Altered temporal connectivity and reduced meta-state dynamism in adolescents born very preterm

Adolescents born very preterm have an increased risk for anxiety, social difficulties and inattentiveness, i.e. the ‘preterm behavioural phenotype’. The extreme end of these traits comprises the core diagnostic features of attention and hyperactivity disorders and autism spectrum disorder, which have been reported to show aberrant dynamic resting-state functional network connectivity. This study aimed to compare this dynamism between adolescents born very preterm and controls. A resting-state functional magnetic resonance imaging was performed on 24 adolescents born very preterm (gestational agePeer reviewe

Thalamocortical Hyperconnectivity and Amygdala-Cortical Hypoconnectivity in Male Patients With Autism Spectrum Disorder

Background: Analyses of resting-state functional magnetic resonance imaging (rs-fMRI) have been performed to investigate pathophysiological changes in the brains of patients with autism spectrum disorder (ASD) relative to typically developing controls (CTLs). However, the results of these previous studies, which have reported mixed patterns of hypo- and hyperconnectivity, are controversial, likely due to the small sample sizes and limited age range of included participants.Methods: To overcome this issue, we analyzed multisite neuroimaging data from a large sample (n = 626) of male participants aged between 5 and 29 years (mean age = 13 years). The rs-fMRI data were preprocessed using SPM12 and DPARSF software, and signal changes in 90 brain regions were extracted. Multiple linear regression was used to exclude the effect of site differences in connectivity data. Subcortical–cortical connectivity was computed using connectivities in the hippocampus, amygdala, caudate nucleus, putamen, pallidum, and thalamus. Eighty-eight connectivities in each structure were compared between patients with ASD and CTLs using multiple linear regression with group, age, and age × group interactions, head movement parameters, and overall connectivity as variables.Results: After correcting for multiple comparisons, patients in the ASD group exhibited significant increases in connectivity between the thalamus and 19 cortical regions distributed throughout the fronto-parietal lobes, including the temporo-parietal junction and posterior cingulate cortices. In addition, there were significant decreases in connectivity between the amygdala and six cortical regions. The mean effect size of hyperconnectivity (0.25) was greater than that for hypoconnectivity (0.08). No other subcortical structures showed significant group differences. A group-by-age interaction was observed for connectivity between the thalamus and motor-somatosensory areas.Conclusions: These results demonstrate that pathophysiological changes associated with ASD are more likely related to thalamocortical hyperconnectivity than to amygdala-cortical hypoconnectivity. Future studies should examine full sets of clinical and behavioral symptoms in combination with functional connectivity to explore possible biomarkers for ASD

Thalamic nuclei segmentation from T1_1-weighted MRI: unifying and benchmarking state-of-the-art methods with young and old cohorts

The thalamus and its constituent nuclei are critical for a broad range of cognitive and sensorimotor processes, and implicated in many neurological and neurodegenerative conditions. However, the functional involvement and specificity of thalamic nuclei in human neuroimaging is underappreciated and not well studied due, in part, to technical challenges of accurately identifying and segmenting nuclei. This challenge is further exacerbated by a lack of common nomenclature for comparing segmentation methods. Here, we use data from healthy young (Human Connectome Project, 100 subjects) and older healthy adults, plus those with minor cognitive impairment and Alzheimer$'$s disease (Alzheimer$'$s Disease Neuroimaging Initiative, 540 subjects), to benchmark four state of the art thalamic segmentation methods for T1 MRI (FreeSurfer, HIPS-THOMAS, SCS-CNN, and T1-THOMAS) under a single segmentation framework. Segmentations were compared using overlap and dissimilarity metrics to the Morel stereotaxic atlas. We also quantified each method$'$s estimation of thalamic nuclear degeneration across Alzheimer$'$s disease progression, and how accurately early and late mild cognitive impairment, and Alzheimers disease could be distinguished from healthy controls. We show that HIPS-THOMAS produced the most effective segmentations of individual thalamic nuclei and was also most accurate in discriminating healthy controls from those with mild cognitive impairment and Alzheimer$'$s disease using individual nucleus volumes. This work is the first to systematically compare the efficacy of anatomical thalamic segmentation approaches under a unified nomenclature. We also provide recommendations of which segmentation method to use for studying the functional relevance of specific thalamic nuclei, based on their overlap and dissimilarity with the Morel atlas.Comment: 10 figures, 4 tables, 3 supplemental figures, 2 supplemental table

