Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

The association of psychotic disorders, dopaminergic agents and resting-state EEG/MEG functional connectivity

Psychotic disorders are complex and heterogeneous mental disorders with low recovery rates despite a great amount of research on the topic. Various hypotheses exist as to the etiology of psychotic disorders. Amongst these, the dopamine hypothesis and the dysconnectivity hypothesis have been the most enduring in the last six decades. Little is known on how the dopamine and the dysconnectivity hypothesis are associated. The overarching research question of this thesis is to investigate this knowledge gap. Resting-state magneto- and electroencephalography (MEG, EEG) were chosen as non-invasive measurement modalities of dysconnectivity at the source and sensor level of the brain in publication 1. Parameters of resting-state EEG microstate classes A-D were used as a global analysis method of functional connectivity at the sensor level of the brain in publications 2 and 3. The first research question focused on finding systematic evidence on the association of the two hypotheses and was addressed by means of a systematic review (publication 1) of 20 studies published since 2000. Based on the review, no definite conclusion on the association of antipsychotic medication (that mainly acts on the dopamine system) and source- and sensor-level EEG/MEG functional connectivity could be drawn. The second research question focused on whether differences in parameters of resting-state EEG microstate classes A-D are associated to antipsychotic medication. It was addressed by a study (publication 2) that compared 19-channel clinical EEG recordings of medicated (mFEP, n = 17) and medication-naïve (untreated; uFEP, n = 30) patients with first-episode psychotic disorders (FEP). The study results revealed significant decrease of microstate class A and significant increase of microstate class B to differentiate mFEP from uFEP. The third research question focused on whether differences in parameters of resting-state EEG microstate classes A-D are associated with psychosis illness progression and transition to psychosis in FEP and ultra-high-risk (UHR) patients. It was addressed by a study (publication 3) that found significantly increased microstate class A to differentiate a combined group of medication-naïve FEP (n = 29) and UHR patients (n = 54) together from healthy controls (HC, n = 25); significantly decreased microstate class B to differentiate FEP from all UHR patients combined; and significantly decreased microstate class D to differentiate UHR-T patients with (n = 20) from UHR-NT patients without (n = 34) later transition to psychotic disorders using 19-channel EEG recordings. In conclusion across all three publications, an association between the dopamine and the dysconnectivity hypothesis could be demonstrated by means of resting-state EEG microstates assessed in publication 2 and 3. No definite conclusion could be drawn by the systematic review (publication 1). More studies with longitudinal designs are needed to rule-out between-subject differences, track response trajectories, pre-post effects of antipsychotic medication and their association with dysconnectivity. With increased effort, resting-state EEG microstates could contribute to establishing a robust biomarker in a multi- domain approach in order to inform clinicians for the diagnosis, treatment and outcome prediction of psychotic disorders

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

Resting state fMRI based multilayer network configuration in patients with schizophrenia.

Novel methods for measuring large-scale dynamic brain organisation are needed to provide new biomarkers of schizophrenia. Using a method for modelling dynamic modular organisation (Mucha et al., 2010), evidence suggests higher 'flexibility' (switching between multilayer network communities) to be a feature of schizophrenia (Braun et al., 2016). The current study compared flexibility between 55 patients with schizophrenia and 72 controls (the COBRE Dataset). In addition, novel methods of 'between resting state network synchronisation' (BRSNS) and the probability of transition from one community to another were used to further describe group differences in dynamic community structure. There was significantly higher schizophrenia group flexibility scores in cerebellar (F (1124) = 9.33, p (FDR) = 0.017), subcortical (F (1124) = 13.14, p (FDR) = 0.005), and fronto-parietal task control (F (1124) = 7.19, p (FDR) = 0.033) resting state networks (RSNs), as well as in the left thalamus (MNI XYZ: -2, -13, 12; F(1, 124) = 17.1, p (FDR) < 0.001) and the right crus I (MNI XYZ: 35, -67, -34; F (1, 124) = 19.65, p (FDR) < 0.001). Flexibility in the left thalamus reflected transitions between communities covering default mode and sensory-somatomotor RSNs. BRSNS scores suggested altered dynamic inter-RSN modular configuration in schizophrenia. This study suggests less stable community structure in a schizophrenia group at an RSN and node level and provides novel methods of exploring dynamic community structure. Mediation of group differences by mean time window correlation did however suggest flexibility to be no better as a schizophrenia biomarker than simpler measures and a range of methodological choices affected results

