stabilized over time for permanent storage

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18 (Nadel and Moscovitch, 1997). All theories of consolidation agree that information is integrated into mind through the action of the MTL and encoded into a memory trace in the form of hippocampal-neocortical connections (Moscovitch et al., 2006). What happens on the long term with the memory trace for the permanent storage is open to debate.

The standard consolidation model postulates that episodic and semantic memories depend on the engagement of the HC for a rapid initial encoding of information (i.e. within minutes to hours). In parallel, or as a consequence, a slower consolidation also occurs in the neocortex (i.e. weeks) upon which the memory trace is permanently stored and completely independent from HC activation (Dudai, 2004). It is mostly based on the observation of temporally graded retrograde amnesia following bilateral medial temporal lobe damage, which is sparing remote memories but not the recent ones (Squire and Alvarez, 1995). At the time of encoding, the various elements of the memory are encoded in the neocortex into separate ensembles depending on their modality (vision, smell, etc.). Because items recently memorized are more fragile, consolidation has two components: slow and fast (Dudai, 2004).

Otherwise, rapid alterations in the neural connections would dramatically affect the memories as they are encoded, creating an interference. Instead the HC is storing the memory traces in parallel. The HC is initially storing the memory by binding this representation together and physically linking the information (i.e. synaptic connections). This rapid learning provided by the HC is critical for later, slower, permanent learning. Over time, the memory in its whole is transferred permanently to the neocortex where the different elements are connected together, and becomes independent of the HC, which is the process of consolidation (Squire and Alvarez, 1995).

Nadel and Moscovitch (1997) however have suggested that following consolidation remote semantic memory will rely on the neocortical connections independently from the HC, whereas aspects of episodic memory will continue to be dependent on the HC. They developed an approach called the Multiple Trace Theory. It is based on the observation that retrieval of vivid remote episodic memories elicits HC activation with the same intensity as more recent memories. Each time an episodic memory is retrieved it is re-encoded within the HC, which forms multiple memory traces that are more widely distributed than recent ones.

Memories that retain vivid details about a given experience will always rely on the HC while blurry and distant memories have become generic and now are only mediating through the neocortex.

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19 1.1.4. Spacing Effect

Information can be retained after one occurrence, but usually repetition improves retention (Bjork, 1970). This is because the memory trace is consolidated all over again.

Repetition can be massed in a short period of time, or delayed over a larger period.

Interestingly, information repeated apart in time, with interfering items between, is usually better memorized than information acquired with immediate repetitions. This phenomenon is called Spacing Effect. It represents one of the most ancient and robust memory phenomenon behaviourally observed and was first identified by Herman Ebbinghaus (1885). The spacing effect, illustrating a “better” encoding, is a well-established phenomenon, although the underlying mechanisms remain poorly understood. Among various theoretical constructs proposed, two main hypotheses emerge. The first possibility is that immediate repetition keeps the memory trace active into working memory. Hence the memory trace is consolidated only once, which decreases the efficiency of processing during retrieval (Challis, 1993; Braun and Rubin, 1998; Davachi et al., 2001). The other possibility is based on the idea that delayed repetition would be more advantageous because it allows for more association to be made at the time of encoding (i.e. more potential cues for retrieval), thus facilitating the retrieval of the memory trace when needed (Melton, 1967; Landauer, 1969; Glenberg, 1979). In any case the mechanism underlying the spacing effect is a process of encoding, one that could provide a significant insight into the memory processes if it could be measured.

1.1.5. False Memories

It is intuitive to think of memory impairment (i.e. not remembering) as a problem of forming a memory or maintaining it, but remembering something that never occurred is a different story. A memory that is partly or completely inaccurate but considered as real by the person in cause is something we refer to as false memories (Roediger and McDermott, 1995).

The memory illusion can be very powerful and the subject convinced of having experienced it. Cabeza et al. (2001) investigated with functional magnetic resonance imaging (fMRI) participants’ activity in response to items never seen before, truly repeated items from the initial list and false items that only resemble the initial list, and found dissociation. The HC was equally activated suggesting semantic processing, while the parahippocampal cortex was more activated for true items, suggesting a retrieval of the perceptual information.

