Impaired Prefrontal Synaptic Gain in People with Psychosis and Their Relatives during the Mismatch Negativity

The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task—for 24 patients with psychosis, 25 of their first‐degree unaffected relatives, and 35 controls—and DCM was used to estimate the excitability (modeled as self‐inhibition) of (source‐specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context‐dependent (condition‐specific) and context‐independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis

Biomarkers of brain function in psychosis and their genetic basis

Psychotic disorders, including schizophrenia and bipolar disorder, are amongst the most severe and enduring mental illnesses. Recent research has identified several genetic variants associated with an increased risk of developing psychosis; however, it remains largely unknown how these lead to the illness. This is where endophenotypes – heritable traits associated with the illness and observed in unaffected family members of patients – could be valuable. Endophenotypes are linked to the genetic underpinnings of disorders, and can help elucidate the functional effects of genetic risk variants. This thesis investigates endophenotypes for psychosis, with the overall aim of identify such biological markers, as well as to examine the relationships between different endophenotypes and their associations with genetic risk for psychosis. A family design has been used throughout, including patients with psychosis, their unaffected first-degree relatives, as well as healthy controls. In chapter 1, I review the endophenotype approach and those markers proposed for psychosis genetic research. Chapters 2 and 3 investigate whether different neurophysiological measures are potential endophenotypes for psychosis. In chapter 2, resting state EEG was studied and it was shown that risk groups, including unaffected relatives and people with an at-risk mental state, presented no abnormalities. This suggests that – rather than endophenotypes – the low frequency electrophysiological abnormalities seen in chronic patients in this study might be related to illness progression or long-term medication effects, and be more useful as biomarkers in non-genetic research. In chapter 3, I used dynamic causal modelling to investigate effective connectivity – the influence that one neuronal system exerts over another – underlying the mismatch negativity evoked potential, a marker of pre-attentive auditory perception. Results indicate that, compared to controls, both patients and their relatives show abnormalities of the excitability of superficial pyramidal cells in prefrontal cortex. Hence, this appears to be linked to the genetic aetiology of psychosis, and constitutes a potential endophenotype. Chapters 4 and 5 investigate several pre-identified endophenotypes for psychosis: Electrophysiological (the P300 event related potential), cognitive (working memory, spatial visualisation, and verbal memory), and neuroanatomical (lateral ventricular volume). In chapter 4, the associations between these endophenotypes were examined. Results showed that the P300 amplitude and latency are independent measures; the former indexing attention and working memory and the latter possibly a correlate of basic speed of processing. Importantly, individuals with psychosis, their unaffected relatives, and healthy controls all showed similar patterns of associations between all pairs of endophenotypes, supporting the notion of a continuum of psychosis across the population. Lastly, in chapter 5, polygenic risk scores – a measure of the combined effect of a large number of common genetic risk variants – were used to investigate the relationships between genetic risk for schizophrenia and bipolar disorder, and the endophenotypes studied in the previous chapter. Results showed that higher polygenic score for schizophrenia nominally predicts poorer performance on a spatial visualisation task; providing some evidence that the two traits share genetic risk variants as hypothesised. No other associations approached significance, possibly due to insufficient statistical power. However, as discovery samples grow, the use of polygenic scores is promising. This thesis has thus contributed to the field of mental health research by investigating key electrophysiological, cognitive and imaging endophenotypes for psychosis, as well as their genetic influences. Well defined and reliably measured endophenotypes are valuable in mental health research by clarifying the functional effects of identified genetic risk factors, and by providing ways of identifying groups of people with similar abnormalities, both within and between current diagnostic categories

