Polygenetics of attention and effort: Uncovering brain circuit pathologies in schizophrenia

Schizophrenia is a severe mental disorder with high morbidity, large impact on patients and their families, and huge costs for society and the health care sector globally. Despite progress in genetic, brain imaging, and cognitive research, the biological deficiencies underlying schizophrenia are still mainly unknown. Cognitive abnormalities are key components of schizophrenia, and unlike positive symptoms, including hallucinations and delusions, cognitive symptoms predate diagnosis, predict functional outcome, resist treatment, and often persist throughout life. Understanding the biological basis of cognitive abnormalities in schizophrenia, at molecular and brain network levels, will be critically important for the development of treatments that can ameliorate them. There is strong evidence for a role of brain neuromodulatory systems in attention and learning, especially involving noradrenaline, acetylcholine, and dopamine, but their interaction patterns are less well understood. We hypothesize that an important basis of cognitive symptoms in schizophrenia is abnormalities in the brainstem noradrenergic system, and particularly its interaction with dopamine systems and brain control networks. We have taken advantage of recent methodological advances to uncover brain circuit malfunctions underlying cognitive abnormalities in schizophrenia. In particular, we combined new methods from with measurements of task-dependent pupil dilations with functional imaging of brain networks that underlie flexible goal-directed behavior. We have developed new experimental paradigms that allows for targeted manipulation of brain activity with particular relevance for the noradrenergic system. This was done through detailed behavioral testing of participants on web-based platforms. To be able to study the role of mental effort and brain activity in different cognitive conditions, the behavioral paradigms were adapted for concurrent registration of physiological indicators such eye movements, fluctuations in pupil size, and oxygen content in blood (functional MRI). We developed an MRI protocol for reliable localization of cell nuclei in the brain stem, and identification of differential activation in these during various kinds and levels of cognitive activity. 400 participants took part in the eye-tracking and pupillometry protocol. 150 participated in the MRI protocol, and for about half of these, MRI was combined with concurrent eye-tracking and pupillometry. The physiological data was registered while the participants worked on cognitive tasks, but also during rest. Some of the main findings from the project were that (1) activity in the brain?s noradrenergic system is an indicator of the mental effort that people invest in a particular task at a particular time, (2) activity in the brain?s noradrenergic system is sensitive to the kind of cognitive activity the occurs, how difficult the cognitive tasks are, and the timing of mental effort, (3) activity in the brain?s noradrenergic system influences functional networks in the brain under focused mental activity and during rest, and (4) individual differences in cognitive capacity and motivation influences all of the above findings. The methodological advances and results of the project has strengthened the foundation for targeted research on the role of noradrenergic dysfunctions in severe psychopathology.

Prosjektet har gjennom utvikling av eksperimentelle kognitive paradigmer og metoder for registrering av fysiologiske korrelater bidratt til et sterkere metodisk grunnlag for å studere betydningen av dysfunksjoner i hjernens noradrenerge system for utvikling, aldring, og i nevropsykiatriske lidelser.

SCZ is a severe mental disorder with high morbidity, large impact on patients and their families, and huge costs for society and the health care sector globally. Despite progress in genetic, imaging, and cognitive research on SCZ, the pathophysiology is s till mainly unknown. There is strong evidence for a role of brain neuromodulatory systems in attention and learning, especially involving noradrenaline, acetylcholine, and dopamine, but their interaction patterns are less well understood. We hypothesize t hat an important basis of cognitive symptoms in SCZ is abnormalities the brainstem noradrenergic system, and particularly its interaction with midbrain dopamine systems and frontostriatal control networks. We will combine novel polygenic analysis methods with task-dependent pupillometry and functional imaging of brainstem noradrenergic activity and connectivity. This is a novel approach that aims to combine the strengths of large-scale genetics research and the functional specificity and theoretical rigor of task-dependent functional imaging. Main questions 1)Is there genetic overlap between attention and effort, and SCZ, and is the overlap larger for processes most strongly dependent on the LC-NE system? Is the genetic overlap different between patients with high vs. low IQ? 2)If any new gene associations are discovered, where in the brain are these particularly active, and are there any developmental differences associated with this expression enrichment? 3)Is LC BOLD activity different between SCZ pati ents and controls during task performance, and is this specific to context updating/attentional refocusing, and/or cognitive load? Are there BOLD activity differences between patients with high vs. low IQ? 4)Is LC connectivity with nodes in the updating/r efocusing network increased during relevant trials, and are there connectivity differences between SCZ patients and controls? Are there differences between patients with high vs. low IQ?