The primary objective of this PhD program was to investigate the impact of training at a constant-load moderate-intensity (FATmax) compared to work-matched high-intensity intervals (HIIT) on the metabolic, physiological and psychosocial health profiles of sedentary overweight and obese men. This study was unique in that it was the first time the effect of exercise intensity had been investigated to examine concurrently the components of whole-body energy metabolism and body composition as measured using gold standard techniques. Based upon the positive alterations in blood lipids, body composition, cardiorespiratory fitness and substrate oxidation, it appears that training at FATmax can positively impact health parameters as well as, or if not better than, high-intensity training. Furthermore, there are ramifications for public health messages and obesity management strategies arising from these findings, primarily attributable to the increased exercise adherence and the reduction in health risks stemming from the significant loss of abdominal visceral adipose tissue after FATmax training.

La mentalisation, ou la capacité d’élaborer des hypothèses sur les états mentaux d’autrui, a fait l’objet de nombreuses études durant les 20 dernières années dans le champ des neurosciences sociales. Toutefois, les bases neurales de cette fonction particulièrement complexe restent mal comprises, notamment en termes de connectivité structurale. Récemment, une organisation anatomo-fonctionnelle en double voie a été proposée. Selon ce modèle, les aspects réflexifs, inférentiels, de la mentalisation seraient sous-tendus par le faisceau cingulaire. Les aspects préréflexifs, identificatoires, seraient médiés, quant à eux, par le complexe faisceau arqué/partie latérale du faisceau longitudinal supérieur (FLS). L’objectif général de ce travail est d’apporter des données originales sur l’organisation anatomo-fonctionnelle du réseau neural impliqué dans la mentalisation basée sur les visages. Pour ce faire, nous avons utilisé comme modèle physiopathologique d’étude le gliome diffus de bas grade. Cette tumeur cérébrale primitive s’avère particulièrement intéressante pour l’étude du rôle de la substance blanche dans la cognition et ce pour deux raisons : (i) les cellules tumorales se propagent préférentiellement le long des fibres blanches ; (ii) l’exérèse chirurgicale est souvent réalisée en condition éveillée avec cartographie fonctionnelle peropératoire pour permettre d’identifier, et ainsi de préserver, les structures fonctionnelles, notamment de substance blanche.Dans une première étude, grâce aux stimulations électriques peropératoires, nous avons pu identifier un vaste réseau cortico-sous-cortical impliqué dans la mentalisation. L’analyse des déconnexions induites par les stimulations de la substance blanche nous a permis de mettre clairement en évidence, et ce pour la première fois, le rôle du faisceau occipito-frontal inférieur (FOFI) tout en confirmant celui du FLS. Dans une deuxième étude, en utilisant des techniques de cartographie lésionnelle chez des patients ayant été opérés, nous avons démontré que les troubles permanents, non compensables, de la mentalisation étaient expliqués par l’atteinte du faisceau arqué. Enfin, dans une dernière étude, en combinant l’imagerie par résonance magnétique fonctionnelle de repos (IRMfr) et les sites corticaux démasqués pendant la chirurgie, nous avons pu générer de véritables cartographies fonctionnelles du réseau cortical de la mentalisation, très similaires à celles observées en imagerie fonctionnelle classique.De façon générale, nos découvertes suggèrent que la mentalisation basée sur les visages reposerait sur l’intégrité d’au moins deux faisceaux associatifs de substance blanche. Elles permettent également de valider l’utilisation combinée de l’IRMfr et des stimulations corticales en tant qu’approche originale pour cartographier les réseaux neurocognitifs.En plus de ces considérations fondamentales, nos résultats ont des implications cliniques, notamment pour la cartographie fonctionnelle peropératoire. Ils permettent en outre de mieux comprendre les pathologies cérébrales caractérisées par un trouble de la mentalisation et une atteinte des voies de substance blanche. / Mentalizing, or the ability of human beings to make assumptions about other people’s mental states, has been the subject of many studies over the last 20 years. The neural bases and especially the white matter connectivity of this complex cognitive function is still poorly understood. Recently, an anatomo-functional organization into two neural pathways has been proposed. According to this model, it is assumed that the reflective, inferential aspects of mentalizing is underpinned by the cingulum. The reflexive, identificatory aspects of mentalizing are thought to be mediated, for their part, by the arcuate fascicle and the lateral part of the superior longitudinal fascicle. The main purpose of this scientific work is to provide original data on the anatomo-functional organization of the neural network involved in the face-based mentalizing. We used as a pathophysiological study model diffuse low-grade gliomas. These primary brain tumors are particularly interesting for the study of the functional role of the white matter for two reasons: (i) the tumor cells propagate preferentially along the white matter fibers; (ii) the surgical resection is often performed in awake condition with intraoperative functional mapping to identify, and thus to preserve functional structures, including the white matter.In our first study, using intraoperative electrical stimulation, we were able to identify a large cortico-subcortical mentalizing network. The analysis of the disconnections induced by the stimulation of the white matter allowed us to clearly highlight, for the first time, the role of the inferior fronto-occipital fascicle. We also confirmed the already established role of the superior longitudinal fascicle in mentalizing. In a second study, using lesion mapping analyses in patients operated on for a diffuse low-grade glioma, we demonstrated that the long-term, non-compensatory mentalizing deficit was explained by the involvement of the arcuate fascicle. Finally, in a third study combining resting-state functional MRI and the cortical sites unmasked during surgery, we were able to identify a large cortical mentalizing networks, which were very similar to those identified by classical task-based functional imaging.In general, our findings suggest that the face-based mentalizing would require the integrity of at least two associative white matter fascicles. They also validate the combined use of resting-state functional MRI and direct cortical stimulations as an original approach to map neurocognitive networks.In addition to these fundamental considerations, our results have also clinical implications, especially regarding the intraoperative functional mapping. They also provide a better understanding of brain pathologies characterized by both mentalizing deficit and white matter impairment.