A comprehensive investigation into the human smooth pursuit eye movement system

Smooth pursuit eye movements (SPEM) are used to maintain the image of a slowly moving stimulus on the fovea. Previous findings on this major oculomotor system show that SPEM performance is degraded in the presence of a structured vs. blank background (background effect) and at faster vs. slower target velocities (velocity effect). In addition, SPEM is considered an important biomarker in schizophrenia research: patients with schizophrenia often present with impaired SPEM performance. However, the exact psychological, molecular, and neural mechanisms underlying SPEM in healthy individuals and in patients with schizophrenia are not well understood. This dissertation aimed to investigate these mechanisms in more detail. To this end, data from five experimental studies are reported. Study I focused on the reliability of SPEM performance in general and, additionally, the reproducibility and reliability of the background and velocity effects. In Study II, a pharmacogenetic study design was used to investigate the associations of the dopaminergic and cholinergic systems with SPEM: Nicotine or placebo was administered to participants grouped according to their genotypes on a variable number of tandem repeats (VNTR) polymorphism in the SLC6A3 gene coding for the dopamine transporter (DAT). The other studies incorporated functional magnetic resonance imaging (fMRI) data to examine the functional connectivity of areas active during SPEM (Studies III–V). In addition, the neural mechanisms underlying the background and velocity effects (Study IV), and differences in the neural correlates of SPEM between patients with schizophrenia and individuals with varying expressions of the personality trait schizotypy were investigated using machine learning methods (Study V). Across all studies, SPEM task effects were found to be very robust. Their high reliability was demonstrated in Study I. However, neither the drug factor (nicotine, placebo) nor the SLC6A3 VNTR genotype factor (9R-carriers, 10R-homozygotes), alone or in interaction, had a significant effect on SPEM performance in Study II. The good replicability of the network underlying SPEM, consisting of visual areas in the occipital cortex, parietal and frontal areas (frontal and supplementary eye fields; SEF, FEF), the lateral geniculate nucleus (LGN), and cingulate cortex, was underlined in Studies III–V. Functional connectivity analyses provided evidence of close cooperation between these areas during SPEM (Studies III–V). While the velocity effect was mainly associated with activations in visual areas, the background effect exhibited more widely distributed activations in clusters encompassing visual, frontal, and parietal areas (Study IV). Only very small deficits in SPEM performance were found in patients with schizophrenia spectrum disorders (Study V), contradicting previous findings. However, a combination of functional connectivity and machine learning approaches cautiously suggested that altered functional connectivity from the right FEF may be present in schizophrenia spectrum disorders. The findings presented here highlight the high replicability of the background and velocity effects and of the activity in the neural network associated with SPEM. The functional connectivity of the components of this network was demonstrated for the first time and showed consistency across studies. SPEM deficits in patients with schizophrenia were more subtle than previously reported. In summary, these findings add considerably to the existing research literature on SPEM, but also leave some questions open for future research.Glatte Augenfolgebewegungen (smooth pursuit eye movements; SPEM) dienen dazu, das Bild eines sich langsam bewegenden Stimulus auf der Fovea zu halten. Frühere Befunde zu diesem wichtigen okulomotorischen System zeigen, dass die SPEM-Leistung bei einem strukturierten vs. leeren Hintergrund (Hintergrundeffekt) und bei schnelleren vs. langsameren Zielreizgeschwindigkeiten (Geschwindigkeitseffekt) abnimmt. Darüber hinaus gelten SPEM als wichtige Biomarker in der Schizophrenieforschung: Patient:innen mit Schizophrenie weisen häufig eine verminderte SPEM-Leistung auf. Die genauen psychologischen, molekularen und neuronalen Mechanismen, die SPEM bei gesunden Personen und bei Patient:innen mit Schizophrenie zugrunde liegen, werden jedoch noch nicht ausreichend verstanden. Ziel dieser Dissertation ist es, diese Mechanismen genauer zu untersuchen. Zu diesem Zweck werden Daten aus fünf experimentellen Studien berichtet. Studie I befasste sich mit der Reliabilität der SPEM-Leistung im Allgemeinen und mit der Reproduzierbarkeit und Reliabilität der Hintergrund- und Geschwindigkeitseffekte. In Studie II wurde ein pharmakogenetisches Studiendesign verwendet, um die Zusammenhänge der dopaminergen und cholinergen Systeme mit SPEM zu untersuchen: Teilnehmer:innen, die nach ihrem Genotyp in einem Polymorphismus mit „variable number of tandem repeats“ (VNTR) im SLC6A3-Gen, das für den Dopamintransporter (DAT) kodiert, gruppiert waren, bekamen entweder Nikotin oder Placebo. In den anderen Studien wurden Daten der funktionellen Magnetresonanztomographie (fMRT) genutzt, um die funktionelle Konnektivität der während SPEM aktiven Areale (Studien III–V) zu untersuchen. Außerdem wurden die neuronalen Mechanismen, die den Hintergrund- und Geschwindigkeitseffekten zugrunde liegen (Studie IV), sowie Unterschiede in den neuronalen Korrelaten von SPEM zwischen Patient:innen mit Schizophrenie und Personen mit unterschiedlichen Ausprägungen des Persönlichkeitsmerkmals Schizotypie mit Hilfe von Methoden des maschinellen Lernens untersucht (Studie V). In allen Studien erwiesen sich die SPEM-Aufgabeneffekte als sehr robust. Ihre hohe Reliabilität zeigte sich in Studie I. Allerdings hatte weder die Substanz (Nikotin, Placebo) noch der SLC6A3 VNTR-Genotyp (9R-Träger, 10R-Homozygote), allein oder Interaktion, einen signifikanten Effekt auf die SPEM-Leistung in Studie II. Die gute Replizierbarkeit des SPEM zugrundeliegenden Netzwerks, bestehend aus visuellen Arealen im okzipitalen Kortex, parietalen und frontalen Arealen (frontale und supplementäre Augenfelder; SEF, FEF), dem Corpus geniculatum laterale (CGL) und dem cingulären Kortex, wurde in den Studien III–V herausgestellt. Funktionelle Konnektivitätsanalysen lieferten Hinweise auf eine enge Zusammenarbeit zwischen diesen Arealen während SPEM (Studien III–V). Während der Geschwindigkeitseffekt hauptsächlich mit Aktivierungen in visuellen Arealen assoziiert war, ging der Hintergrundeffekt mit breiter verteilten Aktivierungen in Clustern einher, die visuelle, frontale und parietale Areale umfassten (Studie IV). Bei Patient:innen mit Schizophrenie-Spektrum-Störungen wurden nur sehr geringe Defizite in der SPEM-Leistung festgestellt (Studie V), was im Widerspruch zu früheren Ergebnissen steht. Die Kombination von Methoden der funktionellen Konnektivität und des maschinellen Lernens deutete jedoch darauf hin, dass bei Schizophrenie-Spektrum-Störungen eine veränderte funktionelle Konnektivität des rechten FEF vorhanden sein könnte. Die hier vorgestellten Ergebnisse unterstreichen die hohe Replizierbarkeit der Hintergrund- und Geschwindigkeitseffekte sowie der Aktivität in dem mit SPEM assoziierten neuronalen Netzwerk. Die funktionelle Konnektivität der Komponenten dieses Netzwerks wurde zum ersten Mal gezeigt und war konsistent zwischen den Studien. SPEM-Defizite bei Patient:innen mit Schizophrenie waren weniger deutlich ausgeprägt als in vorherigen Untersuchungen. Insgesamt stellen diese Ergebnisse eine umfassende Ergänzung der bestehenden Forschungsliteratur zu SPEM dar, sie lassen aber auch einige Fragen für künftige Forschung offen