Research group Neuroimaging

Head : Eva M. Meisenzahl, Hans-Jürgen Möller
Current scientific members: Gisela Schmitt, Thomas Frodl, Thomas Zetzsche, Nikolaos Koutsouleris, Hanna Scheurerecker, Dörthe Seifert, Sandra Ufer, Bernhard Burgermeister
Former scientific members: Tobias Rüther, Thomas Mühlbauer, Eduard Kraft, Alain Marcuse, Torsten Mager

Since Hans-Jürgen Möller took over as chairman, imaging techniques have become an important focus of the hospital’s research strategies. Up to now, the main conceptual focuses have been basic scientific and clinical research to clarify the pathogenesis of schizophrenic and affective disorders. One of the main strategies of the neuroimaging group is the successful approach of investigating scientific hypotheses and comparing study results from large samples of schizophrenic patients with those from cohorts of patients with depressive disorders and personality disorders of the borderline type. The group’s research is strategically aimed at the stringent examination of different levels of the disorders mentioned above:
Imaging procedures to investigate disturbed connectivity in the CNS are on the first level. Our activities focus on the search for abnormal structures and disturbed functions in the CNS of patients with the above mentioned disorders. This approach only makes sense when it is closely interlaced with psychopathological-epidemiological research approaches (epidemiological cross-sectional and follow-up research). This association is necessary since at the moment it can be assumed that the current diagnostic entities may possibly differ from the actual illness groups. Again, the research group has a comparative approach in that it attempts to compare the various diagnostic illness entities with respect to the specificity of their biological markers such as brain structure or function.

Due to the as yet unclear pathogenesis of the named central psychiatric disorders, on a different level intensive work is performed to link various biological markers such as those from imaging procedures with those obtained from genetics (“Imaging Genomics”) and neurophysiology.

On the third level, the research group advances current receptor research on the animal experimental level using AnimalSPET; this work is performed in close cooperation with the department for nuclear medicine.

A broad spectrum of imaging procedures is applied. In the past decade of brain research, the technique of magnetic resonance spectroscopy has taken up the central position in the research activities of the scientific community. Since the beginning, the research group has used structural magnetic resonance imaging intensively to evaluate the neuroplastic changes of macrostructures in the CNS in affective disorders and schizophrenia. The additional use of diffusion tensor imaging has been strongly developed since 2004 and is applied by the research group in pilot studies to investigate the fibre systems of the CNS and their disturbed connectivity, for example to validate the therapeutic approach of electroconvulsive therapy in treatment-refractory depression.

In the psychiatric hospital of the LMU Munich, the application of functional magnetic resonance tomography plays a central role in the evaluation of affective and cognitive processes in healthy subjects and patients. Extensive projects are performed to validate models of disturbances of cerebral networks. An additional important focus is the validation of psychopharmacological and psychotherapeutic strategies using measurement instruments such as fMRT.

For years, the research group has evaluated and measured these data independently with a large degree of know-how. The research group has extensive equipment to perform these tasks, including linux computers and software tools to analyse brain structure and function (SPM, VBM, BRAINS, ANALYZE).

Besides the evaluations of macrostructures and functional connectivity in the CNS, receptor research with SPET and PET is the third method required to investigate pathogenetic causes of affective and schizophrenic disorders. Over the last few years, the research group has worked intensively on using single photon emission tomography to evaluate receptors in patients who have never been treated. A further central aspect is the validation of current receptor targets of different psychopharmacological strategies in order to obtain a clearer understanding of the efficacy and tolerability of psychopharmacological interventions. The application of increasingly specific ligands for the complex regulatory systems of pre- and postsynaptic receptors of the various transmitter substances is a high priority of the research group. Furthermore, as mentioned above the research group has a great interest in the linking of in vivo imaging with basic scientific research in affective disorders with the animal experimental MicroSPECT implemented in cooperation with the department of nuclear medicine.

In schizophrenic neuroimaging research with the focus on possible structural brain changes and the timing of these changes over the course of the disease clear results were achieved from cross-sectional as well as from longitudinal studies. In large samples of patients compared to healthy control subjects there was a highly significant reduction of gray matter density and volume in befrontal-bitemoral areas, and this from the beginning of the disease. Furthermore, the cross-sectional design already shows dynamic structural brain changes: patients with a first manifestation already show noticeable structural brain changes, in particular a reduction of the frontal lobes and hippocampus and an enlargement of the lateral ventricles, which increase significantly in relapsing disorders. These cerebral changes such as reduction of hippocampal volume can also be observed in depressive disorders and personality disorders of the borderline type. The clear increase of the size of the reduction when healthy, depressive and schizophrenic subjects are compared is noteworthy: from the healthy controls through the depressive first manifestations and relapsing disorders, to the schizophrenic disorders, where relapsing disorders exhibit the largest amount of hippocampal reduction.
The subsequent longitudinal imaging studies clearly show a disease-specific reduction of bifronto-temporal brain structures in schizophrenic patients that is beyond what can be expected at the age concerned. This is especially obvious in the first year of illness, but also in the 2nd and 3rd and up to the 12th year, which is the longest time covered by the research group’s follow-up studies so far.
The specific relevance of these structural changes for schizophrenic disorder and its dynamics are being further investigated in ongoing follow-up studies in depressive and borderline patients. Up to now these ongoing projects have demonstrated that after one year – depending on the course of their disease - depressive patients also show hippocampal reduction, and after three years there is a further reduction of brain structures in the whole group of depressive patients, depending on the clinical outcome of these patients.
The research results of the working group in the sector of functional imaging with investigations of neuropsychological deficits support the structural changes, particularly in the frontal cortex. In unmedicated schizophrenic patients they show a clear deficit in executive functions accompanied by reduced activations in the prefrontal cortex. It is noteworthy that these patients show improved executive performance and an at least slight increase in brain activation in the prefrontal cortex after psychopharmacological treatment with an atypical neuroleptic such as quetiapine.
The group’s research strategy deals with comprehensive investigations of the cause of these structural-functional deficits in schizophrenic patients by investigating the disturbance of the dopamine system in never-treated patients. In studies of large samples it became obvious that compared to healthy controls these patients have a significant reduction of postsynaptic striatal D2/D3 receptors for the ligands. Furthermore, there is a significant relationship with the degree of positive symptoms such that the more positive symptoms are present, the lower the degree of D2/D3 receptor availability. This result points very clearly to the dopaminergic overstimulation that is definitely present in the psychotic state. The investigation of the relationship between dopamine, its interactions with another messenger substance, glutamate, and the structural-functional changes have been a focus of extensive research activities in animals for the past year.
In the evaluation of the underlying mechanisms of psychopharmacological strategies, extensive standardised evaluations show that also atypical antipsychotics such as amisulpride, olanzapine and risperidone can sometimes achieve very high D2 receptor blockade profiles, even though clinically they show significantly better tolerability and a lower rate of extrapyramidal side effects. This supports hypotheses that the better tolerability of atypical neuroleptics is explained by either limbic selectivity in the CNS or faster dissociation of these drugs from striatal D2 receptors. Finally, in the area of Imaging Genomics research, yielded fascinating and promising results.

Finally, the impact of genes, that are involved in neuronal development, migration, neuroplasticity and apopthosis on brain structures of healthy control subjects, and specifically on altered brain structures of schizophrenic, depressed patients or patients with a personality disorder was shown extensively by the research group. Especially polymorphisms of genes like the Prion Protein, the interleukin 1ß, or the BDNF polymorphism show clear impact on brain structures and may give in the future a better understanding of the concept of vulnerability for psychiatric diseases in human subjects.

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