Functional neuroimaging of pathophysiological mesolimbic dopamine system and aberrant motivational salience in schizophrenia

Schizophrenia is a common and devastating psychiatric illness with prominent variability regarding its process, symptomatology and treatment response. The disorder is characterized by three broad types of symptoms including positive symptoms such as hallucinations, delusions and disorganized thinking, negative symptoms involving blunted affect and anhedonia as well as cognitive impairments affecting working memory and attentional processes, learning and executive functions. Despite extensive research in the past, the etiology of the disorder remains still undetermined. It is hypothesized that its onset, progression and symptoms are influenced by an interaction of various susceptibility genes and environmental risk factors. Several neurochemical models have been established to explain the emergence and development of the diverse symptoms in schizophrenia. Its pathophysiology involves dysregulation of multiple pathways with strong evidence for dysfunctional neurotransmitter systems involving dopamine, glutamate, gamma-aminobutyric acid (GABA) and choline. Thereby, dopaminergic dysfunction has been proven to play a major role in the pathogenesis of schizophrenia leading to detrimental consequences in reward processing and decision making. Previous studies provided evidence that dopamine metabolites were not elevated in the whole brain but rather that there is a regionally specific prefrontal hypodopaminergic state and a subcortical hyperdopaminergic state in schizophrenia. However, the question of how an increase in striatal dopamine synthesis and release capacity causes the symptoms in schizophrenia remains unresolved. The first aim of the present thesis was to investigate how pathophysiological changes in patients with schizophrenia alter the functional activity and connectivity within the mesocorticolimbic dopamine system during reward-related decision making. In the previously introduced aberrant salience hypothesis it is postulated that in schizophrenic patients dysregulated dopamine transmission leads to an exaggerated release of dopamine and gives rise to the aberrant assignment of inappropriate salience and motivational significance to external objects and internal representations independent of the context. To account for this aspect, the second aim of the present thesis was to examine how the manipulation of salience through relative frequency of neutral and rewarding events affects the neural mechanisms and functional interactions of the mesolimbic dopamine system during decision making and action control. I addressed these questions by the use of functional magnetic resonance imaging (fMRI) and different versions of a reward-based decision making paradigm. In the first study a group of 16 schizophrenic patients were matched to a group of 16 healthy control subjects regarding age, gender and years of education. All subjects had to follow specific task requirements to maximize their profit in the long run. In the desire context (DC), prior conditioned reward stimuli were allowed to obtain, whereas in the reason context (RC) these stimuli had to be rejected in favor of a superordinate long term goal. Compared to healthy controls, schizophrenic patients showed increased ventral striatal activation in response to the previously conditioned reward stimuli. Furthermore, they exhibited an attenuated suppression of reward signals in the ventral striatum (vStr) and ventral tegmental area (VTA) when they had to resist the rewards. This reduced suppression was associated with an impaired functional interaction between the vStr and both the anteroventral prefrontal cortex (avPFC) and ventromedial prefrontal cortex (VMPFC). Overall, the increased bottom-up activation of the vStr may result from an intensified recruitment of this region during exaggerated assignment of salience to the conditioned rewards irrespective of the context. Moreover, the finding of disturbed cortico-striatal functional interaction in schizophrenic patients is in line with the dysconnection hypothesis of schizophrenia. In the second study saliency was implemented by the experimental manipulation of both rewarding and neutral stimuli through relative frequency. Infrequent stimuli with long intervals between consecutive events are unexpected and hence more salient. Behavioral findings confirmed the successful experimental implementation of saliency by both increased error rates and reaction times in response to salient events. Moreover, infrequent neutral and goal-irrelevant events led to an increase of vStr and VTA activation and further cortical brain regions including the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC). This demonstrates that the mesolimbic reward system was activated in response to saliency per se and provided direct evidence for the role of the mesolimbic dopamine system in processing salient events in general. An increase of activation in the vStr and VTA has been further demonstrated in response to infrequently presented rewards in situations where actions required a restraint from immediate rewards, indicating a boosting of activation in both brain regions, probably caused by the salient and rewarding attributes of the stimuli. This boosting of activation was accompanied by increased functional interactions between each other and further cortical brain regions such as the OFC, IFG and ACC. Taken together, these subcortical and cortical brain regions working in collaboration may form a network to enable prioritized processing of salient stimulus attributes leading to adaptive and successful decision making. Altogether, the reported findings addressed the main aims of the present thesis in extending the knowledge about how pathophysiological changes in schizophrenia affect behavior, functional activity and connectivity during reward processing and furthermore, how the manipulation of salience modulates neural mechanisms involved in action control and decision making.2018-04-0