Interestingly, the dorsolateral prefrontal cortex was equally activated for both true and false

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20 items, suggesting a monitoring of information retrieval, whereas the OFC was more activated by false items, suggesting a verification process. Indeed, regions of the prefrontal cortex are known to provoke higher levels of false recognition and confabulations, but not necessarily amnesia (Curran et al., 1997; Schnider, 2008). One potential explanation relates to the perceptual nature of the memory trace. False memories occur because the features of the false item reactivate the features from the true memories (Schacter and Slotnick, 2004). Fabiani et al. (2000), for instance, identified different sensory related signatures in the electrical activity evoked in response to true or false items. This in turn might induce a failure in the process of verification of the memory.

1.1.6. Research question

Although the role of the HC in memory encoding and storage is now widely studied and its mechanism extensively debated, one thing that remains unclear is how the brain distinguishes between memories. Indeed, upon its creation a memory trace only contains information that relate to that moment. Upon reactivation of the trace how could the brain possibly know how the memory relates to the current moment? If the content from memories, perception, or even imagination, is mostly assembled into a coherent trace and orchestrated by the HC, there must be a separate filtering process relating that trace to current perception. The problem is that there is no consensus for a marker of the memory trace so early in the consolidation process and without a marker it is challenging to identify a mechanism modulating the memory content. Thus we ask the question: can we isolate a surrogate marker, both neurally measurable and behaviorally relevant, of the early consolidation process?

1.2. Reality confusion and reality filtering

Reality confusion is a state a patient may find himself mostly in the early stage after brain damage. It is characterized by disorientation of the patient regarding the current time, the place they are in or why they would be there (Schnider et al., 1996b). These patients display signs of amnesia, although it does not suffice to account for their disorientation, nor the fact that patients with normal memory storage can be disoriented nonetheless (Schnider et al., 1996b). Another crucial feature of reality confusion is confabulation, which is “the evocation of memories of events that never took place” (Wernicke, 1900).

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21 1.2.1. Confabulations

The term of confabulation was first coined by Wernicke (1900). It was later used to describe any form of false statement, whether it is related to memory or not. The most common form is momentary confabulation, which occurs during a discussion or upon inquiry.

There is possibly no single underlying mechanism, and thus there is no defined anatomical basis, although those confabulations are more frequent with more anterior brain lesions (Schnider, 2008).

Behaviorally spontaneous confabulations are a subcategory of confabulations where the patients will confabulate about ancient habits or memories and will act upon them as if it was in phase with their current reality (Schnider and Ptak, 1999). Strikingly this has also been observed with the memory of imagined events. A patient suffering from reality confusion was asked to provide details about a personal event depicted on a photograph. Few minutes after, she recounted the discussed event as having just happened on the same day (Schnider et al., 2005a; Schnider, 2008).

Acute confusional states may induce more fantastic confabulations. They involve wild and implausible stories with no root to common notions of reality (i.e. thinking of oneself as God). This form of confabulation was mostly described in severe psychosis (Kraepelin, 1886, 1887; Berlyne, 1972) and some cases of acute brain lesions (Damasio et al., 1985; Nahum et al., 2012).

From an anatomical perspective, behaviorally spontaneous confabulations have been consistently reported in patients with focal brain lesions to the posterior medial OFC (see figure 2.), or any directly connected structure, posing this region as a likely candidate for

Figure 2. Lesions overlap of reality confusing patients. Classic amnesic patients have lesions in MTL but not OFC. Spontaneous confabulators’ lesions overlap in anterior limbic areas, particularly the OFC. Adapted from Schnider et al. (2003).

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22 explaining the mechanisms of reality confusion (Schnider et al., 1996c; Ptak and Schnider, 1999). Fantastic confabulations however are habitually described in the context of dementia or psychosis, and present no reliable basis for an anatomical correlate (Schnider, 2008).

