Neurobiology of schizotypal phenotypes - Schizotypy as a framework for dimensional psychiatry

Complex, dimensional phenotypes represent a valuable framework for the analysis of fundamental neurobiological mechanisms of psychiatric disorders. They facilitate the deconstruction of diagnostic entities and the study of protective processes that prevent progression into clinical domains. Within the psychosis spectrum, schizotypy describes a multidimensional personality construct with behavioural, cognitive, and emotional characteristics similar to key symptoms of schizophrenia, that can equally be grouped into the dimensions positive (magical thinking, unusual perceptions and beliefs), negative (introversion, anhedonia), and disorganised (cognitive disorganisation, eccentricity). Within a continuum model of psychosis, schizotypy is discussed as variation of healthy function, and as risk phenotype of schizophrenia and psychosis proneness, assuming a (partially) overlapping genetic architecture along the spectrum. Current aetiological models propose an impact of genetic liability, in interaction with environmental risk and modulated by protective factors like cognitive function, through disruptions in neuronal development. In fact, recent studies show that schizotypy is associated with brain structural variation, partially overlapping with regions that are also impaired in patients with schizophrenia spectrum disorders. This dissertation characterised neurobiological determinants of schizotypy regarding its genetic basis and neural networks, aiming to develop a multimodal model to integrate those into a joint framework. STUDIES I and IV investigated the genetic structure of schizotypy, demonstrating its association with common variants (single nucleotide polymorphisms, SNPs) in genes (CACNA1C and ZNF804A) involved in processes of neuronal development and identified as risk genes for schizophrenia and other psychiatric disorders (STUDY I). In this association, biological sex has a moderating role. However, a direct association of a polygenic schizophrenia risk score, based on cumulative SNP-risk, was not established (STUDY IV). STUDIES II and III analysed brain structural correlates of schizotypy dimensions, finding an association of the positive dimension (and symptom-associated distress) with grey matter volume in associative brain areas precuneus, striatum and inferior temporal gyrus. STUDY II further indicates that this relationship can be buffered by above average general cognitive function. Study V ultimately integrates the previous results into a joint multivariate model that proves to explain a substantial amount of phenotypic variance. The model shows that the interaction effect of polygenic and poly-environmental risk on positive schizotypy is mediated through brain structural variation in the precuneus, and modulated by the level of executive function. In conclusion, this dissertation shows that schizotypy is associated with genetic polymorphisms involved in neuronal development and function. While those are identified as schizophrenia risk variants, the lack of an association with polygenic schizophrenia risk suggests a limited overlap of the genetic architectures of the phenotypes. The confirmation of the multivariate model, however, indicates an indirect effect through variations in brain structure and modulated by intra- and extrapersonal factors. Accordingly, particularly positive schizotypy is associated with structural alterations in brain regions central for the integration, evaluation, and attribution of perceptual information within associative neuronal networks. Thus, schizotypy is a valuable endophenotype of the schizophrenia spectrum, showing that pathophysiological aberrations lie on a continuum with variation of healthy functioning. Schizotypy, however, also describes the manifestation of interindividual variation in behaviour, cognition, and emotion, with its underlying mechanisms representing an exemplary framework for the study of dimensional, phenotypic spectra

Investigating the Impact of Chronic Stress on Anhedonia Via Alterations in Striatal Dopamine & Reward Circuitry Functioning

In preclinical and human studies, long-term exposure to chronic stress causes distinctive changes in neurobiological systems, including alterations in striatal dopamine (DA) functioning and functional brain reward circuitry (i.e., mesolimbic) that mediate hedonic functioning. However, most of the research linking alterations in brain reward circuitry and anhedonia has been in depressed populations. This is the first study of striatal dopamine functioning and reward circuitry in a transdiagnostic sample of adults with anhedonia, ranging in exposure to chronic stress. Participants completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with the D2/D3 receptor antagonist, [11C]raclopride, which selectively binds to striatal DA receptors. Results presented here provide evidence for reduced striatal DA functioning during reward processing and decreased mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia. This research has the potential to advance our understanding of conditions marked by dysfunctional reward processing, including depression, addiction, and schizophrenia.Master of Art

