In addition to mood symptoms, major depressive disorder (MDD) is characterized by cognitive impairments that can have detrimental impacts on quality of life and daily function, and have been found to persist into remission. In particular, altered affective cognition (e.g. biased attention to negative stimuli) has been reported in MDD, and may continue into remission. Unfortunately, current pharmacotherapies do not adequately address cognitive dysfunction in acute or remitted MDD. Understanding the neurobiological underpinnings of affective cognitive dysfunction in remitted MDD may help inform the development of new interventions to address this lingering problem and the associated poorer functional outcomes. The triple network model posits that altered functioning of three key networks implicated in normal cognitive function – the default mode network (DMN), central executive network (CEN) and salience network (SN) – underlies cognitive dysfunction in a variety of psychiatric illnesses, including MDD. Though notable exceptions exist, work in acutely depressed MDD patients has found evidence of DMN hyperconnectivity, CEN hypoconnectivity and abberant SN connectivity both at rest and during the completion of various cognitive tasks. The evidence for triple network connectivity alterations persisting into remission is less robust, and warrants further investigation. Furthermore, there is a paucity of studies examining remitted MDD connectivity during affective tasks. As such, the primary objectives of this thesis were to: 1) compare resting-state and task triple network connectivity profiles in remitted MDD patients (rMDDs) and healthy volunteers (HVs) at rest, during an affective (emotional Stroop [eStroop]) task, and during rest vs. the task and, 2) assess the relationship between DMN and CEN connectivity and measures of daily functioning, quality of life and/or negative, self-relational rumination in the rMDD cohort. Behaviourally, there were findings of an affective attentional bias and impaired processing speed in the rMDD vs. HVs, as revealed by a computerized cognitive test battery. However, we found no evidence of DMN hyperconnectivity or CEN hyperconnectivity in the rMDD study sample. We did find evidence of altered intrinsic CEN and CEN-SN connectivity between the rest and task conditions that seemed driven by the rMDD sample, as well as positive CEN-DMN correlations across the entire sample both at rest and during the eStroop task. Suprisingly, we also found higher intrinsic DMN connectivity during the eStroop task vs. at rest across the whole sample. Finally, we found a positive relationship between task-based CEN connectivity and hopeless rumination, and a significant negative relationship between resting state and task-based DMN connectivity and psychosocial dysfunction in the rMDD sample. These findings contribute to our understanding of large-scale intrinsic network connectivity alterations during remitted depression, and their relationship to functional outcomes.

The current study explored how hot and cool executive functions (EF) could predict resting-state connectivity of the Default Mode Network (DMN) and Central Executive Network (CEN) in a mixed clinical and typically developing sample of adolescents. It was hypothesized that hot EF would predict a quadratic, inverted U-shaped, relationship between connectivity of the major regions of the DMN: the Posterior Cingulate Cortex (PCC) and the Medial Prefrontal Cortex (MPFC). It also was hypothesized that cool EF would predict a quadratic, inverted U-shaped, relationship between the connectivity of the major regions of the CEN: the right Posterior Parietal Cortex (right PPC) and the right Dorsal Lateral Prefrontal Cortex (right DLPFC). The results suggested that hot EF, specifically emotional regulation, predicted a quadratic relationship in DMN connectivity. However, this relationship was U-shaped instead of an inverted U-shaped. Thus, participants who scored well or poorly in emotional regulation generally had higher connectivity than those with average scores in emotional regulation. There were no significant results between cool EF and the CEN. Additional exploratory analysis suggested that the main hypotheses were not driven or suppressed by group differences. Further exploration observed other brain regions involved in resting-state activity that may play a role in hot or cool EF. Overall, findings support the Internal Mentation Hypothesis of DMN activity and are indicative of a relationship between emotional regulation and DMN resting-state connectivity.