1.2.2. Orbitofrontal Reality Filtering

The Orbitofrontal Reality Filtering (ORFi) hypothesis developed by Schnider (2003, 2008), accounts for behaviorally spontaneous confabulations and disorientation observed in reality-confusing patients. These patients seemingly fail to give a sense of “now” to their memories, incorrectly placing them in time and space, and persisting on ideas not referring to the present (Schnider, 2013). ORFi is a mechanism selecting between memories pertaining to the present moment and memories that do not, which explains how we adapt thoughts to the current reality. Its rationale is based on the clinical observation of confabulating patients and multiple neuro-imaging studies with healthy controls (Schnider et al., 1996c; Ptak and Schnider, 1999; Schnider and Ptak, 1999; Nahum et al., 2012; Bouzerda-Wahlen et al., 2015;

Liverani et al., 2016).

1.2.2.1. Task

Schnider (1996c) developed a task specifically designed to isolate memories in relation to the “now” from other memories that is very efficient to distinguish reality confusing patients from amnesic patients. This task (figure 3) is composed of repeated runs of a continuous recognition task in which subjects are asked to indicate if, within the ongoing run only, pictures are occurring for the first time (i.e. distracter) or are being repeated (i.e.

target). All runs are composed of the same set of pictures but rearranged in a different order.

Pictures are therefore repeated within a run and across the runs.

Figure 3. Continuous Recognition Task. Items are presented in two runs (Run 1 and Run 2). Subjects indicate picture recurrence within a run. Distracters (D1 and D2) are the items appearing for the first time within a run, and targets (T1 and T2) are repeating themselves within the run. Adapted from Schnider (2008).

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23 In the first run, all pictures are completely new. The task only requires learning and, upon picture re-occurrence, recognition on the basis of familiarity alone (Schnider, 2003).

This run is purely reflective of memory encoding.

In the following runs, all the pictures have already been presented and thus are familiar. The task now requires the ability to distinguish the familiarity of a picture seen within the ongoing run from the familiarity of picture having occurred in the previous runs.

Subjects are required to indicate whether a picture is occurring for the first time within the run and to disregard any memories from the previous runs. That capacity – ORFi – lies in the correct handling of the memory trace of the picture at the time it first appears in this run (Schnider, 2008). Typically, healthy subjects will easily succeed in this task while behaviorally spontaneous confabulators will perform with an elevated number of false positive responses; they will confuse pictures occurring for the first time within a run with pictures seen from the previous runs (Schnider and Ptak, 1999).

1.2.2.2. Electrophysiological and anatomical correlates

Using an adapted version of the previously described task, Schnider (2002) described a precise electrophysiological mechanism associated to ORFi. Healthy subjects performed two successive runs while being recorded with electroencephalography (figure 4). Simple picture repetition in the first run induced a posterior positivity between 400-600 ms that was not present for first appearances, indicating the recognition of old pictures in opposition to new pictures not yet encoded. More strikingly, stimulus processing induced a negative potential over frontal electrodes at 200-300 ms in response to most items, except for those first appearing within the second run (i.e. stimuli confabulating patients had failed on; see D2 in figure 3). The stimuli induced a relative frontal positivity (red circle, figure 4). This evoked potential was highly specific to items evaluated as not belonging to the ongoing run and thus was interpreted as a surrogate marker of ORFi.

This signature of ORFi was further supported with topographic cluster analyses. This method identifies periods of stable electrical patterns across all electrodes, something illustrating a specific cognitive process. It was found that distracters of the second run in fact induced the disappearance of an electrical configuration that was present in all other conditions (Michel et al., 2004; Murray et al., 2008). Source localization showed that this suppression corresponded to an absence of synchronized activity in the association cortex

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24 between 220-300 ms that was present with all other stimuli (Schnider, 2003). Those results were later replicated in a different set of subjects (Wahlen et al., 2011).

Performance of a similar task induces activation of orbitofrontal area 13 in healthy subjects as it was demonstrated with positron emission tomography using radio-labeled water (Schnider et al., 2000). First run picture presentation, when there is only learning and recognition, induced activation of medio-temporal areas. OFC activation while performing the second and later runs was further confirmed in later positron emission tomography studies illustrating its ties with the reward system (Treyer et al., 2003) and with meaningful sounds (Treyer et al., 2006). Electroencephalography (EEG) source localization analyses also completed the set of evidences by associating the ORFi marker to stronger OFC activation at 250 ms (Manuel et al., 2014; Bouzerda-Wahlen et al., 2015).