Introdução: A síndrome do intestino curto (SIC) representa um estado clínico de má absorção grave, e a gestão dietética de pacientes com SIC é extremamente desafiadora. Uma vez que o grau de desnutrição é frequentemente considerável, a intervenção dietética bem sucedida depende da estimativa mais exata possível das necessidades energéticas para prever as metas da terapia nutricional. Objetivo: Quantificar o gasto energético total (GET) em pacientes com SIC pelo método da água duplamente marcada (ADM). Materiais e Métodos: Neste estudo observacional, o GET foi mensurado pelo método da água duplamente marcada em 22 voluntários, 11 com SIC e 11 controles pareados por sexo, idade e IMC (grupo Controle). O GET foi estimado pela equação de Escott-Stump e a partir de acelerômetro, e foi comparado com o GET determinado pela ADM. O gasto energético em repouso (GER) foi mensurado por calorimetria indireta (CI) e comparado com o GER estimado pela equação de Harris e Benedict. O acelerômetro também foi utilizado para estabelecer o nível de atividade física. Resultados: Os participantes tinham idade (média ± DP) de 53 ± 8 anos. O GET medido por ADM foi significativamente menor no grupo SIC comparado ao grupo Controle (p < 0,01); no entanto, o GET estimado não diferiu significativamente entre os grupos. O GET medido foi significativamente maior do que o GET estimado por fórmula no grupo SIC, (respectivamente 1875 ± 276 e 1517 ± 175 kcal/dia, p < 0,01), assim como para o grupo Controle (2393 ± 445 e 1532 ± 178 kcal/dia, p < 0,01). No entanto, o GET medido foi significativamente menor do que o GET predito a partir do acelerômetro no grupo SIC (2075 ± 298 kcal/dia, p = 0,02), e não diferiu significativamente no grupo Controle (2207 ± 355 kcal/dia, p = 0,21). Não foram verificadas diferenças significantes entre o GER medido e predito para ambos, e entre os grupos. Conclusão: O GET medido em pacientes com SIC foi significativamente maior do que o GET estimado por fórmula, e foi menor quando comparado com os valores dos sujeitos controles. No entanto, o GET estimado a partir do acelerômetro, superestima o GET medido por ADM. As fórmulas atualmente utilizadas na prática clínica parecem subestimar as necessidades de energia de pacientes com SIC. Desta forma, adaptações da estimativa atual, aumentando as prescrições de ingestão energética nestes pacientes parecem ser adequadas para apoiar as necessidades diárias de energia e evitar a subnutrição. / Background: Short bowel syndrome (SBS) is a serious malabsorption disorder, and dietetic management of SBS patients is extremely challenging. Once the degree of undernutrition has been assessed, successful dietary intervention depends on the most accurate estimation and provision of energy needs to provide nutritional therapy goals. Objective: To quantify total energy expenditure (TEE) in SBS patients using the doubly labeled water (DLW) method. Design: In this observational study, TEE was measured by the DLW method in 22 participants, 11 with SBS and 11 gender-age-and BMI-matched controls (Control group). Predicted energy requirements were determined using the Escott-Stump equation and by using and accelerometer, and they were compared with TEE determined with DLW. Resting energy expenditure (REE) was measured using indirect calorimetry and compared with predict REE using the Harris and Benedict equation. The accelerometer was also used to determine physical activity level. Results: Participants were aged (mean ± SD) 53 ± 8 years. Measured TEE was significantly lower in the SBS group compared to the Control group (p < 0.01); however, predicted TEE did not differ significantly between the groups. Measured TEE was significantly higher than predicted TEE for the SBS group, (1875 ± 276 and 1517 ± 175 kcal/d, p < 0.01) and also for the Control group (2393 ± 445 and 1532 ± 178 kcal/d, p < 0.01) when determined by formula. However, measured TEE was significantly lower than predicted TEE (2075 ± 298 kcal/d, p = 0.02) for the SBS group, and did not differ for the Control group (2207 ± 355 kcal/d, p = 0.21) when determined by accelerometer. No significant differences were seen between measured and predicted REE both within and between groups. Conclusion: Measured TEE in SBS patients was significantly higher than predicted using standard equations, but also lower than values for age, BMI and gender-matched non-SBS controls. However, predicted TEE using accelerometer overestimated the measured TEE. Currently-used formulas in clinical practice appear to underestimate energy requirements of SBS patients. Therefore, adjustments to the current estimation, increasing the energy intake requirements in these patients appear to be adequate to support the daily energy requirements and avoid undernutrition.

A acidose metabólica é um achado comum em pacientes portadores de Doença Renal Crônica (DRC). Acredita-se que a dieta pode afetar o equilíbrio ácidobase do corpo por meio do fornecimento de precursores ácidos ou de base. No entanto, os resultados inconclusivos apontados na literatura indicam que ainda são necessários estudos bem delineados para comprovar a existência dessa associação. O principal objetivo desse estudo foi determinar o potencial de carga ácida renal (PRAL) proveniente da dieta e avaliar a sua associação com o bicarbonato sérico (HCO3) em pacientes com DRC enquanto em suas dietas habituais. Associações do HCO3 com o gasto energético de repouso (GER) e com oxidações proteicas e lipícas também foram estudadas. Trata-se de um estudo transversal realizado com 100 pacientes distribuídos igualmente nos estágios 3 e 4 da DRC entre 20 e 69 anos. Avaliação do estado nutricional foi feita por meio da antropometria, registro alimentar e exames bioquímicos, o qual incluiu os produtos proteicos de oxidação avançada e os isoprostanos. O HCO3 foi determinado por meio da gasometria venosa. GER foi medido pela calorimetria indireta. O PRAL foi determinado por meio do registro alimentar usando um algoritmo que inclui dados dietéticos da ingestão de proteína, fósforo, magnésio, cálcio e potássio descritos por Remer e Manz (1995). Também foi feita a diferenciação no consumo de proteína animal e vegetal. A análise dos resultados foi feita em quartis de HCO3 para as variáveis GER e parâmetros de oxidação, o restante das análises foram feitas por quartis de PRAL. Para comparação das variações médias dos quartis foi utilizado o teste one-way ANOVA. A associação entre a estimativa do PRAL e o HCO3 foi avaliada por modelos de regressão linear ajustados. A maior parte dos nossos pacientes portadores de DRC encontravam-se com excesso de peso associado a um aumento da circunferência abdominal e da porcentagem de gordura corporal. A mediana do PRAL foi de 6,8 mEq/dia com uma variação entre -24 a 52 mEq/dia. O PRAL mais elevado foi associado com o HCO3 mais baixo de uma forma graduada (p < 0.02). Encontramos uma diferença de 2,07 mmol/L no HCO3 entre o primeiro e o último quartil, sendo o valor do último quartil de PRAL menor em relação ao primeiro. A proteína animal apresentou uma correlação inversa com o bicarbonato sérico. O GER e os marcadores de oxidação lipíca e proteica não apresentaram associações com os níveis de HCO3. Esses resultados reforçam a possibilidade de