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Peter Bartenstein

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32 papers
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32

YNIMG Journal 2026 Journal Article

Longitudinal comparison of adaptive neuroplasticity in two rat models of unilateral vestibulopathy by dual-tracer [18F]FDG and [18F]UCB-H PET

  • Isabelle S. Fuxjäger
  • Melissa Antons
  • Emna Marouane
  • Giulia Leschiutta
  • Rosel Oos
  • Giovanna Palumbo
  • Dilara Steenken
  • Simon Lindner

F]FDG uptake in these networks was comparable across both models, synaptic density changes were more pronounced in UVN vs. cUL. Specifically, synaptic density in the vestibular nuclei was significantly lower after UVN, accompanied by a more intense compensatory increase in sensorimotor cortical areas. In conclusion, synaptic density imaging may be a more sensitive method to depict subtle differences in mechanisms of lesion-induced adaptive neuroplasticity than traditional techniques such as imaging of glucose metabolism.

YNICL Journal 2025 Journal Article

Partial volume effect correction impairs the diagnostic utility of [18F]-THK-5351 PET in nonfluent-agrammatic variant primary progressive aphasia

  • Patrick J. Sommer
  • Sebastian Schuster
  • Oliver Goldhardt
  • Nobuyuki Okamura
  • Felix Mueller-Sarnowski
  • Maximilian Scheifele
  • Florian Eckenweber
  • Annika Kreuzer

OBJECTIVES: F]-THK-5351 PET a marker of reactive neuroinflammatory astrogliosis as well as tau-binding. METHODS: F]-THK-5351 PET signal differences between nfv-PPA and controls before and after PVEC. Additionally, a blinded visual read was performed by three nuclear medicine physicians (consensus) before and after PVEC. RESULTS: F]-THK-5351 tracer uptake was significantly higher in the bilateral frontal cortex of patients with nfv-PPA when compared to HC (left > right), despite significant grey matter atrophy in the same brain regions in patients with nfv-PPA. SUVr differences between nfv-PPA and HC were further increased by PVEC in frontal brain regions, but group level variance increased in parallel and reduced the number of significant differences between SUVr of nfv-PPA and HC (uncorrected: 10 significant regions, CoV[nfv-PPA]: 20.8 % ± 4.7 %, CoV[HC]: 7.9 % ± 2.4 %/PVEC: 3 significant regions, CoV[nfv-PPA]: 28.4 % ± 8.9 %, CoV[HC]: 9.8 % ± 2.5 %). Sensitivity/specificity of the visual read for detection of nfv-PPA was 0.85/1.00 without PVEC and 0.85/0.75 with PVEC. CONCLUSIONS: F]-THK-5351 images in patients with nfv-PPA is impaired by PVEC due to loss of specificity and does not support the use of PVEC even in patients with severe atrophy.

YNIMG Journal 2024 Journal Article

Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice

  • Laura M. Bartos
  • Sebastian T. Kunte
  • Stephan Wagner
  • Philipp Beumers
  • Rebecca Schaefer
  • Artem Zatcepin
  • Yunlei Li
  • Maria Griessl

PURPOSE: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. METHODS: Healthy wild-type mice of both sexes (2-21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. RESULTS: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. CONCLUSION: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.

YNIMG Journal 2024 Journal Article

Towards multicenter β-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison

  • Johannes Gnörich
  • Mara Koehler
  • Karin Wind-Mark
  • Carolin Klaus
  • Artem Zatcepin
  • Giovanna Palumbo
  • Manvir Lalia
  • Laura Sebastian Monasor

AIM: β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. METHODS: ) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. RESULTS: =0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). CONCLUSIONS: Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

YNIMG Journal 2024 Journal Article

Validity and value of metabolic connectivity in mouse models of β-amyloid and tauopathy

  • François Ruch
  • Johannes Gnörich
  • Karin Wind
  • Mara Köhler
  • Artem Zatcepin
  • Thomas Wiedemann
  • Franz-Joseph Gildehaus
  • Simon Lindner

F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas β-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different β-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

YNICL Journal 2023 Journal Article

Assessment of synaptic loss in mouse models of β-amyloid and tau pathology using [18F]UCB-H PET imaging

  • Letizia Vogler
  • Anna Ballweg
  • Bernd Bohr
  • Nils Briel
  • Karin Wind
  • Melissa Antons
  • Lea H. Kunze
  • Johannes Gnörich

OBJECTIVE: F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD). METHODS: F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. RESULTS: F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). CONCLUSION: F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.