Brain network signatures of depressive symptoms

Depressive symptoms are common in the general population. Even in individuals who do not meet the criteria for a Major Depression Disorder (MDD), their symptoms are of clinical relevance because they increase the likelihood of progressing into a full-blown depressive episode, which in turn increases the prevalence of future episodes. The studies in this thesis apply advanced computational methods to functional magnetic resonance imaging (fMRI) data to investigate the dynamics of network connectivity, with the aim of understanding what brain mechanisms make a person more vulnerable to depression. Our results suggest that imbalances in whole-brain connectivity can already be linked to higher levels of depressive symptoms in healthy (undiagnosed) individuals. These imbalances correspond to a reduced dynamism in the overall functional organization of the brain, suggesting a link between a ‘rigid brain’ and rigid behavior, such as the lack of flexibility in cognitive and emotional responses that often accompanies depressive symptoms. Additionally, individual differences in the repertoire of brain states indicate that people with more depressive symptoms engage more in states related to self-referential thinking. This tendency was also observed in remitted patients during the transition into a depressive episode. This emphasizes that the present experience of depressive symptoms, whether in healthy individuals or MDD patients, is associated with changes in brain communication. The findings of this thesis lead to a deeper understanding of the complex orchestration of brain communication and its changes concerning depressive symptomatology in clinical and nonclinical populations

Dynamic functional connectivity in schizophrenia and bipolar disorder: A review of the evidence and associations with psychopathological features

Alterations of functional network connectivity have been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BD). Recent studies also suggest that the temporal dynamics of functional connec-tivity (dFC) can be altered in these disorders. Here, we summarized the existing literature on dFC in SCZ and BD, and their association with psychopathological and cognitive features. We systematically searched PubMed, Web of Science, and Scopus for studies investigating dFC in SCZ and BD and identified 77 studies. Our findings support a general model of dysconnectivity of dFC in SCZ, whereas a heterogeneous picture arose in BD. Although dFC alterations are more severe and widespread in SCZ compared to BD, dysfunctions of a triple network system underlying goal-directed behavior and sensory-motor networks were present in both disorders. Furthermore, in SCZ, positive and negative symptoms were associated with abnormal dFC.Implications for understanding the pathophysiology of disorders, the role of neurotransmitters, and treatments on dFC are discussed. The lack of standards for dFC metrics, replication studies, and the use of small samples represent major limitations for the field

Reduced spatiotemporal brain dynamics are associated with increased depressive symptoms after a relationship breakup

Depressive symptoms following a stressful life event, such as a relationship breakup, are common, and constitute a potent risk factor for the onset of a major depressive episode. Resting-state neuroimaging studies have increasingly identified abnormal whole-brain communication in patients with depression, but it is currently unclear whether depressive symptoms in individuals without a clinical diagnosis have reliable neural underpinnings. We investigated to what extent the severity of depressive symptoms in a non-clinical sample was associated with imbalances in the complex dynamics of the brain during rest. To this end, a novel intrinsic ignition approach was applied to resting-state neuroimaging data from sixty-nine participants with varying degrees of depressive symptoms following a relationship breakup. Ignition-based measures of integration, hierarchy, and metastability were calculated for each participant, revealing a negative correlation between these measures and depressive ratings. We found that the severity of depressive symptoms was associated with deficits in the brain’s capacity to globally integrate and process information over time. Furthermore, we found that increased depressive symptoms were associated with reduced spatial diversity (i.e., hierarchy) and reduced temporal variability (i.e., metastability) in the functional organization of the brain. These findings suggest the merit of investigating constrained dynamical complexity as it is sensitive to the level of depressive symptoms even in a non-clinical sample.This work was funded by a donation of Mr. Hazewinkel to Prof. dr. Gert J. ter Horst and the Research School of Behavioural and Cognitive Neurosciences, University of Groningen, the Netherlands. The funder had no role in study design, the collection, analysis and, interpretation of data, the decision to publish, or the writing of the manuscript

Early Gaze Behaviours in Infants at High Familial Risk for Autism Spectrum Disorder: association with brain development

Children diagnosed with Autism Spectrum Disorder (ASD) show impairments in gaze-following and will seldom engage in joint attention (JA). The ability to initiate JA (IJA) can be more impaired than the ability to respond to JA (RJA). In a longitudinal study, 101 high-risk infants for ASD (62% males) completed MRI scans at 4 or 6 months of age. Subcortical volumes (thalamus, basal ganglia, hippocampus, amygdala) were extracted. Gaze and JA behaviours were assessed with standardized measures. The majority of infants were IJA non-responders (n=93, 92%), and over half were RJA non-responders (n=50, 52%). In the non-responder groups, models testing the association of subcortical volumes with later ASD diagnosis accounted for age, sex, and cerebral volumes. It was found that hippocampal and thalamic volumes predicted later ASD diagnosis. Findings suggest that these brain regions may present increased vulnerability early in life and might be key predictors of the development of ASD

