Brain functioning, networks and topology during naturalistic stimulus in first-episode psychosis

Psychosis is a condition where the ability to distinguish between external and internal experiences is diminished or distorted. It is a core symptom of several psychiatric disorders which have a crucial impact on the quality of patients’ lives. Although the neuronal basis of psychosis is unknown, studies suggest that psychosis is derived from glutamate-driven and dopamine-related altered signaling within and between different brain regions. Brain imaging studies have typically used resting state or simple task paradigms to study brain mechanisms related to psychosis. In this thesis, naturalistic stimulus during functional magnetic imaging was used to explore more complex stimulus processing. Movies have been shown to synchronize brain activity across subjects more efficiently than resting state and are increasingly used in neuroscience. The main aim of this thesis was to characterize differences in brain functioning between first-episode psychosis patients and control subjects during naturalistic stimulus, i.e., movie viewing. Participants were drawn from the Helsinki Psychosis Study. The patient group consisted of individuals treated for first psychotic episode in the hospitals and outpatient clinics of the Helsinki University hospital and the city of Helsinki. Age-, sex- and area of residence matched control subjects were recruited via the Finnish Population Registration System. Papers I and II include data from 32 patients and 46 control subjects, and paper III includes 71 patients and 57 control subjects. In paper I, machine learning was used to identify a bilateral region in the precuneus, where activation patterns during movie viewing distinguished patients from control subjects. Classification accuracy was associated with positive symptoms in that the higher the symptom score the more reliable the classification. In paper II, both functional and structural connectivity were studied to establish that the precuneus region showed functional connectivity across the movie to the default mode network and that patients had increased function connectivity between the precuneus seed region and the medial prefrontal cortex. No differences were observed in the underlying white matter structural connectivity. In paper III functional connectivity was used on the whole-brain level to identify a sub-network, or component, where connectivity differed between patients and control subjects. Patients had mainly decreased but also, in some connections, increased functional connectivity. Also, differences between patients and control subjects in graph measures were observed, most prominently in the centrality of the insula. The results suggest brain functioning during naturalistic stimulus is altered in first-episode psychosis. Most prominent differences are concentrated in the hub regions of the brain and regions and functional networks related to salience attribution and model updating. Understanding naturalistic stimulus related brain correlates of aberrant cognitive processes already present during early stages of psychosis might provide better targeted and more efficient biological, cognitive and behavioral interventions in the future.Psykoosilla tarkoitetaan todellisuudentajun vakavaa heikentymistä, mikä voi ilmetä aistiharhoina, harhaluuloina, puheen tai käytöksen hajanaisuutena sekä katatonisina oireina. Psykoosi on usean vakavan mielenterveyden häiriön keskeinen oire. Ensipsykoosilla tarkoitetaan ensimmäistä sairausjaksoa, johon liittyy merkittäviä psykoosioireita. Psykoosiin liittyviä aivojen toiminnallisia muutoksia ei vielä täysin tunneta, mutta niiden uskotaan olevan yhteydessä poikkeavaan viestintään eri aivoalueiden välillä. Tämän tutkielman päätavoitteena on tutkia eroja ensipsykoosiin sairastuneiden ja verrokkihenkilöiden aivotoiminnassa elokuvan katsomisen aikana. Aivokuvantamistutkimuksissa on tyypillisesti käytetty ärsykkeenä lepotila-asetelmaa tai yksinkertaisia tehtäviä. Tässä tutkielmassa käytettiin naturalistista elokuvastimulusta, jolloin ärsykkeen käsittely vastaa paremmin arjen vaatimuksia. Tutkielman potilasaineisto koostuu henkilöistä, joilla oli ensimmäinen hoitokontakti psykoosioireiden vuoksi. Verrokkihenkilöt on rekrytoitu Suomen väestörekisterin kautta. Osatöissä I ja II aineistossa on mukana 32 potilasta ja 46 vertailuhenkilöä ja osatyössä III 71 potilasta ja 57 vertailuhenkilöä. Osatyössä I hyödynnettiin koneoppimismenetelmiä ja tunnistettiin molemminpuolinen alue aivojen etukiilassa (precuneus), jossa aivotoimintaa mittaavan fMRI-signaalin vaihtelu elokuvan aikana erotteli potilaita verrokeista sattumaa merkittävästi paremmalla tarkkuudella. Potilaiden luokittelu oli sitä varmempaa, mitä voimakkaampia positiivisia oireita eli harhaluuloja tai aistiharhoja heillä oli. Osatyössä II tarkasteltiin toiminnallisia ja rakenteellisia potilas - verrokki eroja etukiila-alueen ja muiden aivoalueiden yhteyksissä. Potilailla havaittiin vahvempi toiminallinen yhteys eli konnektiviteetti etukiilan ja etuotsalohkon välillä. Alueita yhdistävissä rakenteissa ei ollut ryhmäeroja. Osatyössä III tarkasteltiin elokuvan aikaista aivotoimintaa koko aivoja kattavan verkoston näkökulmasta ja tunnistettiin alaverkosto, jossa konnektiviteetti poikkesi potilaiden ja verrokkien välillä. Lisäksi havaittiin potilas – verrokki eroja verkoston rakennetta kuvaavissa mittareissa, selkeimmin aivosaarekkeen (insulan) keskeisyydessä