Searching for the genetic underpinnings of schizophrenia and bipolar disorder: Functional neuroimaging markers as potential endophenotypes

According to the Research Domain Criteria (RDoC) framework, mental diseases are conceptualized as disorders of brain circuits, which are measurable, and are based on genetic mechanisms. In the search for genetic underpinnings of psychopathology, the use of endophenotypes constitutes a promising approach. This thesis aimed to contribute to the identification of biosignatures for schizophrenia and bipolar disorder on a neuroimaging and molecular genetic level by using functional neuroimaging endophenotypes and an imaging genetics approach. It comprises two parts: In study 1, neurofunctional correlates of reward processing in unaffected first-degree relatives of patients with schizophrenia and bipolar disorder was examined using the ‘desire-reason dilemma’ paradigm. Study 2 investigated the genetic underpinnings of resting-state functional connectivity between the left fronto-parietal network and Heschl’s gyrus, which constitutes a potential endophenotype for schizophrenia, using a genome-wide association approach in a homogeneous sample of healthy subjects. Study 1 shows disruptions in mesocorticolimbic reward processing in first-degree relatives of patients with schizophrenia and bipolar disorder. Specifically, the study gives evidence for an enhanced bottom-up activation of the ventral striatum in first-degree relatives of patients with schizophrenia, which is in line with the hypothesis of a general hyperdopaminergic state in schizophrenia. In contrast, in first-degree relatives of patients with bipolar disorder, there was no difference in ventral striatal activation compared with controls, indicating intact bottom-up activation of the ventral striatum. More importantly, study results show a disturbed top-down control of mesolimbic reward signals by prefrontal brain regions in first-degree relatives of patients with schizophrenia and bipolar disorder. These results suggest that disrupted reward processing, possibly relying on dopamine malfunction, may be linked with the genetic vulnerability to develop schizophrenia or bipolar disorder, and thus constitutes a potential endophenotype for schizophrenia and bipolar disorder. Although these data suggests a genetic basis for mesocorticolimbic reward processing, an influence by environmental factors cannot be ruled out. Future studies in monozygotic and dizygotic twin pairs discordant for schizophrenia will be necessary to further investigate the genetic determinants of disturbed reward processing. Study 2 was able to identify one genome-wide significant variant, as well as four intronic loci with suggestive evidence for association. Among the top hits was an intronic locus (rs4958456) within calcium/calmodulin dependent protein kinase II alpha (CAMK2a) gene, which is high-specifically expressed in brain cortical tissue. Its gene product CaM-kinase II may function in neurotransmitter release, long-term potentiation and synaptic plasticity in glutamatergic synapses. This finding is in line with earlier studies supporting the role of calcium signaling in schizophrenia. However, replication will be necessary to evaluate these preliminary findings. Taken together, in line with the framework of RDoC, these findings contribute to the understanding of schizophrenia and bipolar disorder on a genomic and brain functional level

Perfiles de actividad magnética cerebral de jóvenes con consumo intensivo de alcohol