Diffusion-weighted and functional magnetic resonance imaging of the brain in preterm and term-born adolescents

Magnetic resonance imaging (MRI) is widely used in clinical and research settings in the adolescent population. Technical development has allowed the use of fine-grained methods to assess both the structural and functional properties of the brain. However, the specific technical limitations and improvements are mostly studied in phantom or adult studies, which may have an impact on their reliability as research tools when studying the younger population. Very preterm (VPT) birth is associated with several neurodevelopmental impairments. The present MRI tools provide opportunities to study brain maturation in detail. This thesis is a part of the multidisciplinary longitudinal follow-up study on the development and functioning of very low birth weight infants from infancy to school age (PIPARI). The follow-up cohort consists of infants born VPT (birth weight ≤1500 g and/or gestational age <32 weeks) in Turku University Hospital in 2001–2006 and term-born controls born in 2001–2004 in the same hospital. This thesis includes only children born VPT in 2004–2006 and controls born between 2003–2004 due to an upgrade of the MRI scanner during the recruitment. In Study I, the diffusion-weighted imaging (DWI) metrics at term-equivalent age were compared to the motor outcome at 11 years of age in children born VPT. Study II assessed the effect of the susceptibility correction to the DWI metrics in a healthy adolescent population. In Study III, temporal fluctuation of the resting state brain functioning was compared between 13-year-old adolescents born VPT and at term. The main prematurity-related findings of this thesis were that the DWI metrics of the corpus callosum, left corona radiata and right optic radiation at term are associated with later motor outcome in children born VPT and that adolescents born VPT show a decrease in active time, fluidity and range in brain activation during rest. These findings may reflect the adjustments in brain microstructure and function caused by the VPT birth. Fine-grained MRI methods are reliable tools for studying the mechanisms behind the clinical phenotypes of adolescents when technical limitations and age-appropriate analysis adjustments are considered.Diffuusiopainotteisen ja toiminnallisen aivojen magneettikuvantamisen käyttö nuoruusiässä entisillä pikkukeskosilla ja täysiaikaisilla verrokeilla Magneettikuvaus (MRI) on laajassa kliinisessä ja tieteellisessä käytössä lapsia ja nuoria tutkittaessa. Tekninen kehitys mahdollistaa yhä hienojakoisempia aivojen tutkimuksia. MRI:n teknisiä korjauksia on tutkittu pääosin mallintamalla tai aikuisilla, mikä voi heikentää luotettavuutta alaikäisillä. Hyvin ennenaikaisesti syntyvillä lapsilla neurologisen kehityksen poikkeavuuksien riski on täysiaikaisena syntyviä suurempi. Poikkeavuudet voivat liittyä aivojen kehityksen muutoksiin, joita nykyisillä tekniikoilla voidaan tutkia aiempaa yksityiskohtaisemmin. Väitöskirja on osa PIPARI-tutkimusta (Pienipainoisten riskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään). Seurantakohortti koostuu pikkukeskosina (syntymäpaino ≤1500 g ja/tai raskauden kesto <32 viikkoa) Tyksissä vuosina 2001–2006 syntyneistä lapsista sekä täysiaikaisena 2001–2004 syntyneistä verrokeista. MRI-laitteiston päivityksestä johtuen osatyöt käsittelevät pikkukeskosina vuosina 2004–2006 ja verrokkeina vuosina 2003–2004 syntyneitä. Ensimmäisessä osatyössä verrattiin aivojen diffuusiokuvantamistuloksia entisten pikkukeskosten motoriseen toimintakykyyn 11-vuotiaana. Toinen osatyö käsitteli suskeptibiliteettikorjauksen vaikutusta aivojen diffuusiokuvantamisen mittaustuloksiin. Kolmannessa osatyössä vertailtiin 13-vuotiaiden entisten pikkukeskosten ja verrokkien aivojen aktiivisuuden vaihtelua lepotilassa toiminnallisen MRI-kuvauksen aikana. Tämän väitöskirjan keskosuuteen liittyvät päätulokset olivat lasketun syntymäajan corpus callosumin, vasemman corona radiatan ja oikean optisen radaston diffuusiomittaustulosten yhteys motoriseen kehitykseen 11-vuotiaana sekä pikkukeskosina syntyneillä havaittu aivojen vähäisempi aktiivinen aika ja alentunut aktiivisuuden vaihtelun joustavuus 13-vuotiaana. Nämä löydökset saattavat olla seurausta varhaiseen syntymään liittyvistä aivojen mikrorakenteen ja toiminnan muutoksista. Hienojakoiset MRI-menetelmät vaikuttavat olevan luotettavia nuorisoikäisiä tutkittaessa, kunhan tekniset rajoitteet ja ikäsovitukset huomioidaan