Neural correlates of thought disorders in mood disorders

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Thesis

Reference

Neural correlates of thought disorders in mood disorders

PIGUET, Camille Marie

Abstract

Les patients présentant des troubles de l'humeur ont souvent des troubles de la pensée, et notamment des pensées accélérées, grouillantes ou des ruminations. Nous voulions investiguer des processus cognitifs qui pourraient être à la base de ces symptômes et leurs substrats neuronaux. Nous avons donc comparé un groupe de patients avec troubles de l'humeur (N=32) et un groupe de participants appariés, afin de tester leur flexibilité cognitive/inhibition, et leur mode d'associations verbales. Les résultats montrent qu'en effet les patients ont plus de difficulté à passer d'une tâche à l'autre, ce qui correspond à une activation inefficace de régions du réseau fronto-pariétal. Ils ont aussi de la peine à désactiver le cortex cingulaire subgénual lors de condition d'inhibition. Lors d'une tâche d'association de mots, les patients inhibent difficilement les automatismes (associé à moins d'activité du réseau sémantique), et activent plus des régions liées au self en réponse à des stimuli émotionnels.

PIGUET, Camille Marie. Neural correlates of thought disorders in mood disorders. Thèse de doctorat : Univ. Genève et Lausanne, 2012, no. Neur. 98

URN : urn:nbn:ch:unige-248618

DOI : 10.13097/archive-ouverte/unige:24861

Available at:

http://archive-ouverte.unige.ch/unige:24861

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 DE MEDECINE Professeur Patrik Vuilleumier, directeur de thèse

Professeur Gilles Bertschy, co-directeur de thèse

TITRE DE LA THÈSE

NEURAL CORRELATES OF THOUGHT DISORDERS IN MOOD DISORDERS

THESE Présentée à la Faculté de Médecine de l’Université de Genève

pour obtenir le grade de Docteur en Neurosciences

par

Camille NEMITZ-PIGUET

de Le Chenit (VD)

Thèse N° 98 Genève

Editeur ou imprimeur : Université de Genève 2012

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"La vérité recule, mais le savant avance. "

"Le désordre des idées est la condition de la créativité de l'esprit."

Henri Poincaré, 1854-1912

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I Remerciements

Je voudrais sincèrement remercier une partie des innombrables personnes nécessaires pour

« réaliser » une thèse, j’en oublie certainement quelques unes, mais en tous cas :

Patrik Vuilleumier bien sûr, qui m’a offert l’opportunité de faire exactement ce à quoi j’aspirais, m’a donné beaucoup de liberté et a vu la psychiatre en moi avant même que je le sache… Je suis encore maintenant admirative de la largesse de ses connaissances.

Gilles Bertschy, dont le sens clinique et la créativité ont donné tout son sens à ce travail, et qui s’est montré disponible quand nécessaire, entre tachypsychie et ruminations.

Martin Desseilles, Alexandre Dayer, mes amis et mentors qui m’ont montré qu’on pouvait être psychiatre, humaniste et scientifique en même temps (et sympas !), et m’ont motivée pour continuer en psychiatrie.

Jean-Michel Aubry, Sophie Favre, Françoise Jermann, Audrey Nallet, Ineke Keizer, Giorgio Michalopoulos, Guido Bondolfi, Markus Kosel, et tous les collègues en clinique qui m’ont soutenue, appris à faire des évaluations cliniques, et adressé des patients malgré l’idée saugrenue de les « mettre dans l’IRM ».

Tous les 101 sujets, patients ou non, qui ont bien voulu participer à mes 2 ou 4h de protocole et avec qui cela a été une rencontre unique à chaque fois.

Ceux qui m’ont introduit au monde des neurosciences cognitives et de la psychologie et m’ont aidée lors de mes débuts de médecin perdue dans ce domaine : Karim N’Diaye, Karsten Rauss, Roland Vocat, Markus Gschwind, Amal Achaibou, Arnaud Saj, Philippe Gay.

Ceux qui m’ont ensuite « tout » appris de l’IRM, du fonctionnement de la machine aux ANOVA SPM, en passant par des heures à faire tourner des scripts : Virginie Sterpenich et Yann Cojan.

Ceux qui m’ont aidé d’une manière ou d’une autre grâce à leurs compétences variées en informatique ou méthodologiques, pour me tenir compagnie à l’IRM, ou pour m’écouter râler: Gwladys Rey, Christoph Hofstetter, Swann Pichon, Sebastian Rieger, Jeremy Hofmeister, Fabien Robineau, Aline Pichon, Leonie Koban, Wiebke Trost, Hamdi Eryilmaz, Kinga Igloi, Mélanie Genetti, Alexis Hervais- Adelman, Tonia Rihs, Sandra Chanraud.

Tous mes autres collègues du LabNIC, qui sont tous des gens passionnants et passionnés, mais la liste est trop longue… en particulier Sophie Schwartz pour son soutien plus « féminin ».

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Ceux qui m’ont montré la voie du MD-PhD en Neuroscience et donné de précieux conseils : Pierre Mégevand, Paul Klauser, Marie Schaer.

Les étudiantes du programme de recherche pour étudiants en médecine (PREM), Karine N’Guyen (2010) et Zoé Schilliger (2012) qui ont consacré 2 mois de leur été à découvrir les neurosciences en me donnant un coup de main.

Thomas Agoritsas pour avoir répondu à mes interrogations statistiques et pour les discussions stimulantes autour du sujet, qui ne sont d’ailleurs certainement pas terminées…

Mes co-auteurs mais aussi ceux qui ont relu des parties de ce manuscrit : Arnaud Saj, Sophie Favre, Marianne Gex-Fabry, Tonia Rihs, Virginie en congé maternité, Yann en Argentine, Martin en plein déménagement ; et pour l’anglais : Meghan, Raphaël, Tessa, Esther et Alison.

Luisa Weiner, dont le travail de doctorat sera en partie dans le prolongement de cette thèse, pour les discussions intéressantes autour de mes résultats et pour sa relecture partielle.