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Psicología, leída el 24-01-2017El patrón de consumo de alcohol binge drinking se caracteriza por la ingesta intermitente de grandes cantidades del alcohol en un corto espacio de tiempo alternándose con periodos de abstinencia. En España, este tipo de consumo de alcohol se asocia al conocido efecto botellón en el que los jóvenes se reúnen en espacios públicos, principalmente los fines de semana, teniendo el alcohol como protagonista. La adolescencia, edad en la que se inicia este tipo de consumo, es considerada un periodo crítico de desarrollo en el que el cerebro experimenta grandes cambios madurativos, fundamentalmente en los lóbulos frontales. Dada su inmadurez, el cerebro adolescente muestra mayor vulnerabilidad ante el efecto neurotóxico del alcohol que el cerebro adulto. Debido a la alta prevalencia que este tipo de consumo presenta entre los jóvenes, la comunidad científica ha mostrado interés en las últimas décadas por estudiar las posibles consecuencias que puede tener en la estructura y funcionamiento del cerebro de jóvenes que beben de este modo. Sin embargo, hasta el momento no existían estudios que evaluasen el efecto del binge drinking en la actividad magnética cerebral. La Magnetoencefalografía es una técnica no invasiva que mide las corrientes magnéticas generadas por las pequeñas corrientes neurales que producen las neuronas. La presente tesis ha utilizado esta técnica a lo largo de los tres experimentos en los que se estudió: 1) la actividad magnética cerebral en el espacio de los sensores asociada del estado de reposo de jóvenes universitarios de 18-19 años con el patrón binge drinking y un grupo control, 2) la actividad magnética cerebral en espacio de las fuentes del estado de reposo y la conectividad estructural de los mismos jóvenes dos años más tarde, con 20-21 años; y 3) la actividad magnética cerebral en espacio de las fuentes asociada a una tarea Go/NoGo de los mismos jóvenes durante la primera fase del estudio, cuando tenían 18-19 años...The alcohol consumption binge drinking pattern is characterized by intermittent intake of large amounts of alcohol in a short space of time, alternated with periods of abstinence. In Spain, this type of alcohol consumption is associated with the well-known “efecto botellón” where young people gather in public spaces, especially on weekends, having the alcohol as the protagonist. Adolescence, the age in which this type of consumption begins, is considered a critical period of neural development in which the brain undergoes maturational changes, mainly in the frontal lobes. Given its immaturity, adolescent brain is more vulnerable to the neurotoxic effects of alcohol than the adult brain. Because of its high prevalence among young adolescents, since last decades the scientific community has shown increasing interest to study the possible consequences that binge drinking may have on the structure and functioning of the brain. However, so far there are no studies assessing the effect of binge drinking with Magnetoencephalography. Magnetoencephalography is a noninvasive technique that measures the magnetic currents generated by neural currents produced by pyramidal neurons. The present dissertation has used this technique over the three experiments, studying: 1) brain magnetic activity in the sensor space associated to resting state of university students of aged 18-19 years old with alcohol binge drinking pattern and also a control group, 2) brain magnetic activity in the source space also associated to resting state and structural connectivity of the same young students two years later, with 20-21 years old; and finally, 3) the brain magnetic activity in source space associated with a Go/NoGo task in the first phase of the study, when the participants were 18-19...Fac. de PsicologíaTRUEunpu

Tracking the Temporal-Evolution of Supernova Bubbles in Numerical Simulations

The study of low-dimensional, noisy manifolds embedded in a higher dimensional space has been extremely useful in many applications, from the chemical analysis of multi-phase flows to simulations of galactic mergers. Building a probabilistic model of the manifolds has helped in describing their essential properties and how they vary in space. However, when the manifold is evolving through time, a joint spatio-temporal modelling is needed, in order to fully comprehend its nature. We propose a first-order Markovian process that propagates the spatial probabilistic model of a manifold at fixed time, to its adjacent temporal stages. The proposed methodology is demonstrated using a particle simulation of an interacting dwarf galaxy to describe the evolution of a cavity generated by a Supernov