YNICL Journal 2021 Journal Article

Cognitive reserve hypothesis in frontotemporal dementia: A FDG-PET study

  • Leonie Beyer
  • Johanna Meyer-Wilmes
  • Sonja Schönecker
  • Jonas Schnabel
  • Julia Sauerbeck
  • Maximilian Scheifele
  • Catharina Prix
  • Marcus Unterrainer

BACKGROUND AND OBJECTIVE: F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET) hypometabolism in FTD. METHODS: Sixty-six FTD subjects (age 67 ± 8 years) and twenty-four cognitively healthy controls (HC) were evaluated. Brain regions with FTD-related glucose hypometabolism in the contrast against HC and brain regions that correlate with the cognitive function were defined by a voxel-based analysis and individual FDG-PET values were extracted from all frontotemporal brain areas. Linear regression analysis served to test if education is associated with residualized cognitive performance and regional FDG-PET hypometabolism after controlling for global cognition. RESULTS: Compared to healthy controls, patients with FTD showed glucose hypometabolism in bilateral frontal and temporal brain areas whereas cognition was only associated with deteriorated glucose metabolism in the left temporal lobe. The education level was significantly correlated with the residualized cognitive performance (residuals from regression analysis between hypometabolism and cognitive function as a quantitative index of reserve) and also negatively correlated with left temporal FDG-PET hypometabolism after controlling for cognition. CONCLUSIONS: In patients with FTD, the education level predicts the existing left temporal FDG-PET hypometabolism at the same cognition level, supporting the cognitive reserve hypothesis in FTD.

YNIMG Journal 2021 Journal Article

Dynamic whole-brain metabolic connectivity during vestibular compensation in the rat

  • Maximilian Grosch
  • Magdalena Lindner
  • Peter Bartenstein
  • Thomas Brandt
  • Marianne Dieterich
  • Sibylle Ziegler
  • Andreas Zwergal

F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

YNIMG Journal 2021 Journal Article

Metabolic connectivity-based single subject classification by multi-regional linear approximation in the rat

  • Maximilian Grosch
  • Leonie Beyer
  • Magdalena Lindner
  • Lena Kaiser
  • Seyed-Ahmad Ahmadi
  • Anna Stockbauer
  • Peter Bartenstein
  • Marianne Dieterich

F]-FDG PET measurements at baseline and 1, 3, 7, and 15 days (= maximum of 5 classes) after UL with 17 rats per measurement day. Classification in different stages after UL was performed by determining connectivity patterns for the different classes by Pearson's correlation between uptake values in atlas-based segmented brain regions. Connections were fitted with a linear function, with which different thresholds on the correlation coefficient (r = [0.5, 0.85]) were investigated. Rats were classified by determining the congruence of their PET uptake pattern with the fitted connectivity patterns in the classes. Overall, the classification accuracy with this method was 84.3% for 3 classes, 75.0% for 4 classes, and 54.1% for 5 classes and outperformed random classification as well as machine learning classification on the same dataset. The optimal classification thresholds of the correlation coefficient and distance-to-fit were found to be |r| > 0.65 and d = 4 when using Siegel's slope estimator for fitting. This connectivity-based classification method can compete with machine learning classification and may have methodological advantages when applied to support PET-based diagnostic decisions in neurological network disorders (such as neurodegenerative syndromes).

YNIMG Journal 2021 Journal Article

Microglial activation in the right amygdala-entorhinal-hippocampal complex is associated with preserved spatial learning in App mice

  • Gloria Biechele
  • Karin Wind
  • Tanja Blume
  • Christian Sacher
  • Leonie Beyer
  • Florian Eckenweber
  • Nicolai Franzmeier
  • Michael Ewers

BACKGROUND: In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo. METHODS: mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance. RESULTS: mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning. CONCLUSION: mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.