Altogether those results indicate that orbitofrontally evoked potential in response to distracters of the second run is a reliable marker of an early, transient, mechanism at 200-300 ms underlying reality filtering.

1.2.3. Orbitofrontal cortex

Lesions to the aforementioned OFC, jointly with neuroimaging evidence (cf. 1.2.2.), are strong indicators of the crucial role this region plays in reality perception. Since the OFC is likely responsible for keeping thoughts in phase with reality we will review the main features of the OFC, anatomically and functionally.

1.2.3.1. Anatomy

From an evolutionary perspective the OFC is old and both the human and the macaque OFC have been subdivided into comparable areas (Petrides and Pandya, 2002).

Figure 4. Evoked potentials from Schnider et al. (2002) in responses to the stimuli described in Fig 3. The early potential of ORFi is indicated with a circle.

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25 The OFC lies in the ventral part of the frontal cortex and often includes the ventral medial prefrontal cortex, an area that is imprecisely defined in the literature. Brodmann (1909), assigned a unique identification number to almost all areas of the brain based on its cytoarchitectonic properties, but the ventral medial prefrontal cortex was left out with many inconsistencies. Brodmann described it as more homogeneous than it is in fact (Nieuwenhuis and Takashima, 2011). The regions presenting an interest to this thesis are defined as Brodmann’s areas 10, 11, 13, 14, and area 47/12 and will be referred as the OFC (Öngür et al., 2003).

OFC connectivity studies suggest that it acts as a convergence zone with a majority of cortico-cortical connections that are reciprocal (Cavada et al., 2000). OFC is the prefrontal structure with the most connections with the medial temporal lobes, including HC, EC and perirhinal cortex, and parahippocampal region (Aggleton and Mishkin, 1983; Zola-Morgan et al., 1986; Markowitsch, 1988; Graff-Radford et al., 1990; Barbas and Blatt, 1995; Parker et al., 1998; Thierry et al., 2000). It also displays a remarkable connectivity to sensory cortices (Rolls, 2000), and other memory related regions (Markowitsch, 1995). Extensive contralateral connections also suggest it may participate in interhemispheric integration on a broad scale (Carmichael and Price, 1995; Cavada et al., 2000).

1.2.3.2. Functions

From its position and connections with structures significant to memory function the OFC has often been seen as the switchman playing a pivotal link in the recollection of the neural networks involved in learning and memory (Cavada et al., 2000; Brincat and Miller, 2015).

Indeed, the OFC receives direct inputs from the HC (Swanson, 1981; Ferino et al., 1987; Thierry et al., 2000), whereas the connections between the HC and most of the neocortex are indirect, further suggesting a role in filtering information from the memory system. This idea was confirmed with rats whose prefrontal cortices were damaged and could no longer switch between familiar tasks despite evident cues. They could not select between conflicting information upon retrieval of related but competing memories (Rich and Shapiro, 2007).

Another particularity of the OFC is the high level of dopaminergic innervation compared to other areas, mostly originating in ventral tegmental area and likely modulating the OFC (Laroche et al., 2000). Neuroimaging studies suggested that, among other roles, the

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26 OFC is involved in optimizing behavior and makes decisions based on the anticipated and obtained value of rewards (Kringelbach, 2005; Schoenbaum et al., 2009; Nahum et al., 2011a). A subpopulation of cells, particularly relevant to this thesis, was indeed found in monkeys to be firing exclusively upon deviation from expectancy of reward (Rosenkilde et al., 1981). In other words, they signal the absence of an expected outcome. Human studies also demonstrated activation of the OFC in response to the absence of anticipated events (Schnider et al., 2005b; Nahum et al., 2011a). Thereby, the OFC appears to encode the type and the expected value of a reward, as suggested by the sustained activation of rats and monkeys OFC neurons preceding a rewarding outcome (Schoenbaum et al., 1998; Wallis and Miller, 2003; Schultz and Tremblay, 2006).

OFC is likely integrating value information from the limbic system with the memory trace from the HC. Memories retrieved from the HC are then evaluated against limbic representations and suppressed in the case of inappropriate activity (Koechlin, 2016). Thus the OFC may control, in an inhibitory manner, activity that would otherwise be irrelevant to the current situation.