que dietas com alto teor de carga ácida podem desempenhar um papel relevante no equilíbrio ácidobase em pacientes portadores de DRC, além de consolidar o uso da carga ácida da dieta como uma abordagem diferencial e complementar às outras estratégias no tratamento dietético da DRC. / Metabolic acidosis is a common complication in patients with chronic kidney disease (CKD). Acid-inducing diets are believed to impact on acid-base balance. However, well-designed studies are still needed to prove the association between dietary acid load and serum bicarbonate. The main aim of this study was to calculate the potential renal acid load (PRAL) of selected, frequently consumed foods and to evaluate its association with serum bicarbonate (HCO3) in patients with CKD. Associations of HCO3 with resting energy expenditure (REE) and with protein and lipid oxidation were also studied. It is a cross-sectional study with 100 patients equally distributed in stages 3 and 4 of CKD between 20 and 69 years. Nutritional status was assessed by anthropometric measurements, 3-day food recall, biochemical analysis including advanced oxidation protein products and isoprostanes. Venous blood gases was used to measure HCO3. GER was measured by indirect calorimetry. PRAL was determined by food record using an algorithm that includes protein, phosphorus, magnesium, calcium and potassium intake described by Remer and Manz (1995). Dietary intake of animal and vegetable protein were also evaluate. For analysis, we used quartiles of HCO3 for GER and oxidation parameters and for the others variables we used quartilhes of PRAL. ANOVA one-way test was used to compare the mean of the quartiles. The association between PRAL and HCO3 was assessed by linear regression models. Most of the patients were overweight with increased waist circumference and body fat. The median PRAL was 6.8 mEq/day with a variation between -24 to 52 mEq/day. Higher PRAL was associated with lower serum bicarbonate in a graded fashion (P trend 0.02). Serum bicarbonate was 2.07 mEq/L lower among those in the highest compared with the lowest quartile of PRAL. Animal protein was inversely correlated with serum bicarbonate. REE and lipid and protein oxidation markers showed no association with HCO3 levels. These results reinforce the possibility that diets with high dietary acid load may play a relevant role in the acid-base balance in CKD patients. In addition to consolidating the use of PRAL as a differential and complementary approach to other strategies in the nutritional treatment of CKD.

Abstract The concept of resting state functional magnetic resonance imaging (fMRI) is built onto an original finding in 1995 that brain hemispheres present synchronous signal fluctuations with distinct patterns. fMRI measurements rely on blood oxygenation changes that indirectly mirror neural activity. Therefore, the origin of functional connectivity patterns, resting state networks (RSNs), has been a widely debated research question and numerous contributing factors have been identified. According to current understanding the fluctuations reflect maintenance of the system integrity in addition to spontaneous thought and action processes in the resting state. A popular method to study the functional connectivity in resting state fMRI is spatial independent component analysis (ICA) that decomposes signal sources into statistically independent components. The dichotomy of functional specialization versus functional integration has a correspondence in fMRI studies where RSNs play the integrative viewpoint of brain function. Although canonical large-scale RSNs are broadly distributed they also express modularity that can be accomplished by ICA with a high number of estimated components. The characteristics of high ICA dimensionality are broadly investigated in the thesis. An enduring issue in resting state research has been the confounding noise sources like motion and cardiorespiratory processes which may hamper the analysis. In this thesis the ability of ICA to separate these noise sources from the default mode network, a major RSN, is studied. Additionally, the suitability of ICA for full frequency spectrum analysis, a relatively rare setting in biosignal analysis, is investigated. The results of the thesis support the viewpoint of ICA as a robust analysis method for functional connectivity analysis. Cardiorespiratory and motion induced noise did not confound the functional connectivity analyses with ICA. High dimensional ICA provided better signal source separation, revealed the modular structure of the RSNs and pinpointed the specific aberrations in the autism spectrum disorder population. ICA was also found applicable for fully explorative analysis in both the spatial and temporal domains and indicated functional connectivity changes induced by transcranial bright light stimulation. / Tiivistelmä Konsepti lepotilan tutkimisesta toiminnallisella magneettikuvauksella (engl. functional magnetic resonance imaging, fMRI) on rakentunut vuonna 1995 tehdylle löydökselle aivopuoliskojen välillä synkronisesta signaalivaihtelusta. Mittaukset perustuvat veren hapetuksen muutoksiin, jotka epäsuorasti heijastelevat hermostollista toimintaa. Tämän takia toiminnallisen kytkennällisyyden muodot, lepotilaverkostot, ovat olleet laajasti väitelty tutkimusaihe ja monia verkostoihin vaikuttavia tekijöitä onkin tunnistettu. Nykykäsityksen mukaan signaalivaihtelut lepotilassa heijastelevat järjestelmän yhtenäisyyden ylläpitoa spontaanin ajattelun ja toiminnan lisäksi. Suosittu menetelmä toiminnallisen kytkennällisyyden tutkimiseen lepotilan fMRI:ssä on spatiaalinen itsenäisten komponenttien analyysi (engl. independent component analysis, ICA), joka hajottaa signaalilähteet tilastollisesti itsenäisiin komponentteihin. Aivotoiminnan mallintamisessa kahtiajaolla toiminnalliseen erikoistumiseen ja toiminnalliseen integraatioon on vastaavuus fMRI-tutkimukseen, jossa lepotilaverkostot vastaavat toiminnallisen integraation näkökulmasta. Vaikka kanoniset lepotilaverkostot ovat laaja-alaisia, ne ovat toisaalta modulaarisia, jota voidaan tutkia tutkimalla korkean komponenttimäärän ICA-hajotelmaa. Korkea- dimensioisen ICA-hajotelman ominaisuuksia tutkitaan laajasti tässä väitöskirjassa. Kestoaihe lepotilatutkimuksessa on ollut analyysiä hankaloittavien kohinalähteiden kuten liikkeen ja kardiorespiratoristen prosessien vaikutus. Väitöskirjassa tutkitaan ICA:n kykyä erotella kohinalähteitä ’default mode’ -verkostosta, joka on merkittävin lepotilaverkosto. Lisäksi tutkitaan ICA:n soveltuvuutta täyden taajuuskaistan analysointiin, joka on verrattain harvinaista biosignaalien analyysissä. Väitöskirjan tulokset tukevat näkemystä ICA:n suorituskyvystä toiminnallisen kytkennällisyyden analyysissä. Kardiorespiratorinen ja liikkeestä lähtöisin oleva kohina ei häirinnyt merkittävästi ICA-tuloksia. Korkeadimensioinen ICA tarjosi paremman erottelun signaalilähteille, paljasti lepotilaverkostojen modulaarisen rakenteen ja määritti erityisen poikkeaman autismin kirjon oireyhtymän populaatiossa. ICA:n havaittiin olevan soveltuva täyseksploratiiviselle analyysille ajassa ja avaruudessa; tulos viittaa toiminnallisen kytkennällisyyden muutoksiin kallon läpäisevän kirkasvalostimulaation aikaansaamana.