Ceux qui se sont occupés d’Elise ces dernières semaines pour que je puisse finir le manuscrit la conscience (presque) tranquille : mon mari Nicolas, mes beaux-parents, et en particulier mes parents, pour leur soutien inconditionnel.

Mes frères pour leur vision différente de la psychiatrie qui enrichit aussi la mienne.

Mes amis qui m’ont soutenue tout au long de ces 4 ans ½ et en particulier ces derniers mois, en s’occupant de mon mari malade et de ma fille en vacances pour que je puisse écrire l’introduction, en m’aidant pour la mise en page, ou en buvant des cafés pour partager nos vicissitudes de MD-PhD students… merci Benoît, Tessa, Marie, Max, Alex, Cecilia, Julien D., Esther, Olivier, Ophélie, Virginie encore, Julien S., Geneviève et tous les autres !

Et finalement, les professeurs Martial Van der Linden et Philippe Fossati, pour avoir accepté de prendre part à ce jury de thèse et le temps qu’ils y ont consacré.

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III

Neural correlates of thought disorders in mood disorders

ABSTRACT

This work aimed at better understanding the processes behind thought disorders in mood disorders. Racing thoughts, crowded thoughts and rumination are common thought disorders both during depressive and manic states, but they are still understudied, although a better characterization might change clinical management. Through two theoretical models, we propose that these thought disorders are underpinned by three basic cognitive processes, the ability to produce an idea and to switch to a new mental set, the ability to inhibit non relevant mental set, and the pattern of association of thoughts. Therefore we attempted to evaluate these cognitive processes through neuropsychological testing and functional neuroimaging in relation to measures of thoughts (speed, control over thought, tendency to ruminate).

The general picture regarding the different behavioral measures of thought speed and production, inhibition and association is complex. At the neural level, we were able to test for emotional task-switching and backward inhibition in healthy subjects, showing that a common

“switch” region exists for all 3 types of task tested (medial superior parietal cortex). Regarding the consequence of inhibition, each specific network involved in each task was deactivated. The same paradigm was applied to mood disorder patients and revealed that patients had greater switch cost and recruit a larger fronto-parietal network in order to switch, and did not deactivate self-related region such as the subgenual cingulate cortex when required to focus on a new external task set . The free word association task used in patients showed that they were less able to produce words and had a smaller activation of semantic network. Their pattern of association was influenced by the condition (automatic or inhibition): they have difficulties inhibiting typical word associations, which is associated with smaller recruitment of fronto-parietal regions. In addition, patients showed greater activation in the parahippocampal gyrus for emotional stimuli.

Finally, in healthy subjects, increased tendency to ruminate was correlated to an enhanced activation in the entorhinal cortex, both at rest and in an easy condition.

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IV

Although it was not possible to disentangle crowded thoughts from racing thoughts, and from rumination on the basis of our measures, our results suggest that rumination and crowded thoughts both result from impaired cognitive control, and are both internally focused. We propose that crowded thoughts are richer and more diverse than rumination regarding the content of association. We did show that mood disorder patients present impaired cognitive flexibility (task-switching and inhibition of automatisms). We also repetitively found hyperactivation of self-related region (parahippocampal gyrus, subgenual cingulate) associated with the tendency to ruminate or mood disorder patients. We conclude that impaired cognitive control and hyperactivation of self-related regions both contribute to the phenomenology of intrusive thoughts in mood disorders. Further research is needed on the causal link between impaired cognitive control of internally focused intrusive thoughts, and qualitative aspect of these processes.

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V

Substrats anatomiques des troubles de la pensée dans les troubles de l’humeur

RESUME

Ce travail avait pour but de mieux comprendre les troubles de la pensée rencontrés dans les troubles de l’humeur (dépression, trouble bipolaire). Les pensées accélérées, grouillantes et les ruminations sont des symptômes fréquents, à la fois lors d’épisodes dépressifs ou hypomanes et maniaques, mais ils sont encore peu étudiés, alors qu’une meilleure caractérisation pourrait changer la prise en charge clinique. A travers deux modèles théoriques, nous proposons que ces troubles de la pensée sont sous-tendus par trois processus cognitifs basiques : la capacité à produire une idée et à passer à un nouveau set mental, la capacité d’inhiber une idée qui n’est plus pertinente, et le mode d’association des idées (étroit ou large). Nous avons essayé d’évaluer ces processus cognitifs par des tests neuropsychologiques et de l’imagerie fonctionnelle, en lien avec des mesures de la pensée (vitesse, contrôle sur les pensées, tendance à ruminer).

Le tableau général, en ce qui concerne les différentes mesures de vitesse de la pensée, de production, d’inhibition et d’association au niveau comportemental, est complexe . Au niveau du cerveau, nous avons été en mesure de tester un paradigme de task-switching émotionnel avec inhibition de retour chez des sujets sains qui a montré qu’une région commune pour le « switch » existe pour 3 types de tâches, mais que pour l’inhibition, chaque réseau individuel est déactivé en conséquence de l’inhibition. Le même paradigme utilisé chez des patients présentant des troubles de l’humeur a montré que ces patients présentaient un plus grand coût de « switch » et recrutaient un réseau fronto-pariétal plus large pour cela. De plus les patients montraient moins de désactivation dans les régions liées au soi (self), comme le cortex cingulaire subgénual. La tâche d’association libre de mots utilisée chez les patients a montré qu’ils produisaient moins de mots, ce qui était au contraire associé avec une plus petite activation du réseau sémantique. Leur mode d’associations était influencé par la condition (automatique ou d’inhibition): ils avaient des difficultés à inhiber les associations typiques de mots, ce qui était associé à un recrutement plus faible du réseau fronto-pariétal. De plus, les patients activaient plus le gyrus parahippocampal pour les stimuli émotionnels. Finalement, chez les sujets sains la tendance à ruminer était

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VI

associée à une plus grande activation du cortex entorhinal dans le lobe temporal médial, à la fois au repos et dans une condition facile au niveau attentionnel.