Data-Driven Approach to Dynamic Resting State Functional Connectivity in Post-Traumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a heterogenous psychological disorder that may result from exposure to a traumatic event. Using functional magnetic resonance imaging (fMRI), symptoms of PTSD have been associated with aberrations in brain networks that emerge in the absence of a given cognitive demand or task, called resting state networks. Most previous research in resting state networks and PTSD has focused on aberrations in the static functional connectivity among specific regions of interest (ROI) in the brain and within canonical networks constrained by a priori hypotheses. However, dynamic fMRI, an approach that examines changes in brain network characteristics over time, may provide a more sensitive measure to understand the network properties underlying dysfunction in PTSD. In addition, a data-driven analytic approach may reveal the contribution of other larger network disturbances beyond those revealed by hypothesis-driven examinations of ROIs or canonical networks. Therefore, the current study used a data-driven approach to characterize and subsequently compare brain network dynamics and recurrent connectivity states in a large sample of trauma exposed individuals (1,000+) with and without PTSD from the ENIGMA-PGC-PTSD workgroup. Static functional connectivity results showed those with PTSD had lower network efficiencies than Controls within and between sensorimotor and visual subnetworks. Further, network dynamics showed increased network efficiencies through the course of the scan for both groups, except in the visual subnetwork where those with PTSD showed blunted efficiencies through time. Those with PTSD also had fewer individual-level connectivity states, especially in the second half of the scan, compared to Controls suggesting a degree of stochasticity in the network over time. Finally, there were no group differences in dwell time or number of transitions of group-level connectivity states. Together, results suggest aberrancies in large-scale brain networks related to PTSD diagnosis beyond the most common analyzed ROIs. Unsurprisingly, in a large and heterogenous trauma sample, larger scale group results were not as robust compared to similar analyses in smaller homogenous trauma samples. Heterogeneity of PTSD, especially within diffuse brain networks, cannot be captured by evaluating only diagnostic groups, further work should be done to evaluate brain network dynamics with respect to specific symptoms and trauma types

Genetics of Impulsive Behavior - endophenotypes, variant discovery by deep sequencing,molecular functionality, animal models and gene-environment interactions

Questa tesi riassume i miei studi sull’ impulsivita’ quale fenotipo intermedio condiviso da vari disturbi psichiatrici. L’impulsivita’, definita come l’incapacita’ di prevedere le conseguenze delle proprie azioni, e’ ereditabile ed in quanto tale dovrebbe essere possibile identificare geni causali di questo tratto comportamentale. Per raggiungere questo scopo ho utilizzato varie metodiche. In particolare il mio lavoro si e’ concentrato sull’identificazione di varianti genetiche rare e comuni, analisi funzionali, studi di associazione, topi ko ed interazioni geni-ambiente per meglio definire l’eziologia del comportamento impulsivo. Utilizzando tecniche di sequenziamento di nuova generazione ho identificato un codone di stop funzionale nel gene HTR2B – che codifica per il recettore 2B della serotonina- che e’ stato associato con comportamenti impulsivi in una popolazione fondatrice di origine finlandese. Inoltre, e’ stato studiato come topi ko per il recettore 5-ht2b sono anch’essi caratterizzati da comportamenti impulsivi e di novelty seeking. L’impulsivita’ e’ stata identificata come meccanismo neuronale di vulnerabilita’ alla dipendenza da sostanze, quale la dipendenza da cocaina. Ho condotto uno studio di aplotipo sul gene HTR2B in una popolazione di Afro-Americani ed un aplotipo con ridotta capacita’ di espressione e’ stato identificato ed associato con dipendenza da cocaina. In parallelo, e’ stato osservato che i topi htr2b-/- presentano maggior locomotor sensitization e conditioned place preference rispetto ai topi wild type in risposta a somministrazione di cocaina. Da studi molecolari sul topo ko e’ emerso come il recettore 2B della serotonina moduli il rilascio di dopamina nel nucleus accumbens e contribuisca ad un circuito neuronale fondamentale nell’eziologia delle dipendenze da sostanze. Infine ho esplorato interazioni geni-ambiente, in particolare come varianti del gene FKBP5, un gene con un ruolo regolatore nell’asse ipotalamo-ipofisi-surrene, modulino esperienze traumatiche dell’infanzia e comportamenti aggressivi in eta’ adulta. Nel futuro prossimo, l’identificazione di varianti genetiche nell’uomo e la loro validazione attraverso analisi molecolari e modelli animali ed interazioni geni-ambiente ci permetteranno di comprendere la patogenesi e di migliorare la prevenzione, gli strumenti diagnostici e lo sviluppo di medicine verso una medicina personalizzata