YNICL Journal 2019 Journal Article

Neuronal injury biomarkers for assessment of the individual cognitive reserve in clinically suspected Alzheimer's disease

  • Leonie Beyer
  • Jonas Schnabel
  • Philipp Kazmierczak
  • Michael Ewers
  • Sonja Schönecker
  • Catharina Prix
  • Johanna Meyer-Wilmes
  • Marcus Unterrainer

OBJECTIVES: ), all according to the A/T/N-classification. The aim of this study was to calculate residual cognitive performance based on neuronal injury biomarkers as a surrogate of cognitive reserve, and to test the predictive value of this index for the individual clinical course. METHODS: . All neuronal injury markers were tested for an association with clinical MMSE and the resulting residuals were correlated with years of education. We used multiple regression analysis to calculate the expected MMSE score based on neuronal injury biomarkers and covariates. The residuals of the partial correlation for each biomarker and the predicted residualized memory function were correlated with individual cognitive changes measured during clinical follow-up (27 ± 13 months). RESULTS: (R = -0.12, p = .22) showed only weak correlations. Residuals of all neuronal injury biomarker regressions correlated significantly with education level, indicating them to be surrogates of cognitive reserve. A positive residual was associated with faster cognitive deterioration at follow-up for the residuals of stand-alone FDG-PET (R = -0.36, p = .01) and the combined residualized memory function model (R = -0.35, p = .02). CONCLUSIONS: These findings suggest that subjects with higher cognitive reserve had accumulated more pathology, which subsequently caused a faster cognitive decline over time. Together with previous findings suggesting that higher reserve is associated with slower cognitive decline, we propose a biphasic reserve effect, with an initially protective phase followed by more rapid decompensation once the protection is overwhelmed.

YNIMG Journal 2018 Journal Article

Coupling between physiological TSPO expression in brain and myocardium allows stabilization of late-phase cerebral [18F]GE180 PET quantification

  • Maximilian Deussing
  • Tanja Blume
  • Lena Vomacka
  • Christoph Mahler
  • Carola Focke
  • Andrei Todica
  • Marcus Unterrainer
  • Nathalie L. Albert

Objectives PET imaging of the 18 kDa translocator protein (TSPO), a biomarker of microglial activity, receives growing interest in clinical and preclinical applications of neuroinflammatory and neurodegenerative brain diseases. In globally affected brains, intra-cerebral pseudo reference regions are not feasible. Consequently, many brain-independent approaches have been attempted, including SUV analysis and normalization to muscle- or heart uptake, aiming to stabilize quantitative analysis. In this study, we systematically compared different image normalization methods for static late phase TSPO-PET imaging of rodent brain. Methods We first obtained gamma counter measurements for gold standard quantitation of [18F]GE180 uptake in brain of C57Bl/6 mice (N = 10) after PET, aiming to identify factors contributing significantly to the quantitative results. Subsequently, data from a large cohort of C57Bl/6 mice (N = 79) were compiled to precisely determine the weighted influence and variance attributable these factors by regression analysis. Scan-rescan variability and agreement with histology were used to validate the tested normalization methods in an Alzheimer's disease (AD) mouse model with pathologically increased TSPO expression (PS2APP; N = 24). Longitudinal data from AD model mice (N = 10) scanned at four different ages were used to challenge and validate the different normalization methods in a practical application. Results Gamma counter results revealed that injected dose, body weight and PET-measured radioactivity concentration in the ventral myocardium all significantly accounted for [18F]GE180 activity in the brain. Skeletal muscle activity had high test-retest variance in this PET only application and was therefore pursued no further. Regression analysis of the large scale evaluation showed that scaling to injected dose or SUV analysis accounted for little variance in brain activity (R2 < 0. 5), but inclusion of myocardial activity together with injected dose and body weight in the regression model accounted for most of the variance in brain uptake (R2 = 0. 94). Scan-rescan stability, correlation with histology and applicability for longitudinal examination in the disease model were also significantly improved by inclusion of myocadial uptake in the quantitative model. Conclusion Cerebral and myocardial TSPO expression are highly coupled under physiological conditions. Myocardial uptake has great potential for stabilization of static late phase [18F]GE180 quantification in brain in the absence of a valid intra-cerebral pseudo-reference region.

YNICL Journal 2017 Journal Article

Evaluation of early-phase [18F]-florbetaben PET acquisition in clinical routine cases

  • Sonja Daerr
  • Matthias Brendel
  • Christian Zach
  • Erik Mille
  • Dorothee Schilling
  • Mathias Johannes Zacherl
  • Katharina Bürger
  • Adrian Danek