Bien que nos résultats ne permettent pas de distinguer complètement les pensées accélérées des pensées grouillantes ou des ruminations, ils suggèrent que les pensées grouillantes et les ruminations résultent d’un déficit de contrôle cognitif, et qu’elles sont toutes les deux dirigées vers le soi. Toutefois, les pensées grouillantes pourraient être plus riches et diverses en terme de contenu. Nous avons pu montrer que les patients avec troubles de l’humeur ont un déficit de flexibilité cognitive (pour le task-switching et l’inhibition des automatismes), associé à un recrutement inefficace ou insuffisant du réseau fronto-pariétal. Nous avons aussi trouvé de manière répétée une hyperactivation des régions liées au soi (parahippocampe, cingulaire subgénual) associée à la tendance à ruminer ou aux troubles de l’humeur en général. Nous concluons qu’un déficit de contrôle cognitif et une hyperactivation des régions liés au soi contribuent ensemble à la phénoménologie des pensées intrusives dans les troubles de l’humeur.

Des recherches supplémentaires sont nécessaires pour établir le lien causal et l’aspect qualitatif de ces processus.

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VII

Abbreviations

ACC: Anterior Cingulate Cortex BD: Bipolar Disorder

BD-I: Bipolar Disorder type I BD-II: Bipolar Disorder type II BDI: Beck Depression Inventory

BOLD: Blood Oxygenation Level Dependent dlPFC: dorso-lateral Prefrontal Cortex

DMN: Default Mode Network

fMRI: functional Magnetic Resonance Imaging GLM: General Linear Model

HS: Healthy Subjects

ICA: Independent Component Analysis IFG: inferior frontal gyrus

IPS: Intraparietal Sulcus

MADRS: Montgomery-Asberg Depression Rating Scale MDD: Major Depressive Disorder

mPFC: medial Prefrontal Cortex MTL: medial Temporal Lobe OFC: Orbitofrontal cortex PCC: Posterior Cingulate Cortex PET: Positron Emission Tomography PFC: Prefrontal Cortex

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VIII PGH: parahippocampal gyrus

QuePAS: Questionnaire des Pensées Accélérées et en Surnombre RRS : Ruminative Response Scale

sgACC: subgenual Anterior Cingulate Cortex SMA: Supplementary Motor Area

SPECT: Single-photon Emission Computed Tomography

SPEED 1 /SPEED 2: visual analog scale of thought speed, pre and post 10 min rest SPL: Superior Parietal Lobule

Ss: Subjects

TCAQ: Thought Control Ability Questionnaire TMT-A and B: Trail-Making Test A and B vlPFC: ventro-lateral Prefrontal Cortex VAS: Visual Analog Scales

WBSI: White Bear Suppression Inventory WCST: Wisconsin Card Sorting Task WM: Working Memory

YMRS: Young Mania Rating Scale

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Foreword

In this work, we focused on particular disabling symptoms of mood disorders, what happens in the head of the patients: thought disorders. Although mood is evidently central to the disease, it is accompanied by symptoms on different dimensions, such as cognitive and vegetative. As it appeared to us that one of the chief complaints expressed by depressed patients was “having too many thoughts in their heads”, we were surprised to see this traditionally hypomanic complaint even in unipolar depressed patients. Since distinguishing between mixed and pure depression might be important for the clinical management of patients, we wondered if mixed depression and hypomania share this psychic activation, as confirmed by common neural correlates. We decided to focus on these symptoms of thought disorders that could reflect a dimensional characteristic of mood disorders.

The thesis starts with a theoretical introduction, in which we will describe the current state of knowledge about mood disorders, their cognitive impairments, and neuroanatomical models, although not exhaustively due to the amount of literature on these subjects. We also delineate thought disorders, namely racing thoughts, crowded thoughts and rumination. We then present two models of thought disorders in mood disorders that arose from our understanding of the literature and the clinical picture.

These models have led to behavioral, cognitive and neuroanatomical hypotheses regarding the basic cognitive processes underlying thought disorders that we attempted to verify by choosing specific neuropsychological paradigms and neuroimaging techniques (fMRI). We then describe the rationale for choosing these paradigms and the main behavioral hypotheses. Finally, we give a brief overview of the technique of functional imaging in general.

The experimental part first reports the results of general behavioral data, then fMRI results in the form of four articles. These articles, which are about to be published, focus on small parts of the global picture we attempted to disentangle. However in the supplementary data of the articles, we report additional results in line with the initial questions. Finally we try to conciliate these behavioral and selected fMRI results to inform our description of the model and put this work in a future perspective.

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3

Introduction

1. M

OOD DISORDERS AND

T

HOUGHT DISORDERS

The existence of mood disorders has long been recognized and described. Hippocrates was the first to describe melancholia, as a lasting depression resulting from excess of black bile (the origin of the name melancholia), and mania (madness in Greek), as an excess of yellow bile (400 BC). Antiquity doctors and writers already had very modern views on the disease, in particular that people could be predisposed to the disease, and that it had a somatic substrate. Areteus of Cappadocia (200 BC) already referred to mania as a variety of melancholia. In 1686 the latin word manico-melancolicus appeared under the quill of Théophile Bonet, but the first well-known clinical conceptualization of mood disorders as one particular disease occurred in the middle of the XIXe century, when French “alienists” Jules Baillarger and Jean-Pierre Falret described circular insanity. German psychiatrist Krapelin, at the end of the 19^th, beginning of the 20^th century, crystallized the term and the concept of manic-depressive insanity that would be separated in the 70 between unipolar and bipolar disorders. Through all its history, this disease has been reported not only as mood deregulation but also more generally as a state of excitation or depression that has consequences on cognition and behavior.

