Attending to the ups and downs of Lewy body dementia: An exploration of cognitive fluctuations
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share similarities in pathology and clinical presentation and come under the umbrella term of Lewy body dementias (LBD). Fluctuating cognition is a key symptom in LBD and manifests as altered levels of alertness and attention, with a marked difference between best and worst performance. Cognition and alertness can change over seconds or minutes to hours and days of obtundation. Cognitive fluctuations can have significant impacts on the quality of life of people with LBD as well as potentially contribute to the exacerbation of other transient symptoms including, for example, hallucinations and psychosis as well as making it difficult to measure cognitive effect size benefits in clinical trials of LBD. However, this significant symptom in LBD is poorly understood. In my presentation I will discuss the phenomenology of cognitive fluctuations, how we can measure it clinically and limitations of these approaches. I will then outline the work of our group and others which has been focussed on unpicking the aetiological basis of cognitive fluctuations in LBD using a variety of imaging approaches (e.g. SPECT, sMRI, fMRI and EEG). I will then briefly explore future research directions.
Hallucinating mice, dopamine and immunity; towards mechanistic treatment targets for psychosis
Hallucinations are a core symptom of psychotic disorders and have traditionally been difficult to study biologically. We developed a new behavioral computational approach to measure hallucinations-like perception in humans and mice alike. Using targeted neural circuit manipulations, we identified a causal role for striatal dopamine in mediating hallucination-like perception. Building on this, we currently investigate the neural and immunological upstream regulators of these dopaminergic circuits with the goal to identify new biological treatment targets for psychosis
CNStalk: Finding the network balance in Parkinson’s hallucinations
A predictive-processing account of psychosis
There has been increasing interest in the neurocomputational mechanisms underlying psychotic disorders in recent years. One promising approach is based on the theoretical framework of predictive processing, which proposes that inferences regarding the state of the world are made by combining prior beliefs with sensory signals. Delusions and hallucinations are the core symptoms of psychosis and often co-occur. Yet, different predictive-processing alterations have been proposed for these two symptom dimensions, according to which the relative weighting of prior beliefs in perceptual inference is decreased or increased, respectively. I will present recent behavioural, neuroimaging, and computational work that investigated perceptual decision-making under uncertainty and ambiguity to elucidate the changes in predictive processing that may give rise to psychotic experiences. Based on the empirical findings presented, I will provide a more nuanced predictive-processing account that suggests a common mechanism for delusions and hallucinations at low levels of the predictive-processing hierarchy, but still has the potential to reconcile apparently contradictory findings in the literature. This account may help to understand the heterogeneity of psychotic phenomenology and explain changes in symptomatology over time.
Virtual Hallucinations to study the Sense of Reality
Hallucinating mice and dopamine – towards mechanistic treatment targets for psychosis
Psychotic disorders are devastating conditions without any mechanistic treatment available. One major hurdle in the biological study of psychosis is the challenge of rigorously probing this condition in pre-clinical animal models. The goal of our research is to develop and exploit innovative frameworks for the study of psychosis in mice. In our present work, where we developed a cross-species computational psychiatry approach to probe hallucination-like perception. This enabled us to directly relate human and mouse behavior, and to demonstrate and dissect the causal role of striatal dopamine in hallucination-like perception. Our results suggest a neural circuit mechanism for the long-standing dopamine hypothesis of psychosis, and provide a new translational framework for the biological study of psychosis. This opens up exciting possibilities for advancing the biological understanding of psychosis and to identify mechanistic treatment targets.