Negative symptoms of schizophrenia: Treatment options and evidence from neuroimaging

This thesis focuses on studies to improve treatment options for patients who suffer from schizophrenia. Lack of initiative (apathy) and a reduced ability to experience pleasure is part of a syndrome, called “negative symptoms”, in these patients. These symptoms are related to severe impairments in social functioning and a reduced ability to live independently. Mainstream treatments for patients with schizophrenia are not effective in reducing negative symptoms. Repetitive Transcranial Magnetic Stimulation (rTMS) is a relatively new treatment option in psychiatry, and is applied to stimulate specific regions of the brain. In the first part of this thesis a double blind randomized controlled trial is reported, which found evidence for the efficacy of high frequency bilateral rTMS treatment of the prefrontal cortex in patients with negative symptoms. This clinical trial was combined with a neuroimaging study, to better understand the origin of negative symptoms and the effects of rTMS. The neuroimaging study showed an increase of brain activity and brain metabolism in the prefrontal cortex of patients with schizophrenia after rTMS treatment. The second section of the thesis explores the underlying neural substrates of negative symptoms. Our fMRI studies found an association of social-emotional withdrawal and reduced frontoparietal activation during a planning task. Expressive deficits were shown to be associated with reduced activation of the prefrontal cortex and fronto-thalamic brain areas during a social cognition task. These findings provide evidence for different neurobiological mechanisms of the two domains of negative symptoms, and may contribute to the development of new treatment options