1.1. Mood disorders

1.1.1. Definition

Mood disorders usually comprise unipolar depression (Major Depressive Disorder, MDD) and bipolar disorder (BD), following the classification of the DSM-IV TR (American Psychiatric Association, 2000) and the ICD-10 (World Health Organization, 1994). Unipolar depression is characterized exclusively by episodes of depression and bipolar disorder by alternation of depressive and manic/hypomanic episodes, with various intensity and frequency. In between episodes, patients can be

“euthymic” or remitted for a more or less long time.

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Following DSM-IV TR classification, a major depressive episode (MDE) is defined by symptoms on various axes, namely mood, pleasure, energy, sleep, appetite, and cognitive processes. Patients typically report ideas of guilt, suicide, and self-negativity that can in extreme cases be psychotic. The classical presentation is that of ideo-motor slowing, with patients mainly still and inexpressive, but sometimes patients report more agitation. To be diagnostic, impairment on five of nine symptoms must last for at least 2 weeks and be present for most of the day, representing a change from previous functioning; at least one of the symptoms must be either depressed mood or loss of interest or pleasure (anhedonia). These changes should not be due to another medical condition (American Psychiatric Association, 2000). Depressive syndromes actually encompass a variety of clinical presentations, which present a more vivid impairment or complain on one axis or the other.

Manic or hypomanic episodes are periods of abnormally elevated mood and activity. DSM-IV TR criteria require “a distinct period of persistently elevated, expansive or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood” (American Psychiatric Association, 2000) and three out of seven others criteria (four if the mood is irritable) at least: inflated self-esteem or grandiosity, decreased need for sleep, more talkative than usual, flight of ideas or subjective experience that thoughts are racing, distractibility, increase in goal-directed activity (at work, at school, or sexually) or psychomotor agitation, and excessive involvement in pleasurable but risky activities. Hypomanic episode must be clearly differentiated from “baseline” behavior and feeling, hence recognizable by others, but must not lead to functional impairment and necessary hospitalization, contrary to manic episode. When patients present episodes of depression and mania, the disorder is refereed as type I, when they present depression and hypomania, as type II; when elevated mood follows the introduction of anti-depressant, it can be called type III (Akiskal et al., 2003) .

It must be noted that actual research in psychiatry is rediscovering the importance of mixed states (episodes with both depressive and manic symptoms), in line with the idea of a continuum from depression to mania (Benazzi, 2007). Moreover, many affective disorder classified as “unipolar” could actually present some sub threshold manic episode (Angst et al., 2010). In the new edition of the DSM-V, which is currently in preparation, the place of mixed state is better recognized, as “mixed features”

could possibly occur with each kind of episode (Kupfer et al., 2011). This speaks in favor of a dimensional approach of mood disorders (Vieta and Phillips, 2007), with a continuum from depression to mania and all the combination in-between (Kraepelin, 1921,see figure 1; Benazzi, 2006), as well as a continuum

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from normal to pathological mood state presence of some manic symptom depression (Goldberg et al., 2009)

three most common symptoms are agitation, irrit last symptom of manic activation appeared

which is the reason why we decided to focus on this cognitive aspe

Figure 1: Classiﬁcation of «mixed states»

1.1.2. Epidemiology

The prevalence of unipolar depression is classically said to be higher in high and among women. Other socio

existence of trauma in the childhood supposed to be in augmentation, but symptoms/syndromes or because of

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m normal to pathological mood state (Gamma et al., 2008). We were particular

presence of some manic symptoms during depressive episode, leading to “agitated” or mixed (Goldberg et al., 2009). Indeed, mixed depression constitutes 30% of all depression

three most common symptoms are agitation, irritability, and racing thoughts (Akiskal et al., 2005) last symptom of manic activation appeared to us more specific for the mixed episode than the others,

reason why we decided to focus on this cognitive aspect.

ﬁcation of «mixed states» based on Weygandt and Kraepelin, Manic 1921 (adapted from Piguet et al. 2010)

revalence of unipolar depression is classically said to be higher in high

socio-demographic factors, like being separated or divorced, age, or the childhood also play a role. Finally, the prevalence of unipolar depression is supposed to be in augmentation, but whether this happens because of better recognition of

because of higher stress level in modern societies

particularly struck by the during depressive episode, leading to “agitated” or mixed . Indeed, mixed depression constitutes 30% of all depressions, and the (Akiskal et al., 2005). This more specific for the mixed episode than the others,

Manic-depressive insanity,

revalence of unipolar depression is classically said to be higher in high-incomes countries, demographic factors, like being separated or divorced, age, or the play a role. Finally, the prevalence of unipolar depression is because of better recognition of is currently debated. A

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recent multi-national study has found an estimated lifetime prevalence of 11.9 % in low-income countries and up to 19% in high-income countries (Bromet et al., 2011).

The lifetime prevalence of bipolar disorder oscillates between 1 to 2.5% of the general population, more exactly 1.0% for BD-I, 1.1% for BD-II, and 2.4% for sub-threshold BD, so 4.5% for the bipolar spectrum overall (Merikangas et al., 2007). It is debated if the actual DSM-IV criteria for hypomania and mania are valid diagnostic tools of the bipolar spectrum (Merikangas and Lamers, 2012).

They might underestimate the phenomenon, leading thus to mistreatment. The more relevant the criteria are, and the more attention is drawn toward this disorder, the higher is the prevalence of bipolar disorder, at least for BP-II (Yutzy et al., 2012). However it must be noted that it might not be a general increase, but rather a shift inside affective disorders from unipolar depression to bipolar disorder type II. The respective borders between BD-I and BD-II are not completely clear yet either (Merikangas and Lamers, 2012). In addition, psychotic features are present in approximately two-thirds of patients with bipolar disorder (Goodwin and Jamison, 2007).