Abstract Neuropsychiatric illnesses usually become overtly manifest in adolescence and early adulthood. A critical long-term aim is to be able to prevent the development of such illnesses, which requires instruments to identify subjects at high risk of illness and to offer them effective interventions. There is an indisputable need for more sophisticated methods to enable more precise detection of adolescents and young adults who are at high risk of developing psychosis. Abnormal function in brain networks has been reported in people with schizophrenia and other psychotic disorders. Similar abnormalities have been found also in people at risk for developing psychosis, but it is not known whether this applies also to spontaneous resting state activity in young people with a familial risk for psychosis. We conducted resting-state functional MRI (R-fMRI) in 72 (29 male) young adults with a history of psychosis in one or both parents (FR) but without psychosis themselves, and 72 (29 male) similarly healthy control subjects without familial risk for psychosis. Both groups in the Oulu Brain and Mind study were drawn from the Northern Finland Birth Cohort 1986. All volunteers were 20–25 years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data was pre-processed using independent component analysis (ICA). A dual regression technique was used to detect between-group differences with p < 0.05 threshold corrected for multiple comparisons at voxel level. FR subjects demonstrated significantly decreased activity compared to control subjects in the default mode network and in the central executive network and increased activity in the cerebellum. The findings clarify previously controversial literature on the subject. The finding suggests that abnormal activity in these brain networks in rest may be associated with increased vulnerability to psychosis. The findings maybe helpful in developing more precise methods for detecting young people at highest risk for developing psychosis. / Tiivistelmä Psykoottisiin häiriöihin sairastutaan yleensä nuoruudessa tai varhaisaikuisuudessa. Psykoositutkimuksen tavoitteena on löytää uusia menetelmiä, joiden avulla kyettäisiin tunnistamaan suurimmassa psykoosiriskissä olevat nuoret, jotta heille voitaisiin tarjota sairautta ennaltaehkäiseviä hoitokeinoja. Skitsofreniaan ja muihin psykoottisiin häiriöihin sairastuneilla on havaittu aivotoiminnan poikkeavuuksia. Samankaltaisia aivotoiminnan poikkeavuuksia on havaittu myös nuorilla, jotka ovat vaarassa sairastua psykoosiin. Toistaiseksi on ollut epäselvää, onko psykoosiin sairastuneiden henkilöiden lapsilla aivohermoverkkojen toiminnan poikkeavuuksia lepotilassa. Suoritimme aivojen lepotilan MRI-tutkimuksen (R-fMRI) 72:lle (29 miestä) nuorelle aikuiselle, joiden jompikumpi vanhempi oli sairastunut psykoosin sekä 72:lle (29 miestä) nuorelle aikuiselle, joiden vanhemmat eivät olleet sairastaneet psykoosia. Molemmat tutkimusryhmät tässä Oulu Brain and Mind -tutkimuksessa olivat Pohjois-Suomen 1986 syntymäkohortin jäseniä. Tutkittavat olivat 20–25 vuoden iässä. Lepotilan toiminnallinen magneettikuvaus suoritettiin 1.5 Teslan Siemensin magneettikuvantamislaitteella. Tutkimuskohteiksi valittiin lepotilan toiminnallinen aivohermoverkko, toiminnan ohjauksesta vastaava aivohermoverkko ja pikkuaivot. Kuvantamisdataan sovellettiin itsenäisten komponenttien analyysia aivohermoverkkojen määrittämistä varten. Ryhmien välisen eron havaitsemiseen käytettiin ei-parametristä permutaatiotestiä, joka kynnystettiin tilastollisesti merkitsevään tasoon (p < 0.05). Lepotilan oletushermoverkossa ja toiminnanohjauksesta vastaavassa aivohermoverkoissa havaittiin vähäisempää aktiivisuutta ja pikkuaivoissa kohonnutta aktiivisuutta perinnöllisessä psykoosiriskissä olevilla nuorilla aikuisilla verrattuna verrokkeihin. Tutkimustulokset selkeyttivät aiempaa ristiriitaista kirjallisuutta tutkimusaiheesta. Tutkimuksessa havaittujen aivoalueiden poikkeava toiminta lepotilassa voi liittyä kohonneeseen psykoosin puhkeamisriskiin. Tutkimuslöydösten avulla voidaan todennäköisesti edesauttaa parempien kuvantamismenetelmien kehittämistä suurimmassa psykoosiriskissä olevien nuorten tunnistamiseen.