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PurposeCalcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression.MethodsPET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance.ResultsIn controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect.ConclusionOur results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

Cochlear implantation constitutes a successful therapy of inner ear deafness, with the majority of patients showing good outcomes. There is, however, still some unexplained variability in outcomes with a number of cochlear-implant (CI) users, showing major limitations in speech comprehension. The current study used a multimodal diagnostic approach combining single-photon emission computed tomography (SPECT) and electroencephalography (EEG) to examine the mechanisms underlying speech processing in postlingually deafened CI users (N=21). In one session, the participants performed a speech discrimination task, during which a 96-channel EEG was recorded and the perfusions marker 99mTc-HMPAO was injected intravenously. The SPECT scan was acquired 1.5 hours after injection to measure the cortical activity during the speech task. The second session included a SPECT scan after injection without stimulation at rest. Analysis of EEG and SPECT data showed N400 and P600 event-related potentials (ERPs) particularly evoked by semantic violations in the sentences, and enhanced perfusion in a temporo-frontal network during task compared to rest, involving the auditory cortex bilaterally and Broca’s area. Moreover, higher performance in testing for word recognition and verbal intelligence strongly correlated to the activation in this network during the speech task. However, comparing CI users with lower and higher speech intelligibility (median split with cutoff + 7.6 dB SNR in the Göttinger sentence test) revealed for CI users with higher performance additional activations of parietal and occipital regions, and for those with lower performance stronger activation of superior frontal areas. Further, SPECT activity was tightly coupled with EEG and cognitive abilities, as indicated by correlations between 1) cortical activation and the amplitudes in EEG, N400 (temporal and occipital areas) / P600 (parietal and occipital areas), and 2) between cortical activation in left-sided temporal and bilateral occipital/parietal areas and working memory capacity. These results suggest the recruitment of a temporo-frontal network in CI users during speech processing and a close connection between ERP effects and cortical activation in CI users. The observed differences in speech-evoked cortical activation patterns for CI users with higher and lower speech intelligibility suggest distinct processing strategies during speech rehabilitation with CI.

PurposeTracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET.MethodsDynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed.ResultsCorrelation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect.ConclusionThese results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.

Activation studies with positron emission tomography (PET) in auditory implant users explained some of the mechanisms underlying the variability of achieved speech comprehension. Since future developments of auditory implants will include studies in rodents, we aimed to inversely translate functional PET imaging to rats. In normal hearing rats, activity in auditory and non-auditory regions was studied using 18F-fluorodeoxyglucose (18F-FDG) PET with 3 different acoustic conditions: sound attenuated laboratory background, continuous white noise and rippled noise. Additionally, bilateral cochlea ablated animals were scanned. 3D image data were transferred into a stereotaxic standard space and evaluated using volume of interest (VOI) analyses and statistical parametric mapping (SPM). In normal hearing rats alongside the auditory pathway consistent activations of the nucleus cochlearis (NC), olivary complex (OC) and inferior colliculus (IC) were seen comparing stimuli with background. In this respect, no increased activation could be detected in the auditory cortex (AC), which even showed deactivation with white noise stimulation. Nevertheless, higher activity in the AC in normal hearing rats was observed for all 3 auditory conditions against the cochlea ablated status. Vice versa, in ablated status activity in the olfactory nucleus (ON) was higher compared to all auditory conditions in normal hearing rats. Our results indicate that activations can be demonstrated in normal hearing animals based on 18F-FDG PET in nuclei along the central auditory pathway with different types of noise stimuli. However, in the AC missing activation with respect to the background advises the need for more rigorous background noise attenuation for non-invasive reference conditions. Finally, our data suggest cross-modal activation of the olfactory system following cochlea ablation-underlining, that 18F-FDG PET appears to be well suited to study plasticity in rat models for cochlear implantation.

Visual reading of [(123)I]IBZM SPECT scans depends on the experience of the interpreter. Therefore, semi-quantification of striatal IBZM uptake is commonly considered mandatory. However, semi-quantification is time consuming and prone to error, particularly if the volumes of interest (VOIs) are positioned manually. Therefore, the present paper proposes a new software tool (\"IBZM tool\") for fully automated and standardised processing, evaluation and documentation of [(123)I]IBZM SPECT scans. The IBZM tool is an easy-to-use SPM toolbox. It includes automated procedures for realignment and summation of multiple frames (motion correction), stereotactic normalisation, scaling, VOI analysis of striatum-to-reference ratio R, classification of R and standardised display. In order to evaluate the tool, which was developed at the University of Hamburg, the tool was transferred to the University of Hannover. There it was applied to 27 well-documented subjects: eight patients with multi-system atrophy (MSA), 12 patients with Parkinson's disease (PD) and seven controls. The IBZM tool was compared with manual VOI analysis. The sensitivity and specificity of the IBZM tool for the differentiation of the MSA subjects from the controls were 100% and 86%, respectively. The IBZM tool provided improved statistical power compared with manual VOI analysis. The IBZM tool is an expert system for the detection of reduced striatal D(2) availability on [(123)I]IBZM SPECT scans. The standardised documentation supports visual and semi-quantitative evaluation, and it is useful for presenting the findings to the referring physician. The IBZM tool has the potential for widespread use, since it appears to be fairly independent of the performance characteristics of the particular SPECT system used. The tool is available free of charge.