Both mood disorders are associated with a tremendous societal and personal burden, high risk of suicidal behavior and committed suicide, as well as other comorbidities such as anxiety disorders, substance abuse disorders and personality disorders. They both have an age of onset around 20 years old, although this is often younger for bipolar patients (between 18-22 years old (Goodwin and Jamison, 2007; Merikangas et al., 2007)) and later for unipolar patients (around 24-25 years old (Bromet et al., 2011). Finally, a wide range of studies have argued against the separation between unipolar and bipolar disorder, based on common genetics, neurotransmitter activity or neuropsychological findings (for a discussion, see Marvel and Paradiso, 2004; Cuellar et al., 2005; Goodwin and Jamison, 2007), which again supports the idea of a dimensional approach when investigating mood disorders.

1.1.3. Etiology

Various putative etiologies exist for mood disorders, implying both psychological (psychoanalytic, systemic or cognitive) and biological modifications (Desseilles, 2010). Research tries now to integrate these models with the new findings of modern neuroscience, combining information brought by the clinical practice with results from genetics, neuroimaging studies, and research on animal models. The heterogeneity of both disorders, rather syndromes than a single pathology, reflects the complexity of their etiology.

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One of the most established hypothesis about the etiology of unipolar depression is the monoamine depletion: depression is thought to be a disorder of monoaminergic neurotransmitters, with proved depletion in serotonin, noradrenalin and dopamine by postmortem, PET or animal model studies (Saveanu and Nemeroff, 2012). The relative efficacy of drug treatment through inhibition of reuptake of serotonin and noradrenalin is a supplementary argument. Moreover, the involvement of dopamine is not surprising since one of the main symptom of depression, and maybe the most pathognomonic one, is anhedonia, whether associated with eating, social, or sexual behavior. Pleasure is primarily mediated by activation of dopaminergic neurons. The stress axis is also known to be disturbed in MDD, with the hypothalamus-pituary-adrenal axis being overactivated and the cortisol level higher than in healthy subjects. Negative feedback on this axis by glucocorticoid receptors is thought to be impaired. Nonetheless, many others biological factors could be involved in the pathophysiology of major depressive disorder (for a review, see Belmaker & Agam (2008). For example, late-onset depression might be provoked by endothelial dysfunction, and early-onset depression could have a large genetic risk factor. Anxious or chronic depression could be related to genetically determined personality factors and epigenetic changes after adverse childhood experiences (Belmaker and Agam, 2008).

Bipolar disorder on the other hand is usually seen as comprising a higher impact of genetics on the development of the disease (McGuffin et al., 2003). First-degree relatives have a risk of developing BD-I of 1-9%, of developing BD-II of 2-8%, and of developing major depressive disorder of 6-26%

(Goodwin and Jamison, 2007), and the monozygote twin concordance is about 45% (Barnett and Smoller, 2009). Genetics studies have identified several potential candidate biomarkers genes associated with increased risk for developing bipolar disorder, involving circadian rhythm, neuronal development, and calcium metabolism. In terms of peripheral biomarkers, repeated studies have found decreased levels of neurotrophic factors and increased proinflammatory cytokines and markers of oxidative stress (Kupfer et al., 2011). As for unipolar depression, various neurobiological abnormalities have been proposed as markers of the disease, such as HPA axis dysfunction, altered intracellular calcium signaling, or alteration in brain metabolites as N-acetylaspartate, as well as candidate neuroimaging markers (for a review, see Langan&MacDonald (2009), Leboyer (2011)).

However, disturbed neurotransmitters are probably only a consequence of a complex physiopathology. The exact etiology of mood disorders is not known yet, and they are probably the result of dynamic genes x environment interactions, at the prenatal level, or via early-life experiences,

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and later life events (Caspi et al., 2003, 2010; Nandrino, 2008). These have consequences on the endocrine, the affective, the immune, the autonomic-vegetative, and the cognitive systems (Price and Drevets, 2010). Although we are still far from understanding “what causes and predisposes the kind of neuronal changes we observe during the various symptoms in MDD” (Northoff et al., 2011), neuroimaging studies can help us to go further along the path of identifying brain regions and associated neural circuits involved in this etiology. We focus here on one aspect of disturbance at the cognitive level, namely thought disorders, because their mechanisms have not been under investigation much contrary to emotion processing, and could help reconsider the present model of mood disorders, since they might be trait characteristic, or transcend unipolar and bipolar categories.

1.2. Thought Disorders in mood disorders

Mood and thoughts have reciprocal relationships. If it is common sense that mood influences the content of thoughts, it is somewhat less evident that mood has an impact on the structure of thoughts. Positive mood for example helps to make broader associations, and in a large sense, promotes creativity (Isen et al., 1985; Fredrickson, 2001). Fredrickson (2001) calls this the broaden-and-build theory of positive emotions that states that some emotions (including joy, interest, contentment, pride, and love) all “share the ability to broaden people's momentary thought-action repertoires and build their enduring personal resources”. Moreover, the reverse is also true: the form of thoughts may influence mood, as shown by the work of Pronin (Pronin and Wegner, 2006; Pronin and Jacobs, 2008;

Pronin et al., 2008). She has given some evidence that induction of fast thinking and variable thinking leads to more positive mood, regardless of the content. Finally the same reciprocal relationship between structure of thoughts such as narrow association and depression has been postulated (Bar et al., 2007;

Bar, 2009). We will first describe the type of thought disorders found in mood disorders and then present some propositions about their mechanisms.

1.2.1. Racing/Crowded thoughts

Racing thoughts, defined as subjective acceleration of thinking, are a frequent symptom in mood disorders and in particular in manic/hypomanic states and mixed episodes. For example, Goodwin and Jamison report a synthesis of 12 studies on cognitive symptoms during mania: the average prevalence of “flight of ideas/racing thoughts” is 76% with a 41 to 100% range (Goodwin and Jamison,

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2007). Even though racing thoughts are usually associated with mania/hypomania, they are also found in depression (Braden and Qualls, 1979; Kirstein and Smith, 1980; Akiskal et al., 2005) or mixed depression (Koukopoulos, 1999; Benazzi, 2005a; Maj et al., 2006). As already stated, of all depressions, about 30% are mixed, with symptoms of agitation, irritability, and racing thoughts (Akiskal et al., 2005).