OBJECTIVES: F]-fluorodeoxyglucose (FDG) PET in a clinical setting. METHODS: All subjects were recruited with clinical suspicion of dementia due to neurodegenerative disease. FDG PET was undertaken by conventional methods, and amyloid PET was performed with FBB, with early recordings for the initial 10 min (early-phase FBB), and late recordings at 90-110 min p.i. (late-phase FBB). Regional SUVR with cerebellar and global mean normalization were calculated for early-phase FBB and FDG PET. Pearson correlation coefficients between FDG and early-phase FBB were calculated for predefined cortical brain regions. Furthermore, a visual interpretation of disease pattern using 3-dimensional stereotactic surface projections (3D-SSP) was performed, with assessment of intra-reader agreement. RESULTS: Among a total of 33 patients (mean age 67.5 ± 11.0 years) included in the study, 18 were visually rated amyloid-positive, and 15 amyloid-negative based on late-phase FBB scans. Correlation coefficients for early-phase FBB vs. FDG scans displayed excellent agreement in all target brain regions for global mean normalization. Cerebellar normalization gave strong, but significantly lower correlations. 3D representations of early-phase FBB visually resembled the corresponding FDG PET images, irrespective of the amyloid-status of the late FBB scans. CONCLUSIONS: Early-phase FBB acquisitions correlate on a relative quantitative and visual level with FDG PET scans, irrespective of the amyloid plaque density assessed in late FBB imaging. Thus, early-phase FBB uptake depicts a metabolism-like image, suggesting it as a valid surrogate marker for synaptic dysfunction, which could ultimately circumvent the need for additional FDG PET investigation in diagnosis of dementia.

YNICL Journal 2017 Journal Article

Identification of brain regions predicting epileptogenesis by serial [18F]GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy

  • Vera Russmann
  • Matthias Brendel
  • Erik Mille
  • Angela Helm-Vicidomini
  • Roswitha Beck
  • Lisa Günther
  • Simon Lindner
  • Axel Rominger

F]GE-180 PET brain imaging can serve as a biomarker of epileptogenesis. The identification of brain regions with predictive value might facilitate the development of preventive concepts as well as the early assessment of the interventional success. Future studies are necessary to further confirm the predictivity of the approach.

YNICL Journal 2016 Journal Article

Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients

  • Angela Deutschländer
  • Christian la Fougère
  • Kai Boetzel
  • Nathalie L. Albert
  • Franz-Josef Gildehaus
  • Peter Bartenstein
  • Guoming Xiong
  • Paul Cumming

Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum.

YNIMG Journal 2015 Journal Article

Improved longitudinal [18F]-AV45 amyloid PET by white matter reference and VOI-based partial volume effect correction

  • Matthias Brendel
  • Marcus Högenauer
  • Andreas Delker
  • Julia Sauerbeck
  • Peter Bartenstein
  • John Seibyl
  • Axel Rominger

Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET. We analyzed [18F]-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal [18F]-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time. Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (−18%) and MCI (−10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0. 907) or with brainstem scaling for the contrast between HC/MCI (0. 658). Longitudinal increases were greatest in all diagnosis groups with application of PVEC, and inter-subject variability was lowest for the white matter reference. Thus, discriminatory power of [18F]-AV45-PET was improved by use of a VOI-based PVEC and white matter or brainstem rather than cerebellum reference region. Detection of longitudinal amyloid increases was optimized with PVEC and white matter reference tissue.

YNIMG Journal 2014 Journal Article

Impact of partial volume effect correction on cerebral β-amyloid imaging in APP-Swe mice using [18F]-florbetaben PET

  • Matthias Brendel
  • Andreas Delker
  • Christina Rötzer
  • Guido Böning
  • Janette Carlsen
  • Clemens Cyran
  • Erik Mille
  • Franz Josef Gildehaus

We previously investigated the progression of β-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel β-amyloid tracer [18F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [18F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [18F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13–20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1. 72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5. 5%, p<0. 005; 20months: +15. 5%, p<0. 05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12. 2% p<0. 005; 20months: +36. 4% p<0. 05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18. 9% for native PET data, and declined to 4. 8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [18F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis.