1.2.4. Model of ORFi

Overall the OFC plays a critical role in handling stimulus value but also stimuli that deviate from expectation, which is the corner stone for a reality checking mechanism. Clinical observations of reality-confusing patients indicate a failure to integrate the absence, even repeated, of an expected event. This failure is referred to as a deficit of extinction. This capacity, initially defined by Pavlov (1927) toward expected rewards, is considered to be the mechanism behind the ability to keep thoughts and behavior in phase with reality (Nahum et al., 2011a; Schnider et al., 2017).

Simply described in most models as a mismatch between what is expected and what happened, the extinction capacity refers to a learning signal updating mental representations between behavior and outcomes. The absence of an anticipated outcome is signaling that previously associated information is no longer valid. The ability to adapt behavior to an alternative outcome and abandon previously valid anticipations corresponds to extinction capacity (Nahum et al., 2009).

Accordingly, Schnider (2007) and Nahum (2011a) tested the hypothesis that the extinction capacity could be the underlying mechanism of ORFi. With electroencephalography on healthy controls performing a reversal learning task, they

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27 demonstrated that the extinction of a learned association induced a frontal positivity at 200- 300 ms, similar to ORFi. These results were further confirmed with an fMRI study showing activation of the OFC upon extinction trial in the same task (Nahum et al., 2011c). Clinically, behaviorally spontaneous confabulators demonstrated higher error rates following extinction in a simple association learning task.

As it was previously described the OFC encodes for the reward value of an outcome similarly to the dopaminergic system (cf. 1.2.3.2.), a structure particularly relevant to ORFi function of thoughts-checking (Schnider et al., 2000). Hence it was hypothesized that dopamine could modulate ORFi. When healthy subjects were under L-DOPA², they had higher false positive rates compared to risperidone, a dopamine antagonist (Schnider et al., 2010). There is also a reported case of a confabulating patient, whose reality confusion (confabulation and disorientation) improved under treatment with risperidone (Pihan et al., 2004). The extinction capacity of the OFC is thus likely mediated by the dopaminergic reward system (Schultz et al., 1997; Schnider et al., 2010).

1.2.5. Other theories

Multiple theories have tried to come up with an explanation to confabulations, but few authors have been able to provide experimental data to support their ideas. None of them, however, specifically referred to the reality confusion characteristic of behaviorally spontaneous confabulation but rather attempted to cover all forms of confabulation. Gap- filling was repeatedly suggested as an intuitive explanation but it was easily dismissed by the fact that spontaneous confabulators do not have a lack of memory trace, but rather a confusion of traces (Schnider et al., 1996c), which better explains momentary confabulations. Other theories tried to account a memory monitoring mechanisms but, despite vivid debates, they remain quite remote and independent from the ORFi hypothesis.

Moscovitch (1992) developed a model for the prefrontal cortex’s role in memory retrieval they coined Working With Memory (WMM). The founding argument to this theory is the difference between prefrontal cortex and MTL role in memory processes, the latter causing profound anterograde amnesia following lesions and the former causing memory impairments only when recollection is self-initiated (i.e. no trigger) (Moscovitch and Winocur, 2002). The framework of WWM places the MTL structures – with the hippocampus

2 L-DOPA is an amino acid precursor to dopamine synthesis. It has the particularity to be able to cross the blood-brain barrier, something dopamine cannot do, which is practical for medical treatment.

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28 – in charge of randomly encoding information, while the prefrontal cortex is a central system required for strategically searching and selecting the stored memories, thus conferring a context and logic to disparate memories. Confabulations are described as impairment in memory retrieval arising when the wrong memory is activated and is not appropriately monitored as such.

WWM was tested with amnesic patients who had to describe, in response to cue- words, personal (episodic) or historical (semantic) events (Moscovitch and Melo, 1997). They found that patients with presumed ventromedial frontal cortex lesions were in fact confabulating to these cue, regardless of the episodic or semantic content. Results are however more relevant to momentary confabulations, since those confabulations were prompted with inciting questions. Moreover, the “confabulating” patients were also lesioned in the temporal lobes and displayed strong deficits on other executive and memory tasks.

