Exploring the longitudinal associations of functional network connectivity and psychiatric symptom changes in youth

Background: Functional connectivity has been associated with psychiatric problems, both in children and adults, but inconsistencies are present across studies. Prior research has mostly focused on small clinical samples with cross-sectional designs. Methods: We adopted a longitudinal design with repeated assessments to investigate associations between functional network connectivity (FNC) and psychiatric problems in youth (9- to 17-year-olds, two time points) from the general population. The largest single-site study of pediatric neurodevelopment was used: Generation R (N = 3,131 with data at either time point). Psychiatric symptoms were measured with the Child Behavioral Checklist as broadband internalizing and externalizing problems, and its eight specific syndrome scales (e.g., anxious-depressed). FNC was assessed with two complementary approaches. First, static FNC (sFNC) was measured with graph theory-based metrics. Second, dynamic FNC (dFNC), where connectivity is allowed to vary over time, was summarized into 5 states that participants spent time in. Cross-lagged panel models were used to investigate the longitudinal bidirectional relationships of sFNC with internalizing and externalizing problems. Similar cross-lagged panel models were run for dFNC. Results: Small longitudinal relationships between dFNC and certain syndrome scales were observed, especially for baseline syndrome scales (i.e., rule-breaking, somatic complaints, thought problems, and attention problems) predicting connectivity changes. However, no association between any of the psychiatric problems (broadband and syndrome scales) with either measure of FNC survived correction for multiple testing. Conclusion: We found no or very modest evidence for longitudinal associations between psychiatric problems with dynamic and static FNC in this population-based sample. Differences in findings may stem from the population drawn, study design, developmental timing, and sample sizes.</p

Towards Patient-Specific Brain Networks Using Functional Magnetic Resonance Imaging

fMRI applications are rare in translational medicine and clinical practice. What can be inferred from a single fMRI scan is often unreliable due to the relative low signal-to-noise ratio compared to other neuroimaging modalities. However, the potential of fMRI is promising. It is one of the few neuroimaging modalities to obtain functional brain organisation of an individual during task engagement and rest. This work extends on current fMRI image processing approaches to obtain robust estimates of functional brain organisation in two resting-state fMRI cohorts. The first cohort comprises of young adults who were born at extremely low gestations and age-matched healthy controls. Group analysis between term- and preterm-born adults revealed differences in functional organisation, which were discovered to be predominantly caused by underlying structural and physiological differences. The second cohort comprises of elderly adults with young onset Alzheimer’s disease and age-matched controls. Their corresponding resting-state fMRI scans are short in scanning time resulting in unreliable spatial estimates with conventional dual regression analysis. This problem was addressed by the development of an ensemble averaging of matrix factorisations approach to compute single subject spatial maps characterised by improved spatial reproducibility compared to maps obtained by dual regression. The approach was extended with a haemodynamic forward model to obtain surrogate neural activations to examine the subject’s task behaviour. This approach applied to two task-fMRI cohorts showed that these surrogate neural activations matched with original task timings in most of the examined fMRI scans but also revealed subjects with task behaviour different than intended by the researcher. It is hoped that both the findings in this work and the novel matrix factorisation approach itself will benefit the fMRI community. To this end, the derived tools are made available online to aid development and validation of methods for resting-state and task fMRI experiments

Prenatal maternal health and child brain structure: Implications for non-verbal ability and optimizing subcortical segmentation

