Cerebral small vessel disease (SVD) is highly prevalent in older adults and is a predictor of stroke, dementia, and death. SVD is also associated with cognitive dysfunction, gait problems, and urinary incontinence. SVD is diagnosed based on white matter hyperintensities on T2 weighted scans. This thesis investigates the cardiac frequency component of resting state functional magnetic resonance imaging data in young healthy adults, older healthy adults, and older adults with pronounced SVD. A cardiac pulsatility metric is defined, and a tissue type contrast is observed between white matter, grey matter, and cerebrospinal fluid. Aging and disease effects are observed on cardiac pulsatility in white matter. The increased pulsatility may reflect the pathology of venous collagenosis and draining vein stenosis. Developing a better understanding of the etiology of SVD is an important step towards treating the disease.

Cerebral small vessel disease (SVD) is highly prevalent in older adults and is a predictor of stroke, dementia, and death. SVD is also associated with cognitive dysfunction, gait problems, and urinary incontinence. SVD is diagnosed based on white matter hyperintensities on T2 weighted scans. This thesis investigates the cardiac frequency component of resting state functional magnetic resonance imaging data in young healthy adults, older healthy adults, and older adults with pronounced SVD. A cardiac pulsatility metric is defined, and a tissue type contrast is observed between white matter, grey matter, and cerebrospinal fluid. Aging and disease effects are observed on cardiac pulsatility in white matter. The increased pulsatility may reflect the pathology of venous collagenosis and draining vein stenosis. Developing a better understanding of the etiology of SVD is an important step towards treating the disease.

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a widespread technique in brain research. The central challenge in fMRI is the detection of relatively small activity-induced signal changes in the presence of various other signal fluctuations. Physiological fluctuations due to respiration and cardiac pulsation are dominant sources of confounding variability in BOLD fMRI. This dissertation seeks to characterize and compensate for non-neural physiological fluctuations in fMRI. First, the dissertation presents an improved and generalized technique for correcting T1 effect in cardiac-gated fMRI data incorporating flip angle estimated from fMRI dataset itself. Using an unscented Kalman filter, spatial maps of flip angle and T1 relaxation are estimated simultaneously from the cardiac-gated time series. Accounting for spatial variation in flip angle, the new method is able to remove the T1 effects robustly, in the presence of significant B1 inhomogeneity. The technique is demonstrated with simulations and experimental data. Secondly, this dissertation describes a generalized retrospective technique to precisely model and remove physiological fluctuations from fMRI signal: Physiological Impulse Response Function Estimation and Correction (PIRFECT). It is found that the modeled long-term physiological fluctuations explained significant variance in grey matter, even after removing short-term physiological effects. Finally, application of the proposed technique is observed to substantially increase the intra-session reproducibility of resting-state networks.

Abstract The concept of resting state functional magnetic resonance imaging (fMRI) is built onto an original finding in 1995 that brain hemispheres present synchronous signal fluctuations with distinct patterns. fMRI measurements rely on blood oxygenation changes that indirectly mirror neural activity. Therefore, the origin of functional connectivity patterns, resting state networks (RSNs), has been a widely debated research question and numerous contributing factors have been identified. According to current understanding the fluctuations reflect maintenance of the system integrity in addition to spontaneous thought and action processes in the resting state. A popular method to study the functional connectivity in resting state fMRI is spatial independent component analysis (ICA) that decomposes signal sources into statistically independent components. The dichotomy of functional specialization versus functional integration has a correspondence in fMRI studies where RSNs play the integrative viewpoint of brain function. Although canonical large-scale RSNs are broadly distributed they also express modularity that can be accomplished by ICA with a high number of estimated components. The characteristics of high ICA dimensionality are broadly investigated in the thesis. An enduring issue in resting state research has been the confounding noise sources like motion and cardiorespiratory processes which may hamper the analysis. In this thesis the ability of ICA to separate these noise sources from the default mode network, a major RSN, is studied. Additionally, the suitability of ICA for full frequency spectrum analysis, a relatively rare setting in biosignal analysis, is investigated. The results of the thesis support the viewpoint of ICA as a robust analysis method for functional connectivity analysis. Cardiorespiratory and motion induced noise did not confound the functional connectivity analyses with ICA. High dimensional ICA provided better signal source separation, revealed the modular structure of the RSNs and pinpointed the specific aberrations in the autism spectrum disorder population. ICA was also found applicable for fully explorative analysis in both the spatial and temporal domains and indicated functional connectivity changes induced by transcranial bright light stimulation. / Tiivistelmä Konsepti lepotilan tutkimisesta toiminnallisella magneettikuvauksella (engl. functional magnetic resonance imaging, fMRI) on rakentunut vuonna 1995 tehdylle löydökselle aivopuoliskojen välillä synkronisesta signaalivaihtelusta. Mittaukset perustuvat veren hapetuksen muutoksiin, jotka epäsuorasti heijastelevat hermostollista toimintaa. Tämän takia toiminnallisen kytkennällisyyden muodot, lepotilaverkostot, ovat olleet laajasti väitelty tutkimusaihe ja monia verkostoihin vaikuttavia tekijöitä onkin tunnistettu. Nykykäsityksen mukaan signaalivaihtelut lepotilassa heijastelevat järjestelmän yhtenäisyyden ylläpitoa spontaanin ajattelun ja toiminnan lisäksi. Suosittu menetelmä toiminnallisen kytkennällisyyden tutkimiseen lepotilan fMRI:ssä on spatiaalinen itsenäisten komponenttien analyysi (engl. independent component analysis, ICA), joka hajottaa signaalilähteet tilastollisesti itsenäisiin komponentteihin. Aivotoiminnan mallintamisessa kahtiajaolla toiminnalliseen erikoistumiseen ja toiminnalliseen integraatioon on vastaavuus fMRI-tutkimukseen, jossa lepotilaverkostot vastaavat toiminnallisen integraation näkökulmasta. Vaikka kanoniset lepotilaverkostot ovat laaja-alaisia, ne ovat toisaalta modulaarisia, jota voidaan tutkia tutkimalla korkean komponenttimäärän ICA-hajotelmaa. Korkea- dimensioisen ICA-hajotelman ominaisuuksia tutkitaan laajasti tässä väitöskirjassa. Kestoaihe lepotilatutkimuksessa on ollut analyysiä hankaloittavien kohinalähteiden kuten liikkeen ja kardiorespiratoristen prosessien vaikutus. Väitöskirjassa tutkitaan ICA:n kykyä erotella kohinalähteitä ’default mode’ -verkostosta, joka on merkittävin lepotilaverkosto. Lisäksi tutkitaan ICA:n soveltuvuutta täyden taajuuskaistan analysointiin, joka on verrattain harvinaista biosignaalien analyysissä. Väitöskirjan tulokset tukevat näkemystä ICA:n suorituskyvystä toiminnallisen kytkennällisyyden analyysissä. Kardiorespiratorinen ja liikkeestä lähtöisin oleva kohina ei häirinnyt merkittävästi ICA-tuloksia. Korkeadimensioinen ICA tarjosi paremman erottelun signaalilähteille, paljasti lepotilaverkostojen modulaarisen rakenteen ja määritti erityisen poikkeaman autismin kirjon oireyhtymän populaatiossa. ICA:n havaittiin olevan soveltuva täyseksploratiiviselle analyysille ajassa ja avaruudessa; tulos viittaa toiminnallisen kytkennällisyyden muutoksiin kallon läpäisevän kirkasvalostimulaation aikaansaamana.