Le but de ce travail de thèse a été de caractériser in vivo chez l’Homme, la connectivité cérébrale sur son versant fonctionnel, par le biais de deux techniques: la stéréoélectroencéphalographie (SEEG) et l’IRM fonctionnelle (IRMf) de repos. Ces travaux se sont intégrés dans le cadre du bilan préchirurgical des épilepsies du lobe temporal pharmacorésistantes, dont le but est de déterminer la zone épileptogène à réséquer pour traiter ces patients. Alors que plusieurs études en électrophysiologie ont montré que durant les crises, il existait une synchronisation anormalement élevée entre les structures impliquées dans les processus épileptogènes, aucune donnée de connectivité n’était disponible en période intercritique. Pourtant, la période intercritique est le siège d’anomalies interictales enregistrées en EEG, de profonds remaniements morphologiques, et est associée à des troubles cognitifs. Nous apportons avec ce travail, grâce au recueil et au traitement de signaux SEEG et IRMf enregistrés durant la période intercritique, de nouvelles connaissances i) sur l’organisation de la connectivité fonctionnelle basale (CFB) chez les sujets sains ; ii) sur les altérations de la CFB chez des groupes de patients mais également au niveau individuel ; iii) sur le rapport entre ces anomalies de CFB et les troubles cognitifs observés chez ces patients ; iv) enfin, sur les différences et les similitudes de la CFB évaluée par SEEG et IRMf chez les mêmes sujets, ouvrant ainsi de nouvelles perspectives dans la compréhension des relations entre le signal BOLD et le signal EEG. / The aim of this thesis was to characterize the Human brain functional connectivity in vivo based on signals recorded using stereoelectroencephalography (SEEG) and resting-state functional MRI (fMRI). This work was conducted during the presurgical assessment of drug resistant temporal lobe epilepsy, which aims at determining the epileptogenic zone to be removed to treat these patients. While several electrophysiological studies have shown high synchronization between structures involved in the epileptogenic process during seizure, no similar connectivity data was available during inter-critical period. However, the interictal period is characterized by spikes recorded on EEG, morphological alterations and cognitive impairment. By analyzing fMRI and SEEG signals recorded during the interictal period, this work provides new insights into, i) basal functional connectivity (BFC) organization in healthy subjects, ii) BFC alterations in patients groups but also at the individual level, iii) the relationship between these BFC abnormalities and cognitive impairment observed in these patients; iv) the differences and similarities of BFC evaluated by SEEG and fMRI in the same subjects, thus opening up new perspectives in better understanding of relationships between BOLD and SEEG signal coupling.

Hintergrund. Exzessives Sorgen ist durch anhaltende, sich wiederholende negative Gedanken gekennzeichnet, die als aufdringlich und unkontrollierbar empfunden werden. Chronisches Sorgen kann zu einer schwer beeinträchtigenden mentalen Aktivität werden und es wird angenommen, dass es zur Entstehung, Aufrechterhaltung und Verschlechterung einer Reihe von somatischen Gesundheitsproblemen und psychischen Störungen beiträgt. Theoretische Modelle und empirische Befunde deuten darauf hin, dass exzessives Sorgen mit einer gestörten Bottom-up-Salienzverarbeitung, einer unzureichenden Top-down-Aufmerksamkeitssteuerung, Defiziten in der Emotionsregulation und abnormalen selbstreferenziellen mentalen Funktionen verbunden sind. Neuroimaging-Studien zu exzessivem Sorgen zeigen Veränderungen funktioneller Aktivierung und Konnektivität in limbischen und paralimbischen Hirnstrukturen, welche die Reaktivität auf emotionale Stimuli unterstützen, in präfrontalen Strukturen, die in Top-down-Prozesse involviert sind, welche der Aufmerksamkeitssteuerung und Emotionsregulation zugrunde liegen, und in medialen kortikalen Mittellinienstrukturen, die an selbstreferenziellen mentalen Aktivitäten beteiligt sind. Im Hinblick auf das Vorhandensein, die genaue Lokalisation der beteiligten Hirnareale und die Richtung der Effekte präsentieren diese Studien jedoch weitgehend heterogene Ergebnisse. Die hohe Variabilität der Befunde erschwert es, ein kohärentes Verständnis der neurobiologischen Mechanismen exzessiven Sorgens zu erlangen. Um dieses Verständnis zu erweitern und künftige Richtungen für die weitere Forschung auf diesem Gebiet aufzuzeigen, verfolgte die vorliegende Dissertationsschrift drei Ziele: (i) die emotionsbezogene, aufgabenbasierte fMRT-Literatur zu exzessivem Sorgen auf quantitative, datengesteuerte Weise zusammenzufassen, um konsistente funktionelle Störungen über Studien hinweg zu identifizieren; (ii) zu bestimmen, mit welchen psychologischen Prozessen die identifizierten Hirnregionen assoziiert sind, und in welchen funktionellen Hirnnetzwerken sie wirken; und (iii) Anomalien in der grundlegenden Hirnorganisation zu untersuchen, die mit exzessivem Sorgen assoziiert sind. Methoden. Eine State-of-the-Art koordinatenbasierte Meta-Analyse wurde unter Anwendung des Activation Likelihood Estimation (ALE) Algorithmus durchgeführt, um die Übereinstimmung zwischen 16 Neuroimaging-Experimenten zu bestimmen, die Veränderungen in der funktionellen Aktivität des Gehirns während der Verarbeitung emotionaler Inhalte zwischen Personen mit hoher und normaler Sorgenneigung berichten. Die identifizierten Regionen wurden mithilfe von Metadaten der funktionellen Magnetresonanztomographie (fMRT) hinsichtlich ihrer psychologischen Funktionen charakterisiert (Verhaltens-Charakterisierung). Zusätzlich wurde meta-analytic-connectivity modeling (MACM) verwendet, um ihre globalen funktionellen Konnektivitätsmuster zu bestimmen und so zugehörige Gehirnnetzwerke zu identifizieren. Schließlich wurde fMRT im Ruhezustand (resting-state) verwendet, um die funktionellen Konnektivitätsmuster zwischen 21 Personen mit hoher und 21 Personen mit normaler Sorgenneigung ohne einer aufgabenbezogenen Gehirnaktivierung zu vergleichen. Dispositionelle