RT Dissertation/Thesis T1 Brain network alterations in Attention-Deficit and Hyperactivity Disorder: towards an integrative perspective based on systems neuroscience A1 Marcos Vidal, Luis AB Attention-Deficit and Hyperactivity Disorder (ADHD) is one of the most commonneurodevelopmental disorders, affecting mainly the school-age population but also havinga moderate prevalence rate into adulthood. It is characterized by symptoms of inattention,impulsivity, and hyperactivity improper for the patient’s age. However, this agedependentcharacterization of ADHD makes the diagnosis such a problematic issue: thematuration rate is different for each child, making the evaluation of what is age-proper asubjective and difficult question. All of this leads to the ubiquitous question of ADHD,namely, whether there is overdiagnosis of the disease or if it even exists. That is whystudying the brain is crucial in ADHD, because finding effective biomarkers able to characterizethe disease will allow us to diagnose it more accurately.Magnetic Resonance Imaging (MRI) is one of the most powerful and versatile tools forstudying the brain, providing information about both its structure and activity. TraditionalMRI studies have focused on analyzing properties of specific brain regions in terms oftheir shape (e.g., the volume of a structure) or their relation with a cognitive function(e.g., if a structure activates during object recognition), finding multiple alterations inADHD [8]. However, these widespread regions that present abnormalities are connectedbetween them and with other areas forming the brain network, and their alterations mayindeed represent different parts of a more global phenomenon [8, 9].There are four main neurobiological models that explain ADHD: the maturational laghypothesis, the dual-pathway model, the Default Mode Network (DMN) interference hypothesis,and multinetwork models. The maturational lag hypothesis is based on ADHDdiagnostic criteria and posits that the brain of people with this condition will resemblea younger one [10]. The dual-pathway model proposes two different processing streamsfor the main symptoms of ADHD: inattention is related to alterations in the corticostriatalexecutive circuits, while impulsivity/hyperactivity is associated with abnormalities inemotional processing [11, 12]. The DMN interference hypothesis posits that this functionalnetwork is not properly suppressed during goal-directed tasks, which is translatedinto intrusion of inner mental activity [13]. Finally, multinetwork models approach theneurobiology of people with ADHD as an alteration of multiple functional networks [14,15].All of these models have received substantial support from neuroimaging studies,which suggests that all of them are correct but incomplete descriptions of the brain profileof people with ADHD. The present dissertation aims to determine whether there is analteration of the global brain organization in people with ADHD that may underlie the featuresthat characterize the different neurobiological models of the disorder. For that, wewill apply two different graph-theory methods based on systems science to the restingstate functional Magnetic Resonance Imaging data of adults and children with ADHD.The two proposed metrics are Stepwise Functional Connectivity (SFC) and Local andDistant Functional Connectivity (LFC and DFC). The first one measures the integrationof information from sensory cortices to areas related to high-order cognitive functions,and in Study 1 [16], it will be applied to a sample of medication-naïve adults with ADHD.LFC and DFC study topological properties with physical distance restrictions, that is, thelevel of connectivity of each voxel with those around it or those far away. This methodwill be applied to a sample of children with ADHD in Study 2 [17] and the same sampleof adults used in Study 1 in Study 3 [18].Our results consist of alterations in widespread regions that overlap with most functionalnetworks [19]. Specifically, in adults with ADHD, we observed a decrease in integrationin the DMN that locally affects the Posterior Cingulate Cortex and its functionalconnectivity with the medial Prefrontal Cortex. Additionally, the integration of sensoryinformation in these areas was also found to be reduced in the same sample. The integrationof the DMN and its development into cortical hubs is a crucial process in thematuration of the brain [20], which relates this finding with a maturational lag. In bothchildren and adults with ADHD, we also observed a lack of segregation between theDMN, the Ventral Attentional Network, and the Frontoparietal Network in a frontal areaof the brain. The developmental trajectory of this area consists of the differentiation ofthree regions, each of them pertaining to one of these networks [21], and thus, it is asign of brain immaturity. Also, overconnectivity (lack of segregation) between these networksunderlies the DMN interference hypothesis and is indeed a multinetwork alteration[14, 22]. We also found abnormalities in the Visual Network in the form of increasedintegration of information in these areas while decreased local functional integration ofthe region, which reflects a behavior more typical of associative than sensory cortices[23, 24]. Finally, local connectivity of sensorimotor cortices presents different maturationtrends between ADHD and controls while predicting ADHD symptomatology in all ofthem.In conclusion, our results suggest that for understanding ADHD, we cannot focusjust on a few areas related to high-order cognitive functions, but the whole brain functionalnetwork is compromised. This goes in line with a recent meta-analysis [8] that wasunable to find convergence in specific regions abnormalities and proposed an analysisbased on network interactions. Altogether, this dissertation reflects the need to approachADHD from a systems neuroscience perspective that encompasses all the currently availablemodels instead of proposing alternative reductionist ones. YR 2022 FD 2022-10 LK https://hdl.handle.net/10016/35978 UL https://hdl.handle.net/10016/35978 LA eng NO Mención Internacional en el título de doctor DS e-Archivo RD 1 sept. 2024