Pathophysiological changes of neurofunctional interaction between the dopaminergic reward system and the hippocampus in schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are severe psychiatric disorders with an overlap in both genotype and phenotype (Cosgrove & Suppes, 2013). Moreover, patients of both disorders have previously been reported to display abnormalities within the dopaminergic reward system (Ashok et al., 2017; Howes & Kapur, 2009), although the nature of these abnormalities is not yet well understood. While former versions of the dopamine hypothesis of psychosis assumed the dopaminergic system to be hyperactive in schizophrenia patients (van Rossum, 1966), more recent versions suggest that the dopaminergic system may be normal in its configuration, but abnormally regulated (Grace, 2012). One candidate modulator region, which might be dysfunctional in schizophrenia, is the hippocampus. In animal models of schizophrenia neurons of the anterior hippocampus have been shown to be hyperactivated, leading to a substantially increased number of spontaneously firing dopamine neurons and thereby increasing the amplitude of the phasic response of dopaminergic neurons in response to salient stimuli (Grace, 2012). Although bipolar disorder is characterized by dopaminergic abnormalities as well, findings about these abnormalities are less consistent (Ashok et al., 2017). Furthermore, there are studies showing both structural and functional abnormalities of the hippocampus (Brambilla et al., 2008; Ng et al., 2009; Otten & Meeter, 2015). Nevertheless, animal models of bipolar disorder do not include lesions of the hippocampus. In the sense of translational research, the goal of this thesis was to investigate the functional interaction of hippocampus and dopaminergic reward system in human patients to confirm and validate findings from animal models in schizophrenia and to inform prospective research with animal models of both schizophrenia and bipolar disorder. Using fMRI, I examined reward-related brain activation and connectivity of the hippocampus and central regions of the dopaminergic reward system, e. g. ventral tegmental area (VTA) and ventral striatum, in a group of 20 schizophrenia patients (study 1) and in a group of 20 bipolar patients (study 2) compared to healthy controls. Therefore, I adapted a modified version of the desire-reason dilemma (DRD) paradigm for the needs and cognitive capacities of psychiatric patients. In this paradigm context-dependent reward stimuli are presented, which have previously been proven to activate both the dopaminergic system and the hippocampus (unpublished data by our group). The selection of context-dependent reward stimuli was associated with a coactivation of bilateral hippocampus, VTA and ventral striatum in healthy controls and both schizophrenia and bipolar patients. Critically, the left ventral striatum activation was abnormally increased in schizophrenia, as previously shown in the study of Richter and colleagues (2015). Furthermore, task-related activity of both the hippocampus and the VTA, was positively correlated with the severity of psychotic symptoms. Although hippocampal structural (e.g. Bogerts et al., 1993; Zierhut et al., 2013) and functional (e.g. Heckers, 2001; Jardri et al., 2011; Lefebvre et al., 2016; Liddle et al., 2000; Schobel et al., 2009) abnormalities have already been noted in previous studies to be related to psychotic symptoms, this is the first neuroimaging study in humans showing both psychosis-related hippocampus activation and psychosis-related activation of the dopaminergic midbrain/VTA, thereby linking hippocampal abnormalities to the hyperdopaminergic state in schizophrenia. As findings from animal models of schizophrenia indicate that VTA activation is dependent on an activation of the hippocampus (for review see e.g. Grace, 2012, 2016), hyperactivation of the hippocampus and the VTA can be expected to be functionally related. In line with that, our study revealed a positive coupling of the left hippocampus with the bilateral VTA in healthy controls. Our results show, that this functional connectivity is disrupted in schizophrenia patients, with a higher psychotic symptom severity related to a reduced functional connectivity. The results of this study are of high relevance, as they shed light on the pathophysiological mechanisms underlying psychotic symptoms in schizophrenia, identifying hyperactivation and dysfunctional coupling of the hippocampus and the VTA as possible neuroimaging markers for psychosis. Replicating the findings from Trost and colleagues (2014), the vStr showed a reduced reward-related activation in bipolar patients compared to healthy controls. Interestingly, this was accompanied by a reduced functional connectivity between hippocampus and VTA, matching the findings from the schizophrenia patients. Although there is evidence from multiple studies concerning abnormal hippocampal structure and function in bipolar disorder (Brambilla et al., 2008; Ng et al., 2009; Otten & Meeter, 2015), this is the first study showing functional connectivity abnormalities of the hippocampus with the dopaminergic midbrain – thereby revealing a shared pathophysiological mechanism of bipolar disorder and schizophrenia.