Sorgen wurden mit dem Penn State Worry Questionnaire als verlässliches Selbstauskunftsmaß für schwere Sorgen erhoben. Saatregion-basierte Analysen mit den meta-analytisch abgeleiteten Hirnregionen als Saatregionen und eine datengesteuerte Multi-Voxel-Pattern-Analyse (MVPA) wurden durchgeführt, um funktionelle Konnektivitätsunterschiede zwischen den beiden Gruppen zu detektieren. Darüber hinaus wurden gruppenüber-greifende Korrelationen zwischen dem aktuellen Sorgenausmaß (State-Sorgen) und den funktionellen Konnektivitätsmustern der Saat-Regionen sowie den aus der MVPA abgeleiteten Komponenten-Werten analysiert. Ergebnisse. Die Meta-Analyse ergab konvergente Anomalien bei Individuen mit hoher im Vergleich mit normaler Sorgenneigung, hauptsächlich in einem linkshemisphärischen Cluster, welcher Teile des mittleren frontalen Gyrus, des inferioren frontalen Gyrus und der anterioren Insula umfasst. Die Verhaltens-Charakterisierung zeigte, dass der identifizierte Cluster mit der Sprachverarbeitung und dem Gedächtnis assoziiert ist. Darüber hinaus ergaben die meta-analytischen Konnektivitätskartierungen starke funktionelle Verbindungen zwischen den beobachteten konvergenten Regionen und frontalen, temporalen und parietalen Hirnregionen, die sich mit Teilen von zwei verhaltensrelevanten Hirnnetzwerken überschneiden, nämlich dem Salienznetzwerk (SN) und dem Default-Netzwerk (DN). Die resting-state funktionellen Konnektivitätsanalysen zeigten keine Unterschiede zwischen Individuen mit hoher und normaler Sorgenneigung und auch keine Korrelationen zwischen den resting-state funktionellen Konnektivitätsmustern und State-Sorgen, weder mit dem auf Saatregionen basierenden Ansatz noch mit dem MVPA-Ansatz. Schlussfolgerungen. Die Ergebnisse dieser Dissertationsschrift deuten darauf hin, dass exzessives Sorgen mit einer gestörten Funktion in Hirnarealen zusammenhängt, die mit bottom-up und top-down Aufmerksamkeitssteuerung sowie Emotionserzeugung und Emotionsregulation in Verbindung gebracht werden. Die Verhaltensanalyse deckte Assoziationen zwischen dem identifizierten Cluster und der Sprachverarbeitung auf, die mit dem übermäßigen inneren Sprechen bei zu Sorgen neigenden Personen zusammenhängen könnten. Diese Assoziation ist bisher eher unbeachtet geblieben und sollte weiter erforscht werden. Darüber hinaus stellen die identifizierten Hirnregionen Schlüsselknoten in interagierenden neuronalen Netzwerken dar, die endogen und exogen orientierte Kognition unterstützen und das dynamische Zusammenspiel zwischen diesen Prozessen steuern. Ihre veränderte netzwerkübergreifende Dynamik könnte die Ursache für die Unfähigkeit von zu schweren Sorgen neigen-den Personen sein, sich von intern orientierten Kognitionen zu lösen, wenn adaptives Reagieren einen externen Fokus der Aufmerksamkeit erfordern würde. Die Nullergebnisse der Ruhezustandsanalysen könnten auf das Studiendesign zurückzuführen sein oder durch Charakteristika des Sorgens selbst verursacht werden, werden aber nicht als Beleg dafür interpretiert, dass Anomalien in der intrinsischen Konnektivität des Gehirns in Verbindung mit exzessivem Sorgen nicht vorhanden sind. Die Ergebnisse dieser Arbeit können zukünftige Forschungen anleiten, die z.B. untersuchen könnten, ob und wie sich die dynamischen zeitlichen Interaktionen innerhalb und zwischen den hier identifizierten Netzwerken in Abhängigkeit vom Schweregrad des Sorgens unterscheiden. Die ALE-Ergebnisse liefern eine A-priori-Auswahl von Hirnregionen für solche Studien. Ein besseres Verständnis der Veränderungen in den Gehirnnetzwerken, die exzessivem Sorgen zugrunde liegen, und der psychologischen Funktionen, die dadurch beeinträchtigt werden, wird Ansatzpunkte für die Verbesserung therapeutischer Interventionen liefern.:Contents TABLES VIII FIGURES IX ABBREVIATIONS X ABSTRACT 1 1 THEORETICAL BACKGROUND 6 1.1 WORRY 6 1.1.1 DEFINITION, NATURE AND FUNCTION OF WORRY 6 1.1.2 THE WORRY CONTINUUM – NORMAL VERSUS MALADAPTIVE WORRY 7 1.1.3 THE DELETERIOUS EFFECTS OF EXCESSIVE WORRY 8 1.1.4 THEORETICAL MODELS OF EXCESSIVE WORRY 11 1.2 FUNCTIONAL BRAIN NETWORKS AND EXCESSIVE WORRY 18 1.2.1 A SYSTEMS NEUROSCIENCE VIEW OF EXCESSIVE WORRY 18 1.2.2 EMPIRICAL EVIDENCE: FMRI STUDIES ON EXCESSIVE WORRY 20 1.3 RESEARCH QUESTION 32 2 STUDY I: A QUANTITATIVE META-ANALYSIS OF FMRI STUDIES INVESTIGATING EMOTIONAL PROCESSING IN EXCESSIVE WORRIERS: APPLICATION OF ACTIVATION LIKELIHOOD ESTIMATION ANALYSIS 35 2.1 ABSTRACT 36 2.2 INTRODUCTION 37 2.3 METHODS 40 2.3.1 LITERATURE SEARCH AND STUDY SELECTION 40 2.3.2 ACTIVATION LIKELIHOOD ESTIMATION 46 2.3.3 META-ANALYTIC CONNECTIVITY MODELING 47 2.3.4 ANALYSIS OF BEHAVIORAL DOMAIN PROFILES 47 2.4 RESULTS 48 2.4.1 SIGNIFICANT ALE CLUSTERS 48 2.4.2 FUNCTIONAL CONNECTIVITY OF THE DERIVED ALE-CLUSTER – MACM-ANALYSIS 51 2.4.3 FUNCTIONAL CHARACTERIZATION OF THE DERIVED ALE-CLUSTER – BEHAVIORAL ANALYSIS 54 2.5 DISCUSSION 55 2.6 CONCLUSION 59 2.7 SUPPLEMENTARY MATERIAL STUDY I: LISTING OF ALE CLUSTERS SIGNIFICANT AT P < 0.001 UNCORRECTED, CLUSTER SIZE > 100MM3 60 3 STUDY II: HIGH AND LOW WORRIERS DO NOT DIFFER IN UNSTIMULATED RESTING-STATE BRAIN CONNECTIVITY 61 3.1 ABSTRACT 62 3.2 INTRODUCTION 63 3.3 MATERIALS AND METHODS 65 3.3.1 PARTICIPANTS AND PROCEDURE 65 3.3.2 FMRI DATA ACQUISITION 66 3.3.3 SELF-REPORT ASSESSMENTS AND STATE WORRY ASSESSMENT 66 3.3.4 STATISTICAL ANALYSES 67 3.4 RESULTS 69 3.4.1 SELF-REPORT MEASURES 69 3.4.2 FMRI RESULTS 72 3.5 DISCUSSION 72 3.6 CONCLUSION 75 3.7 SUPPLEMENTARY MATERIAL STUDY II: STATE WORRY ASSESSMENT 75 4 GENERAL DISCUSSION 76 4.1 CONVERGENT ABERRANT FUNCTION IN THE MFG-IFG-INSULA-CLUSTER 76 4.2 META-ANALYTIC FUNCTIONAL CHARACTERIZATION AND CONNECTIVITY MAPPING OF THE MFG-IFG-INSULA CLUSTER 82 4.3 NO RESTING-STATE FUNCTIONAL CONNECTIVITY DIFFERENCES BETWEEN HW AND LW 84 4.4 STRENGTHS AND LIMITATIONS 87 4.5 FUTURE DIRECTIONS 90 4.6 CONCLUSION 91 REFERENCES 92 APPENDIX: DECLARATION OF HONOUR / EIGENSTÄNDIGKEITSERKLÄRUNG 131 / Background. Excessive worry is characterized by persistent, repetitive negative thoughts that are perceived as intrusive and uncontrollable. Chronic worrying can become