YNICL Journal 2014 Journal Article

Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects

  • Michael Ewers
  • Matthias Brendel
  • Angela Rizk-Jackson
  • Axel Rominger
  • Peter Bartenstein
  • Norbert Schuff
  • Michael W. Weiner

Brain changes reminiscent of Alzheimer disease (AD) have been previously reported in a substantial portion of elderly cognitive healthy (HC) subjects. The major aim was to evaluate the accuracy of MRI assessed regional gray matter (GM) volume, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and neuropsychological test scores to identify those HC subjects who subsequently convert to mild cognitive impairment (MCI) or AD dementia. We obtained in 54 healthy control (HC) subjects a priori defined region of interest (ROI) values of medial temporal and parietal FDG-PET and medial temporal GM volume. In logistic regression analyses, these ROI values were tested together with neuropsychological test scores (free recall, trail making test B (TMT-B)) as predictors of HC conversion during a clinical follow-up between 3 and 4 years. In voxel-based analyses, FDG-PET and MRI GM maps were compared between HC converters and HC non-converters. Out of the 54 HC subjects, 11 subjects converted to MCI or AD dementia. Lower FDG-PET ROI values were associated with higher likelihood of conversion (p = 0.004), with the area under the curve (AUC) yielding 82.0% (95% CI = (95.5%, 68.5%)). The GM volume ROI was not a significant predictor (p = 0.07). TMT-B but not the free recall tests were a significant predictor (AUC = 71% (95% CI = 50.4%, 91.7%)). For the combination of FDG-PET and TMT-B, the AUC was 93.4% (sensitivity = 82%, specificity = 93%). Voxel-based group comparison showed reduced FDG-PET metabolism within the temporo-parietal and prefrontal cortex in HC converters. In conclusion, medial temporal and-parietal FDG-PET and executive function show a clinically acceptable accuracy for predicting clinical progression in elderly HC subjects.

YNIMG Journal 2010 Journal Article

Elevated [18F]FDOPA utilization in the periaqueductal gray and medial nucleus accumbens of patients with early Parkinson's disease

  • Yoshitaka Kumakura
  • Erik H. Danielsen
  • Albert Gjedde
  • Ingo Vernaleken
  • Hans-Georg Buchholz
  • Andreas Heinz
  • Gerhard Gründer
  • Peter Bartenstein

PET studies with the DOPA decarboxylase substrate 6-[18F]fluoro-l-DOPA (FDOPA) reveal the storage of [18F]-fluorodopamine within synaptic vesicles, mainly of dopamine fibres. As such, FDOPA PET is a sensitive indicator of the integrity of the nigrostriatal dopamine innervation. Nonetheless, there have been several reports of focal elevations of FDOPA utilization in brain of patients with Parkinson's disease (PD), all based on reference tissue methods. To investigate this phenomenon further, we used voxel-wise steady-state kinetic analysis to search for regions of elevated FDOPA utilization (K; ml g−1 min−1) and steady-state trapping (V d; ml g−1) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25%) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V d was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal grey of PD patients seems consistent with recent reports of increased activity of serotonin neurons in a rat model of parkinsonism.

YNIMG Journal 2010 Journal Article

Real versus imagined locomotion: A [18F]-FDG PET-fMRI comparison

  • Christian la Fougère
  • Andreas Zwergal
  • Axel Rominger
  • Stefan Förster
  • Gunther Fesl
  • Marianne Dieterich
  • Thomas Brandt
  • Michael Strupp

The cortical, cerebellar and brainstem BOLD-signal changes have been identified with fMRI in humans during mental imagery of walking. In this study the whole brain activation and deactivation pattern during real locomotion was investigated by [18F]-FDG-PET and compared to BOLD-signal changes during imagined locomotion in the same subjects using fMRI. Sixteen healthy subjects were scanned at locomotion and rest with [18F]-FDG-PET. In the locomotion paradigm subjects walked at constant velocity for 10 min. Then [18F]-FDG was injected intravenously while subjects continued walking for another 10 min. For comparison fMRI was performed in the same subjects during imagined walking. During real and imagined locomotion a basic locomotion network including activations in the frontal cortex, cerebellum, pontomesencephalic tegmentum, parahippocampal, fusiform and occipital gyri, and deactivations in the multisensory vestibular cortices (esp. superior temporal gyrus, inferior parietal lobule) was shown. As a difference, the primary motor and somatosensory cortices were activated during real locomotion as distinct to the supplementary motor cortex and basal ganglia during imagined locomotion. Activations of the brainstem locomotor centers were more prominent in imagined locomotion. In conclusion, basic activation and deactivation patterns of real locomotion correspond to that of imagined locomotion. The differences may be due to distinct patterns of locomotion tested. Contrary to constant velocity real locomotion (10 min) in [18F]-FDG-PET, mental imagery of locomotion over repeated 20-s periods includes gait initiation and velocity changes. Real steady-state locomotion seems to use a direct pathway via the primary motor cortex, whereas imagined modulatory locomotion an indirect pathway via a supplementary motor cortex and basal ganglia loop.