Even during classical Major Depressive Episode, a prevalence of racing/crowded thoughts, of around 55% for unipolar patients and around 75% for bipolar II patients, is found if more specific assessment questions are asked, as shown by the work of Benazzi (2003, 2005a). The presence of some form of racing thoughts is important if we consider that they may favor suicidal tendency. Indeed, those suffering from depressions presenting psychomotor agitation or racing thoughts are more at risk for suicidal behavior (Benazzi, 2005b; Balazs et al., 2006). Therefore, clinical experts propose that these patients should maybe not be treated with antidepressant alone, but with mood stabilizer from the start (Akiskal and Benazzi, 2006), and hence need to be clinically identifiable. However, little is known about this type of manic activation co-occurring with depressed mood, nor about the phenomenology of acceleration of thinking in general.

We have previously mentioned that the phenomenology of racing thoughts is not unique. In the context of hypomanic state, racing thoughts may appear as the results of an excessive production of thoughts, the patient switching quickly from one subject to another, usually with a pleasant feeling of fluidity. When really prominent, racing thoughts might lead to extremely loose associations, the so- called flight of ideas that can be seen as the external manifestation of accelerated thinking. In the context of a depressive state, on the other hand, racing thoughts have probably a different aspect, and may be best described as crowded thoughts (Piguet et al., 2010). In this case, thoughts are not characterized only by too many thoughts arising to consciousness, but they are also perceived as unpleasant and hard to catch or to stop (Koukopoulos, 1999). We propose in appendix 2 some verbatim of patients that we believe reflect crowded thoughts; however the research is still ongoing regarding the validation of the concept. Therefore one of our aims was to try to distinguish between linear racing thoughts, occurring mainly during hypomanic states, and crowded thoughts, associated with depressed or irritable mood. At the same time, we wanted to see if the presence of crowded thoughts during depression could have some common neural basis with racing thoughts in hypomania, which would give some support to a differential therapeutic approach for mixed depression and pure depression (Dilsaver and Benazzi, 2008; Correa et al., 2010).

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10 1.2.2. Rumination

Rumination is certainly the thought disorder most commonly associated with mood disorders.

Rumination in general is defined as repetitive and passive thinking, usually negative, which cannot be suppressed (Papageorgiou and Wells, 2004). In the context of depression, rumination is the tendency to focus on negative aspects of one’s self or negative interpretations of one’s life (Ray et al., 2005). In other words, it consists in repetitively thinking about the causes, consequences and symptoms of one’s negative affect and can be seen as a negative coping style (Nolen-Hoeksema et al., 2008), that everyone can experience in period of low mood. Rumination is a form of thinking, not negative per se, since rumination or self-reflection is also a problem-solving strategy (Watkins, 2008). However, it becomes detrimental in the context of depression. Rumination is indeed associated with higher levels of depression, longer lasting depressive symptoms, greater number of episodes, and more intrusive thoughts (Nolen-Hoeksema, 1991; Spasojevic and Alloy, 2001; Watkins and Brown, 2002; McLaughlin and Nolen-Hoeksema, 2011). It has also been associated with suicidal ideation (Surrence et al., 2009). In short, rumination is probably related to the etiology and maintenance of depressive episodes, as shown by studies that predict the development of depressive symptoms and the number and duration of major depressive episodes (Spasojevic and Alloy, 2001; McLaughlin and Nolen-Hoeksema, 2011; Wiersma et al., 2011).

Rumination in depression has been well documented and its conceptualization is quite advanced, with details on contents and dimensions of rumination, propositions about its function, and relationships to other related constructs as intrusive thoughts or worry (for a review see Smith and Alloy, 2009). Because rumination can be viewed as being “stuck in its own self”, much research has recently been done on possible cognitive inflexibility underlying it. The nature of the link with attention and cognitive underpinnings is still debated though. Some impairment in executive functioning may render the allocation of cognitive resources in a controlled fashion difficult, depending on the level of interference (Levens et al., 2009). But rumination could by itself deplete attentional resources toward something else than chronic negative self-preoccupation (Bernblum and Mor, 2010; Koster et al., 2011).

Recent models conciliate this in proposing that rumination might be due to impaired inhibition of negative material (Koster et al., 2011), indeed a lack of executive control, that further dampens cognitive flexibility in subjects and prevents them from switching away from self-related thoughts (De Raedt and Koster, 2010; Gotlib and Joormann, 2010; Koster et al., 2011). We will review the evidences

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for impaired inhibition associated to rumination below (in section 2.3.1), but this converges with a model prepared by our group for racing/crowded thoughts (Piguet et al., 2010) – as described below.

Although rumination has been widely studied among dysphoric subjects or depressive patients, the phenomenon was only recently investigated among bipolar patients as well, where it has been shown to be present not only during depressive episode but also in relation to positive affect (Johnson et al., 2008). It has been postulated that ruminating about positive things in hypomanic state could actually also contribute to worsening the clinical picture (Ghaznavi and Deckersbach, 2012).

1.3. Theoretical Models of thought disorders

The existence of racing thoughts during depressive episodes, that can be called crowded thoughts but are not empirically defined, led us to reflect upon what could differentiate racing thoughts from crowded thoughts, and crowded thoughts from rumination, in terms of phenomenology and basic cognitive processes. We came up with a first model after a review of the literature (Piguet et al., 2010), that we completed with a second model later (Desseilles et al., 2012). Both models try to explain thought disorders in mood disorders by basic underlying dimensions and are complementary.

1.3.1. Model 1 (Piguet et al. 2010)

When tackling the phenomenology of thought disorders, we tried to conceptualize them in terms of more basic cognitive processes, in order to differentiate between racing and crowded thoughts for example. It appeared to us that if the production of thoughts was definitely a general process, in order to describe the composition of mental state at a given time, the ability to inhibit previous thoughts may also be fundamental. In a theoretical review, we suggested that crowded thoughts could be the results of the mix of a hypomanic component, with the augmentation of new thoughts, and a depressive component, implicating a deficit of inhibition of previous thoughts. This last element would make the thoughts more crowded than linear as seen in hypomania. Regarding rumination, they also differ from crowded thoughts mainly by the fact that they concern only a restricted number of topics, usually regarding the self. The production of new thoughts is impaired, and the capacity to inhibit them as well.