Nevertheless, it was suggested by Gilboa (2006) that ORFi could not account solely for confabulation and was arguably a subcomponent of WWM. To support their claim they advanced that confabulating patients not only failed at the continuous recognition task described previously but also when repeated items were either truly repeated or only resembling the previous ones. Using a face recognition task, they similarly found an electrophysiological frontal positivity at 230-260 ms that was absent in a group of patients with ventromedial lesions (Gilboa et al., 2009) further suggesting that both mechanisms could have the same basic process. This study however did not include any active confabulators and electrophysiological deficits were not specific for false positives. Recently the two paradigms were directly compared in two studies with the same recognition task (Wahlen et al., 2011;

Bouzerda-Wahlen et al., 2013). The two processes were found to dissociate electrophysiologically in healthy subjects between 200-300 ms, as well as behaviorally with reality confusing patient as opposed to non-confabulating amnesic patients. This result underscores that ORFi is a distinct memory mechanism and not a subcomponent of WWM.

The third major model accounting for confabulations is called the Source Monitoring Framework (Johnson et al., 1993) and is built on the distinction between memories of things that were experienced as opposed to things that were only imagined. It relies on any feature associated to the time of encoding – being spatial, social or emotional – all tied together in memory and upon which it can provide a context to the origin of the memory when it is reactivated.

The model was tested electrophysiologically with healthy controls (Johnson et al., 1997a) whom were asked to indicate item recurrence during a recognition task (old or new)

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29 but also the context of the item presented (if it was a word or a picture). Dissociation was found over frontal electrodes, but after 1400 ms. The only clinical study (Johnson et al., 1997b) assessing the model was performed on a single confabulating patient whose performance did not differ from non-confabulating frontally lesioned control patients.

Moreover, when directly compared in a unique paradigm (Bouzerda-Wahlen et al., 2015), ORFi and context source monitoring dissociated in terms of behavior – context retrieval induced slower reaction times and higher error rates – and in terms of electrophysiology.

Indeed, while ORFi was characterized with an early 200-300 ms frontal deflection, source monitoring was characterized by a later frontal positivity after 400 ms (Bouzerda-Wahlen et al., 2015), suggesting a different process.

In contrast to ORFi, which relates to present reality, Source Monitoring is a retrospective process only reflecting on a memory trace that was previously encoded (Johnson and Raye, 1981; Johnson et al., 1993; Mitchell and Johnson, 2009). In daily situations it is not always plausibility, based on the complexity of features accompanying a memory trace, we use for knowing whether we have imagined or experienced an event. A more viable explanation would be that this knowledge is established as we experience a situation. Indeed, multiple studies pointed to the importance of activity at encoding for later monitoring (Davachi et al., 2003; Gonsalves et al., 2004; Kensinger and Schacter, 2005; Sugimori et al., 2014).

1.2.6. Research question

The prefrontal cortex, and more specifically the OFC, is likely playing the switchman in organizing and controlling memories rather than storing them. The OFC, for instance, has strong connections to the MTL. Lesions of the OFC do not create memory loss but dysfunction in memory control, such as confabulation. Although ORFi is the more viable candidate for explaining how a memory, or more generally a thought, may relate to current perception, it is still unclear how it interacts with the memory trace. Memories that deviate from the expected outcome (the current perception) have two possible fates. They can be suppressed early in the HC, meaning they are inhibited, or they can be suppressed in the OFC, meaning they are filtered out (Nieuwenhuis and Takashima, 2011). This however remains unexplored. We can only make the hypothesis that at the time of encoding the trace handled by the HC is also modulated by the OFC and that both interact. Thus we ask the question, which one of the encoding signal or the ORFi signal is occurring first?

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30 1.3. Schizophrenia and reality confusion

The term schizophrenia comes from the ancient Greek, meaning “shattered mind”, and was forged by the Swiss psychiatrist Eugen Bleuler (1911). It is a severe chronic disorder defined as a syndrome because it comes with a myriad of symptoms affecting how a person thinks, feels and behave in ways that can vary considerably from a patient to another (Nickl- Jockschat and Abel, 2016). The symptoms fall into three categories (Tandon et al., 2013).

