ZEL

 IBI

 INC

 IME

In charge: Prof. K. Zilles, IME, k.zilles@fz-juelich.de

Aims and Objectives

Research and development in neuroscience is focussed:

• On the understanding of the mechanisms of proteinfunction on the basis of their structure and dynamics.
• In basic research in the field of cellular signaling, in particular in sensory neurons, neurons in general, but also spermatozoa.
• Development and evaluation of medically relevant radioisotopes and of radiopharmaceuticals for the emission-tomographic measurement of molecular processes in the human brain.
• Investigation of the cerebral representation of motoric, sensoric and cognitive brain functions in order to investigate structure-function-relationships.

Significant Results in 2003

• A remarkable progress was achieved in the determination of structure and orientation of peptides bound to membrane proteins by high resolution liquid NMR spectroscopy applied to the example of a fragment of the G-protein transducin in the receptor bound state from transferred residual couplings and transferred NOEs.
• Mirror image phage display was applied for the identification of a small D-amino acid peptide, that specifically binds to Alzheimer's disease amyloid plaques and thus may be suitable for online monitoring of the amyloid plaque load in living brains.
• Functional infrared difference spectra of a protein monolayer of cytochrome c are recorded by exploiting the surface enhancement exerted by a modified gold surface.
• Mutations in the genes coding for CNG channel subunits cause colour blindness.
• The Ca²⁺-regulation of the important Cl^- transduction current in olfactory neurons was analysed.
• A technique was developed using fluorescence quenching to measure the conformational dynamics of biomolecules (peptides) with a time resolution of nanoseconds.
• A novel method was established to determine the 3-dimensional orientation of single fluorescent molecules.
• Means to quantify studies on cerebral adenosine receptors with [¹⁸F]CPFPX and PET have successfully been developed and tested. A series of PET studies on healthy volunteers and patients has been set out to investigate the normal function of adenosine receptors and their involvement in neurological disorders.
• A spatial normalization procedure for 2D and 3D images (MR, histological) of the human brain has been developed. The procedure uses a multiscale registration algorithm and is based on an elastic model.
• Probabilistic cytoarchitectonic maps of 27 cortical areas (including sensorimotor, auditory, visual, language), the amygdala with 11 subnuclei, and 10 fibre tracts have been warped to new references space, which enables the analysis of structural-functional relationship using SPM software.
• A new cortical area has been defined on the basis of cyto- and receptorarchitectonic criteria as the anatomical correlate of a functionally defined region, which is involved in task representation.
• An area in the anterior cingulate cortex of the left and right hemisphere, respectively, has been identified, that controls hemisphere specific functions (left: language; right: visuospatial processing). Furthermore, such hemispheric specialization does not depend on the stimulus material presented but rather the processing types performed with the stimulus.
• The neural mechanisms underlying the amelioration of neglect by vestibular stimulation were identified using galvanic vestibular stimulation during visuospatial processing while measuring increases in neural activity in healthy volunteers: the increases in neural activity in inferior parietal cortex and ventral premotor cortex reflect a successful stimulation of the cortex network supporting visuospatial processing. Stimulation thereof is likely to result in an amelioration of neglect in patients suffering from stroke to one or the other of the two areas.
• A new behavioral treatment for neglect patients was evaluated and it could be proven that the effects of that treatment last for more than 3 months after stopping the treatment.
• For patients with Parkinson's disease, essential tremor and epilepsy we develop a demand-controlled deep brain pacemaker for rapid desynchronization via several sites, which is milder and less energy consuming compared to the standard stimulation.
• Synchronisation and Phase resetting Tomography have been developed and used in studies on early visual processing, demonstrating that brain areas may switch between qualitatively different responses, which cannot be detected with standard averaging techniques.
• For the first time a stereoselective preferred transport of a D-amino acid at the human blood-brain barrier, i.e. D-cis-4-[¹⁸F]fluoroproline, could be demonstrated. D-amino acids are presently discussed as modulators of excitatory neurotransmitter systems.
• Nuclear data measurements for production of the positron emitters ¹⁴O, ⁶⁴Cu and ⁷⁶Br and for activation of tissues during proton-therapy were completed.
• By reaction of asymmetric methoxyphenyl-thiophene-2-yliodonium salts with [¹⁸F]fluoride succeeded the no-carrier-added labelling of electron-rich arenas, was successfully carried out.
• An electrochemical cell, which facilitates the separation of [¹⁸F]fluoride and [¹⁸O]water, was integrated into the routine production of no-carrier-added PET-radiotracers.
• A radioselenated receptor ligand, 5'-(methyl⁷⁵Se]seleno)-N⁶-cyclopentyladenosine, could be prepared for the first time with a newly developed labelling method, which exhibits a high selectivity for the adenosine-A₁ receptor.
• The development of potential ¹⁸F-labelled DAT-ligands included the preparation of the new tracer CIT-Amide. The radiosynthesis of the derivative [¹⁸F]FPCIT was automated and its selective accumulation in human striatum confirmed.
• The listmode acquisition could be implemented for its common use in receptor studies at the PET scanner. Applying this option the motion correction in neurological PET was further developed.
• A new method for the quantitative, in vivo measurement of water content using MRI has been developed. Phantom results indicate an accuracy of lower than 2%.
• Quantitative imaging of the soduim density distribution has been demonstrated on a 4T MRI machine with a scan time of under 2 minutes.
• A high performance small animal PET system for brain studies of small primates and rats, called ClearPET™ Neuro, is in the state of final assembly, according to first test measurements with the novel LSO/LuYAP dual layer crystal detectors have been performed.
• The re-equipment of conventional SPECT cameras with multi-pinhole collimators supply one more than tenth higher sensitivity compared to traditional parallel collimators and a reconstructed resolution of 1.2 mm.
• First is the simultaneous registration and online phase analysis of the signals of the micro electrodes (single cell activity) and of the macro electrodes (local field) successfully performed during the implantation of depth brain electrodes.
• A flexible real-time system was developed for a more efficient conversion of the biophysical model investigations of population of coupled neurons.