An exploration of functional connectivity and GABA in schizophrenia and related conditions

Schizophrenia is a severe and enduring mental illness with psychopathology including positive symptoms, negative symptoms and cognitive impairment. It has been hypothesised that such symptoms represent a loss of integration within and between brain regions. This is known as the dysconnectivity hypothesis and integrates with other neurochemical hypotheses of the disorder. In this thesis, I sought to explore the dysconnectivity hypothesis using amplitude envelope correlation in MEG, firstly in two groups of individuals with schizophrenia. I then sought to address the continuum model of schizophrenia through exploring functional connectivity in two groups with high schizotypy. Next, I explored dysconnectivity in schizophrenia in more depth by looking separately at individuals with recent onset psychosis and those with established schizophrenia. I then went on to look at connectivity following ketamine administration thus seeking to link this model of schizophrenia with my findings in those with schizophrenia. Finally, I explored the GABA hypothesis of schizophrenia using MRS, again in two groups of individuals with schizophrenia, at different stages of illness and linked this with connectivity. Overall, this work supports the dysconnectivity hypothesis of schizophrenia, finding reduced connectivity in schizophrenia. Such changes are found predominantly in the later stages of the disorder suggesting the possibility of progressive changes in connectivity throughout its course. I found increased connectivity following ketamine administration in the same frequency band and region suggesting the drug does not model later stages of the disorder well (where I predominantly found hypo-connectivity). In addition, I found reduced GABA iv in later stages of schizophrenia but not in early stages, again suggesting progressive changes throughout the course of the disorder. Finally, I also found hypo-connectivity in healthy volunteers with high schizotypy scores suggesting biological continuity between subclinical symptoms and diagnosable schizophrenia. Overall, these results add support to the dysconnectivity hypothesis, the GABA/glutamate hypothesis and the continuum hypothesis of schizophrenia

Dynamic functional connectivity and its anatomical substrate reveal treatment outcome in first-episode drug-naïve schizophrenia.

Convergent evidence has suggested a significant effect of antipsychotic exposure on brain structure and function in patients with schizophrenia, yet the characteristics of favorable treatment outcome remains largely unknown. In this work, we aimed to examine how large-scale brain networks are modulated by antipsychotic treatment, and whether the longitudinal changes could track the improvements of psychopathologic scores. Thirty-four patients with first-episode drug-naïve schizophrenia and 28 matched healthy controls were recruited at baseline from Shanghai Mental Health Center. After 8 weeks of antipsychotic treatment, 24 patients were re-scanned. Through a systematical dynamic functional connectivity (dFC) analysis, we investigated the schizophrenia-related intrinsic alterations of dFC at baseline, followed by a longitudinal study to examine the influence of antipsychotic treatment on these abnormalities by comparing patients at baseline and follow-up. A structural connectivity (SC) association analysis was further carried out to investigate longitudinal anatomical changes that underpin the alterations of dFC. We found a significant symptomatic improvement-related increase in the occurrence of a dFC state characterized by stronger inter-network integration. Furthermore, symptom reduction was correlated with increased FC variability in a unique connectomic signature, particularly in the connections within the default mode network and between the auditory, cognitive control, and cerebellar network to other networks. Additionally, we observed that the SC between the superior frontal gyrus and medial prefrontal cortex was decreased after treatment, suggesting a relaxation of normal constraints on dFC. Taken together, these findings provide new evidence to extend the dysconnectivity hypothesis in schizophrenia from static to dynamic brain network. Moreover, our identified neuroimaging markers tied to the neurobiology of schizophrenia could be used as potential indicators in predicting the treatment outcome of antipsychotics

The function of the endocannabinoid system and glial cells in vivo in patients with first episode psychosis