YNIMG Journal 2010 Journal Article

Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: Effects of the novel P-glycoprotein inhibitor tariquidar

  • Christian la Fougère
  • Guido Böning
  • Hero Bartmann
  • Björn Wängler
  • Sebastian Nowak
  • Theresa Just
  • Erika Wagner
  • Petra Winter

We used microPET to map the dose–response to the novel P-glycoprotein (P-gp) inhibitor tariquidar (TQD) of the initial influx of the P-gp substrate [18F]-MPPF in rat brain, and to test for effects of P-gp inhibition on the subsequent binding of [18F]-MPPF to serotonin 5-HT1A receptors. Summation maps of [18F]-MPPF uptake during the first 100 seconds after intravenous injection were calculated in groups of rats with vehicle (glucose 5%) pretreatment, or following pretreatment with TQD at doses of 5, 15, or 30 mg/kg. The early summation image (K 1-weighted), were validated as a surrogate marker for the physiological blood–brain clearance (K 1; ml g− 1 min−1) by linear graphic analysis of the unidirectional blood–brain clearance relative to an image-based arterial input measured in the left ventricle of the heart. In the same animals, parametric maps of the [18F]-MPPF binding potential (BPND) were calculated from the entire 60-minute emission recordings using conventional reference tissue methods. All [18F]-MPPF recordings were followed by an [18F]-FDG emission recording, the summation of which was used for spatial normalization to a rat brain atlas. Test–retest variability of K 1-weighted uptake and BPND was 25%. TQD treatment evoked a global dose-dependent increase in K 1-weighted summation, which increased 2. 5-fold with TQD (30 mg/kg), suggesting an IC50 of 5 mg/kg TQD. All TQD doses increased the apparent [18F]-MPPF BPND calculated by the Logan method by 30%–40%, a bias likely arising due to increased free [18F]-MPPF concentrations in brain. TQD (15 mg/kg) evoked a 45% global increase in [18F]-FDG uptake, suggesting perturbation of brain energy metabolism due to P-gp blockade.

YNIMG Journal 2009 Journal Article

SPM-based count normalization provides excellent discrimination of mild Alzheimer's disease and amnestic mild cognitive impairment from healthy aging

  • Igor Yakushev
  • Alexander Hammers
  • Andreas Fellgiebel
  • Irene Schmidtmann
  • Armin Scheurich
  • Hans-Georg Buchholz
  • Jürgen Peters
  • Peter Bartenstein

Statistical comparisons of [18F]FDG PET scans between healthy subjects and patients with Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI) using Statistical Parametric Mapping (SPM) usually require normalization of regional tracer uptake via ROIs defined using additional software. Here, we validate a simple SPM-based method for count normalization. FDG PET scans of 21 mild, 15 very mild AD, 11 aMCI patients and 15 age-matched controls were analyzed. First, we obtained relative increases in the whole patient sample compared to controls (i. e. areas relatively preserved in patients) with proportional scaling to the cerebral global mean (CGM). Next, average absolute counts within the cluster with the highest t-value were extracted. Statistical comparisons of controls versus three patients groups were then performed using count normalization to CGM, sensorimotor cortex (SMC) as standard, and to the cluster-derived counts. Compared to controls, relative metabolism in aMCI patients was reduced by 15%, 20%, and 23% after normalization to CGM, SMC, and cluster-derived counts, respectively, and 11%, 21%, and 25% in mild AD patients. Logistic regression analyses based on normalized values extracted from AD-typical regions showed that the metabolic values obtained using CGM, SMC, and cluster normalization correctly classified 81%, 89% and 92% of aMCI and controls; classification accuracies for AD groups (very mild and mild) were 91%, 97%, and 100%. The proposed algorithm of fully SPM-based count normalization allows for a substantial increase of statistical power in detecting very early AD-associated hypometabolism, and very high accuracy in discriminating mild AD and aMCI from healthy aging.

YNIMG Journal 2008 Journal Article

Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: A positron emission tomography study in healthy subjects

  • Ingo Vernaleken
  • Yoshitaka Kumakura
  • Hans-Georg Buchholz
  • Thomas Siessmeier
  • Ralf-Dieter Hilgers
  • Peter Bartenstein
  • Paul Cumming
  • Gerhard Gründer

The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D2/3-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[18F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [18F]fluorodopamine formed in brain (k loss) and the storage for FDOPA and its brain metabolites (Vd ). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [18F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [18F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in individuals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D1-receptor mediated transmission during D2 blockade.

