schizophrenia; formal thought disorder; semantic processing; resting perfusion; GABA; glutamate; ASL; MRS; EEG; N400
Stegmayer Katharina, Horn Helge, Federspiel Andrea, Razavi Nadja, Bracht Tobias, Laimböck Karin, Strik Werner, Dierks Thomas, Wiest Roland, Müller Thomas J, Walther Sebastian (2014), Ventral striatum gray matter density reduction in patients with schizophrenia and psychotic emotional dysregulation., in NeuroImage. Clinical
, 4, 232-9.
Horn Helge, Jann Kay, Federspiel Andrea, Walther Sebastian, Wiest Roland, Müller Thomas, Strik Werner (2012), Semantic network disconnection in formal thought disorder., in Neuropsychobiology
, 66(1), 14-23.
Background: Schizophrenia is one of the most common disorders in medicine affecting 1% of the world’s population. Despite intensive research, not only the etiology, but also the pathophysiology is still unclear. There is growing evidence that the investigation of specific symptoms is a promising approach to overcome the often explored heterogeneity of results in schizophrenia in general. This approach has been successful in investigating hallucinations and formal thought disorder (FTD). One of the major symptoms of schizophrenia is FTD. Recently our own group showed reduced gray matter also in the anterior cingulated cortex, the precuneus, the angular gyrus and the superior temporal sulcus to be connected to the severity of FTD. However, structural deficits alone cannot explain the often waxing and waning character of FTD. FMRI studies using language tasks found reduced BOLD response in the left posterior STG. In our previous SNF project we provided evidence that the reduced BOLD response in the left posterior STG in previous studies is due to an elevated resting perfusion in this region that is proportional to the severity of FTD. Moreover, we demonstrated increasing resting perfusion in the left inferior frontal gyrus (IFG) with increasing severity of FTD. Together with EEG findings of increased spreading activations in cortical regions involved in semantic processing in patients with FTD, our results indicate structural deficits combined with an increased neuronal activity in the left hemispheric language system as a key for the pathophysiology of FTD in schizophrenia.Study objectives: Based on our previous results the proposed project will further investigate the pathophysiology of the increased neuronal activity on the level of neurotransmitters (GABA / glutamate). We hypothesize an imbalance with diminished GABA and elevated glutamate levels within the region of hyperperfusion in patients with severe FTD. In a second part of the proposed project, we will try normalize the elevated neuronal activity in the left posterior STG / angular gyrus by inhibitory Transcranial Magnetic Stimulation (TMS) as proof of concept and a possible symptom specific and non pharmacological therapy option.Experimental design and methods: As in the previous SNF project, we will collect a sample of 50 patients with schizophrenia varying mainly in the severity of FTD and 20 healthy controls. All patients will be tested extensively for their psychopathology. In all patients and controls we will measure absolute resting blood flow as in the previous SNF project. In the same MRI session we will measure the regional concentration of GABA and glutamate in the center of gravity of elevated blood flow within the left posterior STG / angular gyrus by means of magnetic resonance spectroscopy. In a second part we will apply inhibitory continuous theta burst TMS in order to reduce the regional neuronal activity in the left posterior STG /angular gyrus. Neuro navigation will be used to target the individual defined region of maximum blood flow within the left posterior STG / angular gyrus.Expected value of the proposed project: In schizophrenic patients, FTD has a major impact on social interactions and daily functioning. Therefore the improvement of FTD is of paramount interest for successful social rehabilitation of these patients. Up to now, there is no specific treatment for FTD, as most schizophrenic symptoms are treated by antipsychotic agents interacting with dopaminergic neurotransmission throughout the whole brain with several important side effects affecting social interactions and cognitive performance. The proposed project will allow to further test our pathophysiological hypothesis of FTD, and to conjoin the results of previous studies comprising regional abnormalities in structure, resting perfusion, language related activation in fMRI and increased spreading activation at the level of neurotransmitters. Furthermore, it will explore a novel, direct and specific treatment approach for FTD in schizophrenia. Additionally, the proposed project will provide new hints to better understand the origin of symptom diversity of schizophrenia. Moreover, it will give insights into the regional interrelation of GABA and glutamate levels with the regional CBF in schizophrenic subjects in general, and in healthy subjects.