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Formal thought disorder: Pathophysiology and its implication for specific treatment

English title Formal thought disorder: Pathophysiology and its implication for specific treatment
Applicant Strik Werner
Number 127359
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik und Poliklinik für Psychiatrie
Institution of higher education University of Berne - BE
Main discipline Neurology, Psychiatry
Start/End 01.05.2010 - 31.07.2014
Approved amount 375'000.00
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All Disciplines (3)

Discipline
Neurology, Psychiatry
Neurophysiology and Brain Research
Pathophysiology

Keywords (10)

schizophrenia; formal thought disorder; semantic processing; resting perfusion; GABA; glutamate; ASL; MRS; EEG; N400

Lay Summary (English)

Lead
Lay summary
There is growing evidence that the investigation of specific symptoms is a promising approach in schizophrenia research 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 superior temporal gyrus (STG). In a previous study 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 previous 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.Based on our previous results the current project will investigate in 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 current 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.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. 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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Ventral striatum gray matter density reduction in patients with schizophrenia and psychotic emotional dysregulation.
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.
Semantic network disconnection in formal thought disorder.
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.

Collaboration

Group / person Country
Types of collaboration
AMSM Inselspital Bern Switzerland (Europe)
- Research Infrastructure
Institut für Neuroradiologie, Inselspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2nd SFCNS Congress 2013 Poster Functional Connectivity of Broca’s region – Symptom Specific Changes in Formal Thought Disorder (FTD) in Schizophrenia 07.06.2013 Montreux, Switzerland Horn Helge; Müller Thomas; Laimböck Karin; Federspiel Andrea; Strik Werner;
DGPPN Jahrskongress 2012 Poster Spezifische Konnektivitätsveränderungen im Sprachsystem bei formaler Denkstörung 23.11.2012 Berlin, Deutschland, Germany Müller Thomas; Strik Werner; Horn Helge; Laimböck Karin; Federspiel Andrea;
DGPPN Jahreskongress 2012 Poster rTMS als therapeutische Intervention bei formalen Denkstörungen 23.11.2012 Berlin, Germany Strik Werner; Federspiel Andrea; Horn Helge; Laimböck Karin; Müller Thomas;
Jahrestagung SNG & SGBP & SGVN Poster Altered Functional Connectivity in Formal Thought Disorder in Schizophrenia 09.11.2012 Basel, Switzerland Laimböck Karin; Horn Helge; Strik Werner; Müller Thomas; Federspiel Andrea;


Associated projects

Number Title Start Funding scheme
100823 Pathophysiology of psychopathology: Formal thought disorder measured by combined fMRI and EEG. 01.12.2003 Project funding (Div. I-III)
156952 Magnetic resonance techniques to determine metabolite levels: extending scope and clinical robustness 01.12.2014 Project funding (Div. I-III)
135743 Magnetic Resonance Techniques to Investigate Human Brain Physiology: Acquisition and Postprocessing Tools to Advance Spectroscopy at Clinical and High Magnetic Fields 01.06.2011 Project funding (Div. I-III)

Abstract

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.
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