Activation studies with positron emission tomography (PET) in auditory implant users explained some of the mechanisms underlying the variability of achieved speech comprehension. Since future developments of auditory implants will include studies in rodents, we aimed to inversely translate functional PET imaging to rats. In normal hearing rats, activity in auditory and non-auditory regions was studied using .sup.18 F-fluorodeoxyglucose (.sup.18 F-FDG) PET with 3 different acoustic conditions: sound attenuated laboratory background, continuous white noise and rippled noise. Additionally, bilateral cochlea ablated animals were scanned. 3D image data were transferred into a stereotaxic standard space and evaluated using volume of interest (VOI) analyses and statistical parametric mapping (SPM). In normal hearing rats alongside the auditory pathway consistent activations of the nucleus cochlearis (NC), olivary complex (OC) and inferior colliculus (IC) were seen comparing stimuli with background. In this respect, no increased activation could be detected in the auditory cortex (AC), which even showed deactivation with white noise stimulation. Nevertheless, higher activity in the AC in normal hearing rats was observed for all 3 auditory conditions against the cochlea ablated status. Vice versa, in ablated status activity in the olfactory nucleus (ON) was higher compared to all auditory conditions in normal hearing rats. Our results indicate that activations can be demonstrated in normal hearing animals based on .sup.18 F-FDG PET in nuclei along the central auditory pathway with different types of noise stimuli. However, in the AC missing activation with respect to the background advises the need for more rigorous background noise attenuation for non-invasive reference conditions. Finally, our data suggest cross-modal activation of the olfactory system following cochlea ablation-underlining, that .sup.18 F-FDG PET appears to be well suited to study plasticity in rat models for cochlear implantation.

Coupled modelling of soil erosion, carbon redistribution, and turnover has received great attention over the last decades due to large uncertainties regarding erosion-induced carbon fluxes. For a process-oriented representation of event dynamics, coupled soil–carbon erosion models have been developed. However, there are currently few models that represent tillage erosion, preferential water erosion, and transport of different carbon fractions (e.g. mineral bound carbon, carbon encapsulated by soil aggregates). We couple a process-oriented multi-class sediment transport model with a carbon turnover model (MCST-C) to identify relevant redistribution processes for carbon dynamics. The model is applied for two arable catchments (3.7 and 7.8 ha) located in the Tertiary Hills about 40 km north of Munich, Germany. Our findings indicate the following: (i) redistribution by tillage has a large effect on erosion-induced vertical carbon fluxes and has a large carbon sequestration potential; (ii) water erosion has a minor effect on vertical fluxes, but episodic soil organic carbon (SOC) delivery controls the long-term erosion-induced carbon balance; (iii) delivered sediments are highly enriched in SOC compared to the parent soil, and sediment delivery is driven by event size and catchment connectivity; and (iv) soil aggregation enhances SOC deposition due to the transformation of highly mobile carbon-rich fine primary particles into rather immobile soil aggregates.

Purpose Treating segmental long-bone defects remains a major challenge. For defects >3 cm, segmental transport represents the gold standard, even though the method is time consuming and afflicted with several complications. The aim of this study was to evaluate healing of such defects after grafting an osteogenic scaffold previously seeded with stem cell concentrate. Methods We evaluated five patients with segmental long-bone defects (3–14 cm) treated with bone marrow aspirate concentrates (BMAC) seeded onto a bovine xenogenous scaffold. The healing process was monitored by X-rays and positron emission tomography–computed tomography (PET-CT) three months after surgery. Results Centrifugation led to a concentration of leukocytes by factor 8.1 ± 7.5. Full weight bearing was achieved 11.3 ± 5.0 weeks after surgery. PET analysis showed an increased influx of fluoride by factor 8.3 ± 6.4 compared with the contralateral side ( p  < 0.01). Bone density in the cortical area was 75 ± 16 % of the contralateral side ( p  < 0.03). The patient with the largest defect sustained an implant failure in the distal femur and finally accomplished therapy by segmental transport. He also had the lowest uptake of fluoride of the patient collective (2.2-fold increase). Conclusion Stem cell concentrates can be an alternative to segmental bone transport. Further studies are needed to compare this method with autologous bone grafting and segmental transport.

Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with 15O-water, respectively, 13N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.