Positive symptoms reflect a loss of contact with some aspects of reality and an unusual behavior. Negative symptoms translate turmoil in emotions and normal behavior. Symptoms of the third category, cognitive symptoms, are usually fainter, but may induce deficits of memory or other aspects of thinking. It is however not considered a diagnostic criterion. Inter- individual variance is high and a patient experiencing psychosis, with hallucinations and delusion, can be diagnosed as schizophrenic as well as someone with negative symptoms, such as disorganized speech and apathy (Nickl-Jockschat and Abel, 2016). Here we are mostly interested in schizophrenic patients experiencing a loss of reality, as they are suggested to have a defect in filtering or gating sensory input (Andreasen et al., 1994). They present a unique opportunity into investigating mechanism of reality perception and its deficits, reality confusion, also present in non-developmental disorders, such as behaviorally spontaneous confabulations (Schnider, 2013).

1.3.1. Hallucinations and confabulations

Hallucinations refer to a sensory perception experienced in the absence of an external stimulus (Grossberg, 2000). It is a major symptom of psychosis and reflects, along with delusion, a general confused sense of what reality is (Kahn and Keefe, 2013; Cullberg, 2014).

Schizophrenic patients with psychosis will typically be described to attribute self-generated events to an external source, as if those events were actually experienced (Hawco et al., 2015). Kraepelin, (1919) described patients with schizophrenia to be telling “extraordinary stories […] in the form of personal experiences”, which falls into the category of fantastic confabulations. Schizophrenic patients, when asked to retell a story, will reorganize and reconstruct the original story in addition to inventing new material (Nathaniel-James and Frith, 1996; Lorente-Rovira et al., 2007). This observation differs from most neurological patients, where entirely new material is introduced during confabulation but, somehow,

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31 resemble the spontaneous confabulators who will compose their confabulations from personal habits, recent doings and memories from a different time (Schnider, 2008).

For some researchers, hallucinations may result from particular deficits in reality monitoring, a sub-component of source monitoring (cf. chapter 1.2.5.) where a patient will typically attribute self-generated events to an external source, as if those events were actually experienced (Johnson and Raye, 1981; Ditman and Kuperberg, 2005).

Brunelin et al. (2006) tested source memory in a group of hallucinating and non- hallucinating patients diagnosed with schizophrenia. The two groups did not differ in global source monitoring; they could distinguish words generated by themselves that they only imagined or said out loud. Hallucinating patients however misattributed internal events (words they imagined) to an external source (words said by the experimenter) more frequently than non-hallucinating. Another study (Brébion et al., 2009) tested a group of 41 patients with schizophrenia. They were asked to learn multiple lists of words divided into semantic categories and then were evaluated with immediate free recall. Verbal hallucination score was specifically correlated to intrusions of words they imagined, suggesting verbal hallucinations might develop from deficits in monitoring internal speech. Mistakes on semantic categories (intra-list intrusions) were associated with global hallucination scores but not verbal hallucinations, suggesting a failure to recall the context in which the words have been encoded and reflecting a broader cognitive deficit underlying positive symptom.

Interestingly, two studies tested hallucinating patients using an adapted version of the continuous recognition task developed by Schnider (1996b; 1999) for testing reality filtering in confabulating patients (cf. chapter 1.2.2.1.). The first study (Waters et al., 2003) tested 42 patients diagnosed with schizophrenia. All patients were in deficit on measures of inhibition.

Hallucination levels were associated with an increased number of false positives in the last runs of the continuous recognition task. It was concluded that hallucinating patients presented impaired inhibitory control because they could not repress memories that were no longer relevant. The second study (Michie et al., 2005) similarly demonstrated that patients with auditory hallucinations were more likely to respond positively to distractors seen on previous runs (false positives) than non-hallucinating patients or controls. The authors proposed a model, where auditory hallucinations may reflect a deficit of inhibition combined to a deficit in binding contextual cues (i.e. episodic memory deficit).

Taken together those results suggest that hallucinations and confabulations may both reflect a deficit in suppressing memories of events no longer pertaining to the current reality.

Patients with psychotic symptoms are often presented as having a defect in filtering sensory