Brain development starts in utero, and the fetal brain can already be affected by the environment, including chemical exposures and maternal health characteristics. These factors range from exposures to large quantities of teratogens (such as alcohol) to variations in the behaviors and characteristics of healthy individuals (such as age, diet, and subclinical levels of depressive and anxiety symptoms), which can nonetheless have long-lasting adverse effects. In this thesis, we reviewed the literature on the effects of prenatal exposures on human neurodevelopment, as well as cognitive, behavioral, and health outcomes. In Study I we found that prenatal exposures are often reported poorly in infant neuroimaging studies and gave recommendations for reporting in future studies. In Study II, we examined which early life factors predicted cortical structure in 5-year-olds. The results from Study II were utilized to make an informed decision regarding confounders in future studies in the 5-year-old neuroimaging sample of the FinnBrain Birth Cohort study. In Study III, we explored the cortical structural correlates of non-verbal ability in 5-year-olds. The findings were generally in line with prior results from adult and adolescent studies, with the important addition of a positive association between gray matter volume and surface area in the right medial occipital region and non-verbal ability as well as visual abstract reasoning ability. Finally, in Study IV, we compared the results from two common segmentation tools, FSL-FIRST and FreeSurfer, against manual segmentation in the hippocampus and subcortical structures. Overall, the agreement with manual segmentation was good, although results were suboptimal for the hippocampus, amygdala, and nucleus accumbens, and careful visual quality control is still recommended. This thesis summarized different perinatal factors affecting the developing brain, and ensured the high quality of our neuroimaging data. This foundational work, together with the multidisciplinary, longitudinal data collection in the FinnBrain Birth Cohort study, can be used to discover how environmental factors affect brain development.Äidin raskausajan terveys ja lapsen aivojen rakenne: yhteydet ei-kielellisiin taitoihin ja subkortikaalisen segmentaation optimointi Aivojen kehitys alkaa kohdussa ja jatkuu läpi elämän. Jo sikiöaikana aivot ovat alttiina ympäristön vaikutuksille, ml. kemialliset altisteet sekä äidin terveyteen liittyvät tekijät. Nämä altisteet vaihtelevat suurista annoksista teratogeeneille (esim. alkoholille) eroihin terveiden yksilöiden ominaisuuksissa ja toiminnassa (esim. ikä, ruokavalio sekä vähäiset masennus- ja ahdistusoireet ilman mielenterveyshäiriön diagnoosia), joilla voi kuitenkin olla kauaskantoisia seuraamuksia. Tässä väitöskirjassa teemme katsauksen raskaudenaikaisten altisteiden vaikutuksista yksilön kehitykseen sekä siihen liittyviin muutoksiin aivoissa. Tutkimuksessa I toteamme, että raskaudenaikaiset altisteet kuvataan usein puutteellisesti vauvojen aivokuvantamista koskevissa tutkimuksissa ja annamme suosituksia raportoinnista. Tutkimuksessa II tutkimme varhaisten altisteiden yhteyksiä 5-vuotiaiden aivojen rakenteeseen. Tämän tutkimuksen tulokset ohjasivat kontrolloitavien muuttujien valintaa. Tutkimuksessa III tutkimme aivokuoren rakenteen yhteyksiä ei-kielelliseen kognitiiviseen kyvykkyyteen 5-vuotiailla. Tulokset olivat pitkälti linjassa aiempien, vanhemmilla osallistujilla tehtyjen tutkimusten kanssa. Uutena tuloksena löysimme yhteyden oikean takaraivolohkon mediaalisen osan tilavuuden ja pinta-alan olevan yhteydessä ei-kielelliseen kyvykkyyteen sekä erityisesti näönvaraiseen päättelyyn. Tutkimuksessa IV vertailimme kahta yleistä segmentointityökalua (FreeSurfer ja FSL-FIRST) käsin tehtyyn segmentaatioon hippokampuksessa ja aivokuoren alaisissa tumakkeissa. Tulokset vaihtelivat paljon rakenteesta riippuen. Huolellista laadunvarmistusta aivoalueiden koon määrityksen yhteydessä suositellaan vahvasti. Tämä väitöskirja antaa kokonaisvaltaisen ymmärryksen aivoihin vaikuttavista varhaisen elämän altisteista. Yhdessä korkealaatuisen aivokuvantamisdatamme sekä muun FinnBrain-syntymäkohortissa kerättävän aineiston kanssa tätä tietoa voidaan hyödyntää useissa tulevissa aivojen kehitystä selvittävissä tutkimuksissa

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

Altered spontaneous brain activity in Down Syndrome and its relation with cognitive outcome

Although Down syndrome (DS) is the most common genetic cause of neurodevelopmental delay, few neuroimaging studies have explored this population. This investigation aimed to study whole-brain resting-state spontaneous brain activity using fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) strategies to find differences in spontaneous brain activity among young people with DS and controls and to correlate these results with cognitive outcomes. The sample comprised 18 persons with DS (age mean = 28.67, standard deviation = 4.18) and 18 controls (age mean = 28.56, standard deviation = 4.26). fALFF and ReHo analyses were performed, and the results were correlated with other cognitive variables also collected (KBIT-2 and verbal fluency test). Increased activity was found in DS using fALFF in areas involving the frontal and temporal lobes and left cerebellum anterior lobe. Decreased activity in DS was found in the left parietal and occipital lobe, the left limbic lobe and the left cerebellum posterior lobe. ReHo analysis showed increased activity in certain DS areas of the left frontal lobe and left rectus, as well as the inferior temporal lobe. The areas with decreased activity in the DS participants were regions of the frontal lobe and the right limbic lobe. Altered fALFF and ReHo were found in the DS population, and this alteration could predict the cognitive abilities of the participants. To our knowledge, this is the first study to explore regional spontaneous brain activity in a population with DS. Moreover, this study suggests the possibility of using fALFF and ReHo as biomarkers of cognitive function, which is highly important given the difficulties in cognitively evaluating this population to assess dementia. More research is needed, however, to demonstrate its utility