Psychoses are relatively common and often severely debilitating mental disorders with a multifactorial etiological background involving both psychosocial and biological factors. Previously reported associations between the endocannabinoid and immune systems, and psychotic disorders, suggest that they are involved in the etiology of psychosis. Healthy individuals were studied with the selective type 1 endocannabinoid receptor (CB1R) radiotracer [18F]FMPEP-d2, and positron emission tomography (PET), for possible demographic confounders. Radiotracer synthesis and the compound’s behaviour in blood and brain tissues, were in line with reports from previous validation studies. Females had lower availabilities of CB1R than males in 17 discrete brain regions. Separate samples of male patients with first-episode psychosis (FEP) were then studied concurrently in Turku and London, using the CB1R radiotracers [18F]FMPEP-d2 and [11C]MEPPEP respectively. Lower CB1R availability was seen in FEP as compared to healthy controls. The availability of CB1R was also inversely associated with the symptomatology of the psychoses. Translocator protein (TSPO) expression has been postulated to represent glial cell and mitochondrial functions, both of which are influenced by endocannabinoid signalling. Another sample of male and female patients with first episode psychoses was studied using PET with the selective TSPO radiotracer [11C]PBR28. Male and female FEP subjects showed globally lower availability of brain TSPO in comparison to healthy controls. Two concurrent samples of FEP individuals showed persistent elevations of the chemokine CCL22 when compared to population controls. A subgroup of patients with the highest levels of CCL22 also had aberrant levels of other cyto- and chemokines. These results indicate that the immune and brain endocannabinoid systems have become dysregulated in early psychosis. Aberrant glial cell function and/or disturbances in cell metabolism are indicated by the lower availability of TSPO.Endokannabinoidijärjestelmän ja gliasolujen toiminta ensipsykooseissa Psykoosit ovat verrattain yleisiä, vakavia mielenterveyshäiriöitä, joiden syntyyn vaikuttaa sekä psykososiaaliset että biologiset tekijät. Endokannabinoidi- ja immuunijärjestelmien yhteydet psykooseihin, sekä dopamiinijärjestelmän toimintaan, viittaavat näiden järjestelmien toimivan osana psykoosien etiologiaa. Terveiden koehenkilöiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin tyypin 1 endokannabinoidireseptorin (CB1R) merkkiaineella [18F]FMPEPd2, ja positroniemissiotomografialla (PET), mahdollisten sekoittavien tekijöiden tunnistamiseksi. Merkkiaineen tuotannon laatua kuvaavat tunnusluvut, sekä merkkiaineen käyttäytyminen veressä ja aivokudoksessa, vastasivat aiempien validointitutkimusten tuloksia. Naiskoehenkilöillä oli alhaisemmat [18F]FMPEP-d2:n jakautumistilavuudet 17 aivoalueella verrattuna miehiin. Miespuolisten ensipsykoosipotilaiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin erikseen Turussa ja Lontoossa PET:lla vastaavasti CB1R merkkiaineilla [18F]FMPEP-d2 ja [11C]MEPPEP. Molempien otosten ensipsykoosipotilailla oli alhaisemmat merkkiaineiden jakautumistilavuudet verrattuna terveisiin koehenkilöihin. Merkkiaineen sitoutumiselle vapaat CB1R:t olivat lisäksi käänteisesti yhteydessä psykoosioireiden vaikeusasteeseen. Aivojen tukisolujen ja näiden mitokondrioiden toimintaan vaikuttavat sekä endokannabinoidiviestintä, että translokaattoriproteiinin (TSPO) toiminta. Ensipsykoosipotilailla oli kauttaaltaan alhaisemmat TSPO PET merkkiaineen [11C]PBR28 jakautumistilavuudet verrattuna terveisiin verrokkihenkilöihin. Ensipsykoosipotilaiden kemokiini CCL22:n pitoisuudet olivat verrokkien pitoisuuksia korkeammat. Korkeimpia CCL22:n pitoisuuksia omaavien potilaiden immuuniviestintä poikkesi muista verrokki- ja potilastutkittavista laaja-alaisesti. Nämä tulokset osoittavat, että immuuni- ja endokannabinoidijärjestelmät toimivat poikkeavasti ensipsykooseissa. TSPO:n poikkeava toiminta viittaa siihen, että aivojen tukisolut ja/tai solujen aineenvaihdunta häiriintyvät psykooseissa