Brain correlates of obsessive-compulsive symptoms in healthy children

Abstract

Esta tesis busca contribuir al estudio de los correlatos neurobiológicos de los síntomas obsesivos-compulsivos subclínicos (SOCS) con la esperanza de que sus hallazgos puedan ser eventualmente vinculados al desarrollo del trastorno obsesivo-compulsivo (TOC) y servir para identificar individuos vulnerables a desarrollarlo. Para ello, presentamos tres estudios realizados en una muestra de niños sanos, en los que utilizamos un enfoque multidimensional de los síntomas e implementamos distintas modalidades de neuroimagen, así como la combinación de datos de neuroimagen y genética, para aportar una visión integral de los factores que subyacen los SOCS. En el primer estudio, analizamos cambios volumétricos en la sustancia gris y blanca asociados a los SOCS y, en el segundo, evaluamos alteraciones de conectividad funcional asociadas a estos síntomas. En ambos, estudiamos el efecto de la edad y el sexo en dichas asociaciones. Finalmente, en el tercer estudio, identificamos nodos cerebrales en los que la conectividad funcional dinámica tiende a reverberar (atractores) y estudiamos su relación con los SOCS y su base genética.

Nuestros resultados vinculan los SOCS totales con alteraciones en el circuito cortico-estriato- talamo-cortical (CSTC), hecho que concuerda con el modelo neurobiológico del TOC, pero también en regiones límbicas fuera de este circuito. También observamos que diferentes síntomas se asocian a alteraciones neurobiológicas distintas, lo que coincide con el modelo multidimensional del trastorno. Además, encontramos que los cambios estructurales relacionados con los síntomas de orden eran específicos de niños menores de 10 años, mientras que los cambios estructurales y funcionales asociados con los síntomas de acumulación eran específicos de sujetos de más de 10 años, especialmente en niñas, lo que sugiere que estos grupos demográficos pueden ser especialmente vulnerables a desarrollar dichos síntomas. Finalmente, identificamos polimorfismos en los genes GRM7 y GNAQ, implicados en la modulación de la neurotransmisión glutamatérgica, y PARVA, asociado a la regulación del citoesqueleto de actina, que predisponen al aumento de la capacidad atractora del hipocampo, vinculada a los SOCS totales. Del mismo modo, hallamos polimorfismos en los genes ATP1B1 y TESC, implicados en el mantenimiento de gradientes electroquímicos, que predisponen y protegen, respectivamente, al aumento de las propiedades atractoras del córtex parietal superior, relacionadas con los síntomas de orden.

Obsessive-compulsive disorder (OCD) is characterized by the presence of intrusive thoughts that cause anxiety (obsessions) and lead to repetitive behaviors or mental acts aimed at reducing this anxiety (compulsions). Although OCD has been associated with alterations in the cortico-striato- thalamo-cortical (CSTC) circuits, the clinical heterogeneity of the disorder makes its neurobiology difficult to investigate. Given that the evidence suggests that different OCD symptoms could arise from distinct neurobiological alterations, the use of the multidimensional model, which allows characterizing different symptom dimensions, could help define more homogeneous subgroups of patients and identify more robust endophenotypes. However, the studies that have used this approach have given heterogeneous findings, possibly due to differences between patients in terms of medication, chronicity, or comorbidities. Notably, epidemiological studies show that obsessive-compulsive symptoms (OCSs) in childhood predispose to developing OCD in adulthood. Furthermore, the symptom profile observed in adulthood is consistent with the same symptom precursors in childhood. Therefore, OCSs could be studied in samples of healthy children from a dimensional perspective, thus avoiding the confounding factors typically observed in clinical samples.

This thesis seeks to contribute to the study of the neurobiological correlates of OCSs in hopes that its findings may eventually be linked to the development of OCD and serve to characterize at-risk individuals. With that aim, we present three studies assessing a sample of healthy children, in which we use a multidimensional approach and implement different neuroimaging modalities and techniques, as well as the combination of neuroimaging and genetic data, to provide a comprehensive view of the factors underlying OCSs. In the first study, we analyzed volumetric changes in gray and white matter associated with total and dimensional OCSs whereas, in the second one, we evaluated functional connectivity alterations associated with total and dimensional OCSs. In both studies, we also assessed the effect of age and sex on these associations. In the third one, we identified brain nodes in which dynamic functional connectivity tends to reverberate (attractors) and we studied their relationship with total and dimensional OCSs. Furthermore, by combining neuroimaging and gene expression data, we identified genetic variants that moderated the relationship between OCSs and attractors.

Our results link total OCSs with alterations in the CSTC circuit, which concurs with the prevailing neurobiological model of OCD, but also in limbic regions outside of this circuit. We also observed that different symptoms were associated with distinct neurobiological alterations: obsessing symptoms were related to alterations in limbic regions; doubt/checking symptoms were associated with changes in the ventral cognitive CSTC loop, the insula and regions mediating frontal processing; ordering symptoms were associated with alterations in the ventral cognitive and sensorimotor CSTC loops and the superior parietal cortex; hoarding symptoms were related to alterations in different CSTC loops, suggesting a larger CSTC alteration. Structural changes related to ordering symptoms were specific to boys under 10 years of age, whereas structural and functional changes associated with hoarding symptoms were specific to children over 10 years of age, especially to girls, which suggests that these demographic groups may be more susceptible to developing such symptoms. Finally, we identified polymorphisms in the GRM7 and GNAQ genes, involved in the modulation of glutamate neurotransmission, and in the PARVA gene, associated with the regulation of the actin cytoskeleton, that predisposed to an increase in the attractor properties of the hippocampus, linked to total OCSs. We also found polymorphisms in the ATP1B1 and TESC genes, involved in the maintenance of electrochemical gradients, that predisposed and protected, respectively, to an increase in the attractor properties of the superior parietal cortex, related to ordering symptoms.