YNIMG Journal 2007 Journal Article

A fronto-parietal network is mediating improvement of motor function related to repetitive peripheral magnetic stimulation: A PET-H2O15 study

  • Albrecht Struppler
  • Ferdinand Binkofski
  • Bernhard Angerer
  • Michael Bernhardt
  • Sabine Spiegel
  • Alexander Drzezga
  • Peter Bartenstein

Repetitive peripheral magnetic stimulation (RPMS) is a focused and painless stimulation method, in which muscle contractions are elicited by depolarization of the terminal motor branches. Clinical–experimental investigations on different disorders of sensorimotor integration in the last decade have shown that RPMS can be used for the rehabilitation of motor functions after stroke. It is supposed that this therapeutic effect is based on the RPMS-induced proprioceptive inflow to the CNS. To analyze the conditioning effects of RPMS on reorganization of the motor system on cortical level positron emission tomography (PET) is used. Regional cerebral blood flow (rCBF) has been measured using H2O15-PET in eight patients with arm paresis following focal cerebral ischemic infarction before and after treatment using RPMS on upper arm flexor muscles. Behavioral measures showed a significant improvement of kinematics of finger movements and a reduction of spasticity in the affected arm following RPMS treatment. The recovery was associated with significant increase of neural activation within the superior posterior parietal lobe and the premotor cortex (PM) areas. The increase of activation of the parieto-premotor network following RPMS treatment indicates a significant conditioning effect of RPMS on the cortical level. These results emphasize the positive therapeutic effect of RPMS and describe the physiological bases of its function on the central level.

YNIMG Journal 2007 Journal Article

Asymmetry in dopamine D2/3 receptors of caudate nucleus is lost with age

  • Ingo Vernaleken
  • Carsten Weibrich
  • Thomas Siessmeier
  • Hans-Georg Buchholz
  • Frank Rösch
  • Andreas Heinz
  • Paul Cumming
  • Peter Stoeter

Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24–60 years; 35±10). For volumetric analysis, high-resolution T1-weighted MR-images were obtainedin 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of young subjects that decreased with age (r=0. 577, p=0. 006; Pearson correlation; two-tailed). An age-independent analysis showed a right-ward asymmetry in NC of the whole subject group (left: 1. 49±0. 35; right: 1. 65±0. 43 [mean±S. D. ]; p=0. 020). No such side lateralization or age-effects could be found in the putamen. Volumes tended to be asymmetric in the putamen (right: 4. 85±0. 56 cm3; left: 4. 64±0. 86 cm3 [mean±S. D. ]; p=0. 063), but not in NC. The decline of putamen volume during aging was significant in the right putamen (r =−0. 613; p=0. 007; Pearson correlation; two-tailed). There were no other significant correlations between striatal volumes and age or BP. Because ventral striatal dopamine neurotransmission is involved in cognitive processes, this loss of physiological asymmetry in NC dopamine transmission during aging might be involved in age-related declines of cognitive performance.

YNIMG Journal 2006 Journal Article

High opiate receptor binding potential in the human lateral pain system

  • Ulf Baumgärtner
  • Hans-Georg Buchholz
  • Alexander Bellosevich
  • Walter Magerl
  • Thomas Siessmeier
  • Roman Rolke
  • Sabine Höhnemann
  • Markus Piel

To determine how opiate receptor distribution is co-localized with the distribution of nociceptive areas in the human brain, eleven male healthy volunteers underwent one PET scan with the subtype-nonselective opioidergic radioligand [18F]fluoroethyl-diprenorphine under resting conditions. The binding potential (BP), a parameter for the regional cerebral opioid receptor availability, was computed using the occipital cortex as reference region. The following regions of interest (ROIs) were defined on individual MR images: thalamus, sensory motor strip (SI/MI area), frontal operculum, parietal operculum, anterior insular cortex, posterior insular cortex, anterior cingulate cortex (ACC; peri- and subgenual part of “classical ACC” only), midcingulate cortex (MCC, posterior part of “classical ACC”), putamen, caudate nucleus and the amygdala. BP for [18F]fluoroethyl-diprenorphine was lowest in the sensory motor strip (0. 30). Highest BP was found in thalamus (1. 36), basal ganglia (putamen 1. 22, caudate 1. 16) and amygdala (1. 21). In the cingulate cortex, ACC (1. 11) had higher BP than MCC (0. 86). In the operculo-insular region, we found high BPs in all ROIs: anterior insula (1. 16), posterior insula (1. 05), frontal operculum (0. 99) and parietal operculum (0. 77). Factor analysis of interindividual variability of opiate receptor BP revealed four factors (95% explained variance): (1) operculo-insular areas, ACC, MCC and putamen, (2) amygdala and thalamus, (3) caudate and thalamus, (4) SI/MI and MCC. Nociceptive areas of the lateral pain system (frontoparietal operculum and insula) have opiate receptor BPs significantly higher than SI/MI, comparable to anterior and midcingulate areas of the medial pain system. These findings suggest that the cortical anti-nociceptive effects of opiates are not only mediated by ACC and MCC, but also by the operculo-insular cortex, if it can be assumed that opioid binding mediates anti-nociception in those structures.