a severely debilitating mental activity and is thought to contribute to the development, maintenance and deterioration of a range of somatic health problems and mental disorders. Theoretical accounts and empirical findings suggest that excessive worry is associated with impaired bottom-up salience-processing, insufficient top-down attentional control, deficits in emotion regulation and abnormal self-referential mental functions. Neuroimaging studies of excessive worry indicate functional activation and connectivity alterations in limbic and paralimbic brain structures that support reactivity to emotional stimuli, in prefrontal structures implicated in top-down processes underlying attentional control and emotion regulation, and in cortical midline structures involved in self-referential mental activity. However, with regard to the presence, the exact localization of the brain areas involved and the directionality of the effects, these studies have presented largely heterogenous results. The high variability of findings makes it difficult to achieve a coherent understanding of the neurobiological mechanisms of excessive worry. To extend this understanding and provide future directions for continued research in this area, the aim of this thesis was threefold: (i) to synthesize the emotional task-based fMRI literature on excessive worry in a quantitative, data-driven manner for the purpose of identifying consistent functional perturbations across studies; (ii) to determine the psychological processes with which the identified brain regions are associated and the functional brain networks in which they operate; and (iii) to examine abnormalities in basic brain organization associated with excessive worry. Methods. A state-of-the-art coordinate-based meta-analysis was conducted applying the activation likelihood estimation (ALE) algorithm to determine concordance among 16 neuroimaging experiments reporting alterations in brain functional activity during emotional processing between individuals experiencing high versus normal levels of worry. The identified regions were behaviorally characterized using functional magnetic resonance imaging (fMRI) metadata. Additionally, meta-analytic-connectivity modeling (MACM) was used to determine their global functional connectivity (FC) patterns and thus identify related brain networks. Finally, resting-state fMRI was used to compare FC patterns between 21 high and 21 low worriers in the absence of task-related brain activation. Dispositional worry was assessed using the Penn State Worry Questionnaire as a reliable self-report measure of severe worry. Seed-based analyses with the meta-analytically derived brain regions as seeds and a data-driven multi-voxel pattern analysis (MVPA) were performed to detect FC differences between the two groups. In addition, cross-group correlations between state worry levels and the FC patterns of the seed regions as well as the MVPA-derived component scores were analyzed. Results. The meta-analysis revealed convergent aberrations in high compared to normal worriers mainly in a left-hemispheric cluster comprising parts of the middle frontal gyrus, inferior frontal gyrus and anterior insula. Behavioral characterization indicated the identified cluster to be associated with language processing and memory. Furthermore, meta-analytic connectivity mapping yielded strong functional connections between the observed convergent regions and frontal, temporal, and parietal brain regions that overlap with parts of two behaviorally relevant brain networks, specifically the salience network (SN) and the default network (DN). The resting-state FC (rsFC) analyses revealed no differences between high and normal worriers and also no correlations between rsFC patterns and state worry, neither using the seed-based nor the MVPA approach. Conclusions. The results of this thesis indicate that excessive worry is related to disturbed functioning in brain areas that have been related to bottom-up and top-down attentional control as well as emotion generation and regulation. Behavioral analysis uncovered associations between the identified cluster and language processing that might be related to the exaggerated inner speech processes in worry prone individuals. This association has so far remained rather unnoticed and requires further exploration. Moreover, the identified brain regions constitute key nodes within interacting neural networks that support internally and externally oriented cognition and control the dynamic interplay among these processes. Their altered cross-network dynamics may underlie the inability of worry-prone individuals to disengage from internally oriented cognitions when adaptive responding would require an external focus of attention. The null-findings of the resting-state analyses might be due to the study design or caused by characteristics of worry itself, but are not interpreted as evidence that abnormalities in the brain's intrinsic connectivity associated with excessive worrying are absent. The results of this thesis may guide future research that could, for example, investigate whether and how the dynamic temporal interactions within and between the networks identified here differ depending on the severity of worry. The ALE results provide an a priori selection of brain regions for such studies. Increasing our understanding of the aberrations in brain networks that underlie excessive worry and the psychological functions that are impaired as a result will provide targets for improving therapeutic interventions.:Contents TABLES VIII FIGURES IX ABBREVIATIONS X ABSTRACT 1 1 THEORETICAL BACKGROUND 6 1.1 WORRY 6 1.1.1 DEFINITION, NATURE AND FUNCTION OF WORRY 6 1.1.2 THE WORRY CONTINUUM – NORMAL VERSUS MALADAPTIVE WORRY 7 1.1.3 THE DELETERIOUS EFFECTS OF EXCESSIVE WORRY 8 1.1.4 THEORETICAL MODELS OF EXCESSIVE WORRY 11 1.2 FUNCTIONAL BRAIN NETWORKS AND EXCESSIVE WORRY 18 1.2.1 A SYSTEMS NEUROSCIENCE VIEW OF EXCESSIVE WORRY 18 1.2.2 EMPIRICAL EVIDENCE: FMRI STUDIES ON EXCESSIVE WORRY 20 1.3 RESEARCH QUESTION 32 2 STUDY I: A QUANTITATIVE META-ANALYSIS OF FMRI STUDIES