As we will describe later, both cognitive flexibility and inhibition deficit have been described in mood disorders, as well as initiation/production impairment, but not in relation to thought processes and with

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few replicated results, except for the link between impaired inhibition and rumination.

these two distinct dimensions, production of new thoughts and ability to inhibit previous thoughts could thus help explain most of the

crowded thoughts, rumination and “blank” mind

Figure 2: Model of thought

1.3.2. Model 2 (Desseilles et al. 2012)

However, if we take into account underlying thought disorders, we do not

depression is the negative bias found in memory, interpretation of sit has also been shown that a depressed mood lead

Indeed, two cognitive models have and Jacobs (2008) propose that thought combination of each axis in “up” or “down”

12

, except for the link between impaired inhibition and rumination.

dimensions, production of new thoughts and ability to inhibit previous thoughts explain most of the thought disorders seen in mood disorders, namely racing thoughts, crowded thoughts, rumination and “blank” mind (figure 2).

Model of thought disorders explained by basic cognitive processes (adapted from 2010)

(Desseilles et al. 2012)

ver, if we take into account in this first model the quantitative aspect disorders, we do not consider the qualitative aspect. Yet a

depression is the negative bias found in memory, interpretation of situation, emotion processing depressed mood leads to a narrowing of attentional focus models have considered the variability of thoughts. In their review paper

e that thought processes are underlined by speed and variability, and that the combination of each axis in “up” or “down” directions may describe many thought

, except for the link between impaired inhibition and rumination. In our view, dimensions, production of new thoughts and ability to inhibit previous thoughts, seen in mood disorders, namely racing thoughts,

adapted from Piguet et al.

quantitative aspect of processes et a well-known aspect of uation, emotion processing, etc. It narrowing of attentional focus (Bar, 2009).

n their review paper, Pronin processes are underlined by speed and variability, and that the many thought disorders in mood

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disorders, independently of the content. A complementary model by Bar, based on visual context association, also proposes that mood and associative processes are closely linked: a depressed mood leads to narrow association, elated mood to creativity. However, as in Pronin and Jacobs, the reverse is also true: wide associations or artificial fast thinking promote elevated mood (Bar, 2009). We tried to integrate this novel parameter of thoughts variability, in respect to mood, in a second, more complex theoretical model, in order to explain certain clinical phenomena more exhaustively, such as increased creativity in depression or the presence of crowded thoughts in certain depressive and mixed states (Desseilles et al., 2012). In this model, the relevant axes are emotional valence, thought quantity, and associative pattern (narrow or wide), that can explain many clinical and non clinical states encountered in daily life (cf Fig. 5).

Figure 3: Three-dimensional model with emotional valence, thought quantity and thought associative pattern (adapted from Desseilles et al. 2012)

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14 1.3.3. Summary

These models motivated the subsequent thesis to test the cognitive processes implicated in thought disorders by investigating mental flexibility and associative processes. The first model proposed that clinical thought disorders such as racing thoughts, crowded thoughts, and rumination might be explained by two processes, generation of a new mental set and inhibition of the previous mental set.

Thus, in our empirical studies, we will the employ task-switching paradigm allowing us to disentangle production (switching to a new mental set) and inhibition processes (inhibition of previous mental set).

This permits simple predictions at the behavioral level for racing thoughts (high production, no inhibition deficit), crowded thoughts (high production, impaired inhibition), and rumination (low production, impaired inhibition). The second model added the notion of associative pattern, being broad or narrow and more or less original, as being central in resulting thought content. Therefore we designed a free word association paradigm to get insight about the pattern of association in mood disorder patients. In the end, we assumed that production, inhibition and associations of thoughts constitute the main processes involved in the generation of thoughts and their disorders, motivating us to explore these different processes in patients. However, because acceleration of thinking has been little studied and is highly subjective, we decided to use multiple indices for these basic processes. In our empirical studies, we then also used verbal fluency tasks to test for production and variability/originality measures, as well as different self-reported measures of thought processes. We describe the chosen paradigms and questionnaires in chapter 4, after a general overview of related cognitive experiments in mood disorders and putative neural correlates of mood disorders and some thought processes.

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15

2. C

OGNITIVE FUNCTIONS IN MOOD DISORDERS

2.1. Introduction

Beside rumination, thought processes in themselves are not a huge field of investigation.

However, many inquiries on cognitive functions among psychiatric patients have been conducted, with still heterogeneous results and methodologies. Verbal memory, executives functions and attention have been tested among bipolar and unipolar patients, but the exact pattern of impairment and its relationship to the presence of psychotic or sub-threshold depressive symptoms, to medication, to the trait/state nature and the type of mood disorders are still not fully defined yet (McClintock et al., 2010;

Sole et al., 2012). Globally, impairments are present in euthymic state of bipolar disorder but might by more sustained in depressive or manic state, depending on the function (Clark and Sahakian, 2008; Kurtz and Gerraty, 2009; Raust and Bellivier, 2011), mainly in domains such as attention, processing speed (semantic fluency), verbal memory and learning, and in response inhibition and set-shifting (Arts et al., 2008; Kurtz and Gerraty, 2009; Bora et al., 2010). A meta-analysis found no difference in cognitive deficits between bipolar and unipolar patients with affective psychosis, past or present (Bora et al., 2010), and another meta-analysis by the same group reported no difference in severity of impairment between BD-I and II, except for memory and semantic fluency (Bora et al., 2011). On the other hand, a study found that some executive functions (spatial working memory, set-shifting, etc.) in unmedicated unipolar patients were defective whereas it was not the case for unmedicated bipolar II patients (Taylor Tavares et al., 2007). Others studies revealed worse impairment for bipolar than unipolar patients in remitted state (Iverson et al., 2011), but the same neurocognitive profile in depressive state (Maalouf et al., 2010). Hence results are still controversial. There is for sure a general impairment in unipolar depression that lasts even after the treatment of its symptoms and the imporvment of the patient’s condition, though the impairment tends to decrease over time (Douglas and Porter, 2009). But again the precise nature of the impairment is not known, although speed processing and cognitive flexibility are often cited in a broad sense (Fossati et al., 2002; Hasselbalch et al., 2012). Deficits in executive functions correlate with the level of depression (McDermott and Ebmeier, 2009) and are prominent with tasks using emotional stimuli (Murphy et al., 2012).