YNIMG Journal 2006 Journal Article

Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge

  • Ingo Vernaleken
  • Yoshitaka Kumakura
  • Paul Cumming
  • Hans-Georg Buchholz
  • Thomas Siessmeier
  • Peter Stoeter
  • Matthias J. Müller
  • Peter Bartenstein

In animal studies, acute antipsychotic treatment was shown to enhance striatal DOPA-decarboxylase (DDC) activity. However, this phenomenon has not been demonstrated in humans by positron emission tomography (PET). Therefore, we investigated acute haloperidol effects on DDC activity in humans using [18F]fluorodopa (FDOPA) PET. Nine healthy volunteers were scanned with FDOPA in drug-free baseline conditions and after 3 days of haloperidol treatment (5 mg/day). A continuous performance test (CPT) was administered in both conditions. The net blood–brain clearance of FDOPA (K in app) in striatum, mesencephalon, and medial prefrontal cortex was calculated by volume-of-interest analysis. The macroparameter K in app is a composite of several kinetic terms defining the distribution volume of FDOPA in brain (V e D) and the relative activity of DOPA decarboxylase (k 3 D). Therefore, compartmental kinetic analysis was used to identify the physiological basis of the observed changes in K in app period. The magnitude of K in app was significantly increased in the putamen (18%) and mesencephalon (36%). Furthermore, V e D in the brain was increased by 15%. Increments of k 3 D in the basal ganglia did not attain statistical significance. The significant worsening of CPT results did not correlate with changes in FDOPA utilization. The present PET results indicate potentiation of FDOPA utilization in human basal ganglia by acute haloperidol treatment, apparently due to increased availability throughout the brain. The stimulation of DDC cannot be excluded due to insufficient statistical power in the estimation of k 3 D changes.

YNIMG Journal 2004 Journal Article

The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans

  • Mathias Schreckenberger
  • Christian Lange-Asschenfeld
  • Matthias Lochmann
  • Klaus Mann
  • Thomas Siessmeier
  • Hans-Georg Buchholz
  • Peter Bartenstein
  • Gerhard Gründer

Background: Purpose of this study was to investigate the functional relationship between electroencephalographic (EEG) alpha power and cerebral glucose metabolism before and after pharmacological alpha suppression by lorazepam. Methods: Ten healthy male volunteers were examined undergoing two F18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scans with simultaneous EEG recording: 1× placebo, 1× lorazepam. EEG power spectra were computed by means of Fourier analysis. The PET data were analyzed using SPM99, and the correlations between metabolism and alpha power were calculated for both conditions. Results: The comparison lorazepam versus placebo revealed reduced glucose metabolism of the bilateral thalamus and adjacent subthalamic areas, the occipital cortex and temporo-insular areas (P < 0. 001). EEG alpha power was reduced in all derivations (P < 0. 001). Under placebo, there was a positive correlation between alpha power and metabolism of the bilateral thalamus and the occipital and adjacent parietal cortex (P < 0. 001). Under lorazepam, the thalamic and parietal correlations were maintained, whereas the occipital correlation was no longer detectable (P < 0. 001). The correlation analysis of the difference lorazepam-placebo showed the alpha power exclusively correlated with the thalamic activity (P < 0. 0001). Conclusions: These results support the hypothesis of a close functional relationship between thalamic activity and alpha rhythm in humans mediated by corticothalamic loops which are independent of sensory afferences. The study paradigm could be a promising approach for the investigation of cortico-thalamo-cortical feedback loops in neuropsychiatric diseases.