INVESTIGATING EMOTIONAL PROCESSING IN EXCESSIVE WORRIERS: APPLICATION OF ACTIVATION LIKELIHOOD ESTIMATION ANALYSIS 35 2.1 ABSTRACT 36 2.2 INTRODUCTION 37 2.3 METHODS 40 2.3.1 LITERATURE SEARCH AND STUDY SELECTION 40 2.3.2 ACTIVATION LIKELIHOOD ESTIMATION 46 2.3.3 META-ANALYTIC CONNECTIVITY MODELING 47 2.3.4 ANALYSIS OF BEHAVIORAL DOMAIN PROFILES 47 2.4 RESULTS 48 2.4.1 SIGNIFICANT ALE CLUSTERS 48 2.4.2 FUNCTIONAL CONNECTIVITY OF THE DERIVED ALE-CLUSTER – MACM-ANALYSIS 51 2.4.3 FUNCTIONAL CHARACTERIZATION OF THE DERIVED ALE-CLUSTER – BEHAVIORAL ANALYSIS 54 2.5 DISCUSSION 55 2.6 CONCLUSION 59 2.7 SUPPLEMENTARY MATERIAL STUDY I: LISTING OF ALE CLUSTERS SIGNIFICANT AT P < 0.001 UNCORRECTED, CLUSTER SIZE > 100MM3 60 3 STUDY II: HIGH AND LOW WORRIERS DO NOT DIFFER IN UNSTIMULATED RESTING-STATE BRAIN CONNECTIVITY 61 3.1 ABSTRACT 62 3.2 INTRODUCTION 63 3.3 MATERIALS AND METHODS 65 3.3.1 PARTICIPANTS AND PROCEDURE 65 3.3.2 FMRI DATA ACQUISITION 66 3.3.3 SELF-REPORT ASSESSMENTS AND STATE WORRY ASSESSMENT 66 3.3.4 STATISTICAL ANALYSES 67 3.4 RESULTS 69 3.4.1 SELF-REPORT MEASURES 69 3.4.2 FMRI RESULTS 72 3.5 DISCUSSION 72 3.6 CONCLUSION 75 3.7 SUPPLEMENTARY MATERIAL STUDY II: STATE WORRY ASSESSMENT 75 4 GENERAL DISCUSSION 76 4.1 CONVERGENT ABERRANT FUNCTION IN THE MFG-IFG-INSULA-CLUSTER 76 4.2 META-ANALYTIC FUNCTIONAL CHARACTERIZATION AND CONNECTIVITY MAPPING OF THE MFG-IFG-INSULA CLUSTER 82 4.3 NO RESTING-STATE FUNCTIONAL CONNECTIVITY DIFFERENCES BETWEEN HW AND LW 84 4.4 STRENGTHS AND LIMITATIONS 87 4.5 FUTURE DIRECTIONS 90 4.6 CONCLUSION 91 REFERENCES 92 APPENDIX: DECLARATION OF HONOUR / EIGENSTÄNDIGKEITSERKLÄRUNG 131

Several lines of evidence suggest that asymmetric anterior brain activation is related to affective style, linking left hemisphere activation to positive affect and right hemisphere activation to negative affect. However, previous reports of left frontal hypoactivation in depressed patients were not confirmed in recent studies. This study evaluated additional characteristics of resting EEG alpha (8–13 Hz) asymmetry in 15 clinically depressed patients and 22 healthy adults by recording EEG activity on two separate occasions, 2–4 weeks apart. Across both sessions, group differences in anterior EEG asymmetry were compatible with the original hypothesis. However, groups differed in temporal stability of anterior EEG asymmetry, which was retest reliable in controls but not depressed patients. In contrast, temporal stability of posterior EEG asymmetry was acceptable in both groups. Increased variability of anterior EEG asymmetry may be a characteristic feature for depression, and, if so, this would challenge the notion that anterior EEG alpha asymmetry is a trait marker for depression. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Environ 25% de la population mondiale est atteinte de troubles psychiatriques qui sont typiquement associés à des problèmes comportementaux, fonctionnels et/ou cognitifs et dont les corrélats neurophysiologiques sont encore très mal compris. Non seulement ces dysfonctionnements réduisent la qualité de vie des individus touchés, mais ils peuvent aussi devenir un fardeau pour les proches et peser lourd dans l’économie d’une société. Cibler les mécanismes responsables du fonctionnement atypique du cerveau en identifiant des biomarqueurs plus robustes permettrait le développement de traitements plus efficaces. Ainsi, le premier objectif de cette thèse est de contribuer à une meilleure caractérisation des changements dynamiques cérébraux impliqués dans les troubles mentaux, plus précisément dans la schizophrénie et les troubles d’humeur. Pour ce faire, les premiers chapitres de cette thèse présentent, en intégral, deux revues de littératures systématiques que nous avons menées sur les altérations de connectivité cérébrale, au repos, chez les patients schizophrènes, dépressifs et bipolaires. Ces revues révèlent que, malgré des avancées scientifiques considérables dans l’étude de l’altération de la connectivité cérébrale fonctionnelle, la dimension temporelle des mécanismes cérébraux à l’origine de l’atteinte de l’intégration de l’information dans ces maladies, particulièrement de la schizophrénie, est encore mal comprise. Par conséquent, le deuxième objectif de cette thèse est de caractériser les changements cérébraux associés à la schizophrénie dans le domaine temporel. Nous présentons deux études dans lesquelles nous testons l’hypothèse que la « disconnectivité temporelle » serait un biomarqueur important en schizophrénie. Ces études explorent les déficits d’intégration temporelle en schizophrénie, en quantifiant les changements de la dynamique neuronale dite invariante d’échelle à partir des données magnétoencéphalographiques (MEG) enregistrés au repos chez des patients et des sujets contrôles. En particulier, nous utilisons (1) la LRTCs (long-range temporal correlation, ou corrélation temporelle à longue-distance) calculée à partir des oscillations neuronales et (2) des analyses multifractales pour caractériser des modifications de l’activité cérébrale arythmique. Par ailleurs, nous développons des modèles de classification (en apprentissage-machine supervisé) pour mieux cerner les attributs corticaux et sous-corticaux permettant une distinction robuste entre les patients et les sujets sains. Vu que ces études se basent sur des données MEG spontanées enregistrées au repos soit avec les yeux ouvert, ou les yeux fermées, nous nous sommes par la suite intéressés à la possibilité de trouver un marqueur qui combinerait ces enregistrements. La troisième étude originale explore donc l’utilité des modulations de l’amplitude spectrale entre yeux ouverts et fermées comme prédicteur de schizophrénie. Les résultats de ces études démontrent des changements cérébraux importants chez les patients schizophrènes au niveau de la dynamique d’invariance d’échelle. Elles suggèrent une dégradation du traitement temporel de l’information chez les patients, qui pourrait être liée à leurs symptômes cognitifs et comportementaux. L’approche multimodale de cette thèse, combinant la magétoencéphalographie, analyses non-linéaires