Functional network connectivity and topology during naturalistic stimulus is altered in first-episode psychosis

Background: Psychotic disorders have been suggested to derive from dysfunctional integration of signaling between brain regions. Earlier studies have found several changes in functional network synchronization as well as altered network topology in patients with psychotic disorders. However, studies have used mainly resting-state that makes it more difficult to link functional alterations to any specific stimulus or experience. We set out to examine functional connectivity as well as graph (topological) measures and their association to symptoms in first-episode psychosis patients during movie viewing. Our goal was to understand whole-brain functional dynamics of complex naturalistic information processing in psychosis and changes in brain functional organization related to symptoms. Methods: 71 first-episode psychosis patients and 57 control subjects watched scenes from the movie Alice in Wonderland during 3 T fMRI. We compared functional connectivity and graph measures indicating integration, segregation and centrality between groups, and examined the association between topology and symptom scores in the patient group. Results: We identified a subnetwork with predominantly decreased links of functional connectivity in firstepisode psychosis patients. The subnetwork was mainly comprised of nodes of and links between the cinguloopercular, sensorimotor and default-mode networks. In topological measures, we observed between-group differences in properties of centrality. Conclusions: Functional brain networks are affected during naturalistic information processing already in the early stages of psychosis, concentrated in salience- and cognitive control-related hubs and subnetworks. Understanding these aberrant dynamics could add to better targeted cognitive and behavioral interventions in the early stages of psychotic disorders.Peer reviewe

Activation of the motivation-related ventral striatum during delusional experience

Delusion is the most characteristic symptom of psychosis, occurring in almost all first-episode psychosis patients. The motivational salience hypothesis suggests delusion to originate from the experience of abnormal motivational salience. Whether the motivation-related brain circuitries are activated during the actual delusional experience remains, however, unknown. We used a forced-choice answering tree at random intervals during functional magnetic resonance imaging to capture delusional and non-delusional spontaneous experiences in patients with first-episode psychosis (n = 31) or clinical high-risk state (n = 7). The motivation-related brain regions were identified by an automated meta-analysis of 149 studies. Thirteen first-episode patients reported both delusional and non-delusional spontaneous experiences. In these patients, delusional experiences were related to stronger activation of the ventral striatum in both hemispheres. This activation overlapped with the most strongly motivation-related brain regions. These findings provide an empirical link between the actual delusional experience and the motivational salience hypothesis. Further use and development of the present methods in localizing the neurobiological basis of the most characteristic symptoms may be useful in the search for etiopathogenic pathways that result in psychotic disorders.Peer reviewe

Is It Possible to Predict the Future in First-Episode Psychosis?

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features—like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis—are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognostic markers in FEP. Combination of different markers in ML models with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future

Aberrant Cortical Integration in First-Episode Psychosis During Natural Audiovisual Processing

BACKGROUND: Functional magnetic resonance imaging studies of psychotic disorders have reported both hypoactivity and hyperactivity in numerous brain regions. In line with the dysconnection hypothesis, these regions include cortical integrative hub regions. However, most earlier studies focused on a single cognitive function at a time, assessed by delivering artificial stimuli to patients with chronic psychosis. Thus, it remains unresolved whether these findings are present already in early psychosis and whether they translate to real-life-like conditions that require multisensory processing and integration. METHODS: Scenes from the movie Alice in Wonderland (2010) were shown to 51 patients with first-episode psychosis (16 women) and 32 community-based control subjects (17 women) during 3T functional magnetic resonance imaging. We compared intersubject correlation, a measure of similarity of brain signal time courses in each voxel, between the groups. We also quantified the hubness as the number of connections each region has. RESULTS: Intersubject correlation was significantly lower in patients with first-episode psychosis than in control subjects in the medial and lateral prefrontal, cingulate, precuneal, and parietotemporal regions, including the default mode network. Regional magnitude of between-group difference in intersubject correlation was associated with the hubness. CONCLUSIONS: Our findings provide novel evidence for the dysconnection hypothesis by showing that during complex real-life-like stimulation, the most prominent functional alterations in psychotic disorders relate to integrative brain functions. Presence of such abnormalities in first-episode psychosis rules out long-term effects of illness or medication. These methods can be used in further studies to map widespread hub alterations in a single functional magnetic resonance imaging session and link them to potential downstream and upstream pathways.Peer reviewe

Is It Possible to Predict the Future in First-Episode Psychosis?