Thus, if investigating the neural correlates of production and inhibition of mental set in task- switching and of pattern of word association in the context of mood disorders has not been done yet,

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other related cognitive functions have been under study. To the best of our knowledge, neither study on the neural correlates of free word association in mood disorders has been done, nor on emotional backward inhibition in task-switching in mood disorders. Nevertheless, some others paradigms have been employed to evaluate general cognitive processes thought to be impaired in mood disorder patients and relevant to thought disorders, namely inhibition and flexibility. We will try to give a general overview of the concept of cognitive flexibility and of the means by which it has been tested, as well as findings in mood disorder patients.

2.2. Concepts of cognitive flexibility and inhibition

Cognitive flexibility, as the term is referred to in the literature, is generally assessed with the Intra-Dimensional/Extra Dimensional Set-Shift subtest (IDED, (Owen et al., 1991)) of the Cambridge Neuropsychological Test Automated Battery (CANTAB; Cambridge Cognition, Cambridge, UK), the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT-A and B) (for explanations on these tasks, see Lezak et al., 2004 and appendix 1). Task-Switching is naturally associated with the concept of cognitive flexibility as well and will be described in details later. However, all these tasks are typically complex tasks that involve more than one specific cognitive process, although task-switching is considered a purer task than WCST. Importantly, both WCST and task-switching are considered to contain an inhibitory component. The two processes are indeed almost always interwoven, and we could say that some inhibition is necessary to ensure a good cognitive flexibility. Some research has tried to disentangle switching and inhibition inside task-switching, as we will expose later, by comparing sequences of trials were the subject has to go back to a previously inhibited task, or not. This inhibition cost is called backward inhibition.

Regarding inhibition, we must first keep in mind that it is an umbrella term that covers various cognitive concepts (McLeod C. et al., 2003; Aron, 2007), and there is no common accepted classification or gold-standard task. For example, one seminal study by Nigg (2000) proposed that voluntary executive inhibition (= cognitive control) could be divided between a) interference control, b) cognitive inhibition, c) behavioral inhibition, and d) oculomotor inhibition. Based on this, Dillon and Pizzagalli (2007) categorize various forms of inhibition in a) response inhibition (e.g., inhibition of prepotent or reflexive behavioral responses), b) cognitive inhibition (e.g., inhibition of irrelevant information), and c) emotional inhibition (e.g., inhibition of fear responses). By using latent variable analysis, Friedman and Miyake

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(2004) give one example of a more precise taxonomy of inhibition. They show that a) prepotent response inhibition (tested by Stop-signal task, Stroop task), b) resistance to distractor interference (tested by Eriksen flanker task, word naming, shape matching task) are related constructs; whereas c) resistance to proactive interference (using different tasks of recall) is probably separable, related to internal interference inhibition, and is more automatic. The latter implies the “ability to resist memory intrusions from information that was previously relevant to the task but has since become irrelevant”, which seems very close to the concept of inhibition of previous thoughts in order to be able to clear consciousness. However, the way it is presented and tested links it to memory processes rather than immediate thought processes. A conception restricted to working memory is also present in the work of Hasher et al. (1999), who write: “Inhibitory mechanisms serve to restrict access to information that is relevant, delete information that is no longer relevant, and restrain production of strong but potentially incorrect retrieval of information from working memory”. Friedman and Miyake (2004) do agree that thought processes share many similarities with the inhibition of proactive interference, but since they didn’t look precisely at inhibition cost inside task-switching (as we propose to do), they didn’t find a direct association between task-switching and resistance to proactive interference. Research on rumination has linked deficit in working memory (WM) to inhibition processes, and it has been demonstrated that MDD patients show increased interference from irrelevant negative material when updating WM (Joormann and Gotlib, 2008). Recently Zetsche et al. (2012) integrated the taxonomy of Friedman, Miyake et al. (2000; 2004) and finally proposed that inhibition could be divided between inhibition of prepotent response (mainly behavioral), set shifting, and a) controlling access to WM (interference control) b) removing no longer relevant material from WM (updating working memory).

They suggest that only one of these components is actually associated with rumination (inhibition of no longer relevant material) and test the first component by flanker tasks and the second component by working memory selection tasks. Thus we see that the relationship between working memory and inhibition in the context of depressive rumination needs to be further explored. Moreover, the results from Zetsche et al. (2012) are not straightforward, and we could conclude that both types of inhibition play a role in thought disorders. Intrusive thoughts such as worries and obsessions have also been linked to two types of inhibition (inhibition of prepotent response and resistance to proactive interference) through the different facets of impulsivity (Gay et al., 2011).

Other paradigms have been used to test for deficit of inhibition in the context of task-switching and focus-switching in the context of rumination. For example, an internal switch task has been

Neural correlates of thought disorders in mood disorders

Thesis

Reference

Neural correlates of thought disorders in mood disorders

NEURAL CORRELATES OF THOUGHT DISORDERS IN MOOD DISORDERS

Camille NEMITZ-PIGUET

Neural correlates of thought disorders in mood disorders

Substrats anatomiques des troubles de la pensée dans les troubles de l’humeur

Abbreviations

TABLE OF CONTENTS

Foreword

Introduction

1. M

T

2. C