et apprentissage machine, permet de mieux caractériser l’organisation spatio-temporelle du signal cérébrale au repos chez les patients atteints de schizophrénie et chez des individus sains. Les résultats fournissent de nouvelles preuves supportant l’hypothèse d’une « disconnectivité temporelle » en schizophrénie, et étendent les recherches antérieures, en explorant la contribution des structures cérébrales profondes et en employant des mesures non-linéaires avancées encore sous-exploitées dans ce domaine. L’ensemble des résultats de cette thèse apporte une contribution significative à la quête de nouveaux biomarqueurs de la schizophrénie et démontre l’importance d’élucider les altérations des propriétés temporelles de l’activité cérébrales intrinsèque en psychiatrie. Les études présentées offrent également un cadre méthodologique pouvant être étendu à d’autres psychopathologie, telles que la dépression. / Psychiatric disorders affect nearly a quarter of the world’s population. These typically bring about debilitating behavioural, functional and/or cognitive problems, for which the underlying neural mechanisms are poorly understood. These symptoms can significantly reduce the quality of life of affected individuals, impact those close to them, and bring on an economic burden on society. Hence, targeting the baseline neurophysiology associated with psychopathologies, by identifying more robust biomarkers, would improve the development of effective treatments. The first goal of this thesis is thus to contribute to a better characterization of neural dynamic alterations in mental health illnesses, specifically in schizophrenia and mood disorders. Accordingly, the first chapter of this thesis presents two systematic literature reviews, which investigate the resting-state changes in brain connectivity in schizophrenia, depression and bipolar disorder patients. Great strides have been made in neuroimaging research in identifying alterations in functional connectivity. However, these two reviews reveal a gap in the knowledge about the temporal basis of the neural mechanisms involved in the disruption of information integration in these pathologies, particularly in schizophrenia. Therefore, the second goal of this thesis is to characterize the baseline temporal neural alterations of schizophrenia. We present two studies for which we hypothesize that the resting temporal dysconnectivity could serve as a key biomarker in schizophrenia. These studies explore temporal integration deficits in schizophrenia by quantifying neural alterations of scale-free dynamics using resting-state magnetoencephalography (MEG) data. Specifically, we use (1) long-range temporal correlation (LRTC) analysis on oscillatory activity and (2) multifractal analysis on arrhythmic brain activity. In addition, we develop classification models (based on supervised machine-learning) to detect the cortical and sub-cortical features that allow for a robust division of patients and healthy controls. Given that these studies are based on MEG spontaneous brain activity, recorded at rest with either eyes-open or eyes-closed, we then explored the possibility of finding a distinctive feature that would combine both types of resting-state recordings. Thus, the third study investigates whether alterations in spectral amplitude between eyes-open and eyes-closed conditions can be used as a possible marker for schizophrenia. Overall, the three studies show changes in the scale-free dynamics of schizophrenia patients at rest that suggest a deterioration of the temporal processing of information in patients, which might relate to their cognitive and behavioural symptoms. The multimodal approach of this thesis, combining MEG, non-linear analyses and machine-learning, improves the characterization of the resting spatiotemporal neural organization of schizophrenia patients and healthy controls. Our findings provide new evidence for the temporal dysconnectivity hypothesis in schizophrenia. The results extend on previous studies by characterizing scale-free properties of deep brain structures and applying advanced non-linear metrics that are underused in the field of psychiatry. The results of this thesis contribute significantly to the identification of novel biomarkers in schizophrenia and show the importance of clarifying the temporal properties of altered intrinsic neural dynamics. Moreover, the presented studies offer a methodological framework that can be extended to other psychopathologies, such as depression.

A sister group of the Arthropoda, the Tardigrada are micrometazoans that occupy a diversity of niches in freshwater, marine, and terrestrial habitats. Commonly called water bears because of their slow, lumbering gait, these molting lobopods have four pairs of legs, usually terminating in claws. Most are less than 1 mm in length, with a complete digestive tract, a dorsal gonad with one or two gonoducts, and a dorsal lobed brain with a ventral nerve cord and four bilobed ganglia, one per leg-bearing metamere. The body cavity (hemocoel) functions in respiration and circulation. Over 1200 species have been described based primarily on the morphology of the claws and buccal-pharyngeal apparatus. Individuals may be either gonochoric, unisexual, or hermaphroditic, with fertilized or unfertilized eggs deposited either freely or within the shed exuvium. Parthenogenesis occurs frequently in limnic and terrestrial tardigrades, allowing them to colonize new territories by passive dispersal of a single individual. Cryptobiosis (anhydrobiosis, anoxybiosis, cryobiosis, and osmobiosis) and diapause (encystment and resting eggs) occur during the life history. Active adults (surrounded by water) and cryptobiotic adults and eggs are primarily dispersed passively, but some active dispersal can also occur. Due to the characteristic patchy distributions of tardigrade populations, little is known about their population dynamics and trophic relationships. Improved methods for collection, microscopy, culturing, and molecular analyses have been have contributed much to our knowledge of tardigrades.