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognosticmarkers in FEP. Combination of differentmarkers inMLmodels with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.Peer reviewe

Childhood adversities and clinical symptomatology in first-episode psychosis

In addition to severe traumatic experiences, milder, more common childhood adversities reflecting psychosocial burden may also be common in people with psychotic disorders and have an effect on symptomatology and functioning. We explored eleven negative childhood experiences and their influence on clinical symptoms among young adults with first-episode psychosis (FEP, n = 75) and matched population controls (n = 51). Individuals with FEP reported more adversities than controls. Specifically serious conflicts within the family, bullying at school, maternal mental health problems, and one's own and parents' serious illness during childhood were experienced by the patients more often than by controls. In the FEP group, the severity of adversity was associated with increased anxiety, manic, and obsessive-compulsive symptoms, but not with the severity of positive psychotic symptoms. Adversity produced a more pronounced effect on symptoms in male patients than in female patients. To conclude, in line with earlier studies of more chronic psychosis, a majority of the participants with FEP reported exposure to childhood adversities, with the FEP group reporting more adversities than controls. High levels of mood and anxiety symptoms in patients with FEP may be related to cumulative exposure to childhood adversities. This should be taken into account in the treatment for FEP.Peer reviewe

Low-grade inflammation in first-episode psychosis is determined by increased waist circumference

Psychosis is associated with low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), a risk factor for cardiovascular events and mortality in the general population. We investigated the relationship between hs-CRP and anthropometric and metabolic changes in first-episode psychosis (FEP) during the first treatment year. We recruited 95 FEP patients and 62 controls, and measured longitudinal changes in hs-CRP, weight, waist circumference, insulin resistance, and lipids. We used linear mixed models to analyze the longitudinal relationship between hs-CRP and clinical, anthropometric and metabolic measures. At baseline, patients with FEP had higher levels of insulin resistance, total and low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Baseline weight, waist circumference, hs-CRP, fasting glucose, and high-density lipoprotein cholesterol were similar between patients and controls. Marked increases in anthropometric measures and hs-CRP were observed in FEP during the 12-month follow-up. However, glucose and lipid parameters did not change significantly. In the mixed models, waist circumference and female sex were significant predictors of hs-CRP levels in FEP. Prevention of the early development of abdominal obesity in FEP is crucial, as abdominal obesity is accompanied by chronic low-grade inflammation, which increases further the cardiovascular risk in this vulnerable population.Peer reviewe

Connectivity of the precuneus-posterior cingulate cortex with the anterior cingulate cortex-medial prefrontal cortex differs consistently between control subjects and first-episode psychosis patients during a movie stimulus

Background: Functional connectivity is altered in psychotic disorders. Multiple findings concentrate on the default mode network, anchored on the precuneus-posterior cingulate cortex (PC-PCC). However, the nature of the alterations varies between studies and connectivity alterations have not been studied during an ecologically valid natural stimulus. In the present study, we investigated the functional and structural connectivity of a PC-PCC region, where functioning differentiated first-episode psychosis patients from control subjects during free viewing of a movie in our earlier study. Methods: 14 first-episode psychosis patients and 12 control subjects were imaged with GE 3T, and 29 patients and 19 control subjects were imaged with a Siemens Skyra 3T scanner while watching scenes from the movie Alice in Wonderland. Group differences in functional connectivity were analysed for both scanners separately and results were compared to identify any overlap. Diffusion tensor measures of 26 patients and 19 control subjects were compared for the related white matter tracts, identified by deterministic tractography. Results: Functional connectivity was increased in patients across scanners between the midline regions of the PC-PCC and the anterior cingulate cortex-medial prefrontal cortex (ACC-mPFC). We found no group differences in any of the diffusion tensor imaging measures. Conclusions: Already in the early stages of psychosis functional connectivity between the midline structures of the PC-PCC and the ACC-mPFC is consistently increased during naturalistic stimulus. (c) 2018 Elsevier B.V. All rights reserved.Peer reviewe