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Klaus Scheffler

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YNICL Journal 2021 Journal Article

Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer’s disease spectrum

  • Chimezie O. Amaefule
  • Martin Dyrba
  • Steffen Wolfsgruber
  • Alexandra Polcher
  • Anja Schneider
  • Klaus Fliessbach
  • Annika Spottke
  • Dix Meiberth

BACKGROUND: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. METHOD: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. RESULT: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. CONCLUSION: Consistent associations between cognitive domain scores and both regional atrophy and network-specific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum.

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YNIMG Journal 2020 Journal Article

Eye-selective fMRI activity in human primary visual cortex: Comparison between 3 ​T and 9.4 ​T, and effects across cortical depth

  • Natalia Zaretskaya
  • Jonas Bause
  • Jonathan R. Polimeni
  • Pablo R. Grassi
  • Klaus Scheffler
  • Andreas Bartels

The primary visual cortex of humans contains patches of neurons responding preferentially to stimulation of one eye (the ocular dominance columns). Multiple previous studies attempted to detect their activity using fMRI. The majority of these fMRI studies used magnetic field strengths of 4 ​T and higher. However, there have been reports of reliable eye-selective activations at 3 ​T as well. In this study we investigated the possibility of detecting eye-selective V1 activity using high-resolution GE-EPI fMRI at 3 ​T and sub-millimeter resolution fMRI at ultrahigh 9. 4 ​T magnetic field strengths with acquisition parameters optimized for each field strength. High-resolution fMRI at 9. 4 ​T also allowed us to examine the eye-selectivity responses across the cortical depth, which are expected to be strongest in the middle layers. We observed a substantial increase in the percentage of eye-selective voxels, as well as a doubling in run-to-run consistency of eye preference at ultrahigh field compared to 3 ​T. We also found that across cortical depth, eye selectivity increased towards the superficial layers, and that signal contrast increased while noise remained nearly constant towards the surface. The depth-resolved results are consistent with a distortion of spatial specificity of the GE-EPI signal by ascending venules and large draining veins on the cortical surface. The effects of larger vessels cause increasing signal amplitude, but also displacement of the maximum BOLD signal relative to neural activity. In summary, our results show that increase in spatial resolution, reduced partial volume effects, and improved sensitivity at 9. 4 ​T allow for better detection of eye-selective signals related to ocular dominance columns. However, although ultrahigh field yields higher sensitivity to the ocular dominance signal, GE-EPI still suffers from specificity issues, with a prominent signal contribution at shallow depths from larger cortical vessels.

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YNIMG Journal 2020 Journal Article

Impact of prospective motion correction, distortion correction methods and large vein bias on the spatial accuracy of cortical laminar fMRI at 9.4 Tesla

  • Jonas Bause
  • Jonathan R. Polimeni
  • Johannes Stelzer
  • Myung-Ho In
  • Philipp Ehses
  • Pablo Kraemer-Fernandez
  • Ali Aghaeifar
  • Eric Lacosse

Functional imaging with sub-millimeter spatial resolution is a basic requirement for assessing functional MRI (fMRI) responses across different cortical depths and is used extensively in the emerging field of laminar fMRI. Such studies seek to investigate the detailed functional organization of the brain and may develop to a new powerful tool for human neuroscience. However, several studies have shown that measurement of laminar fMRI responses can be biased by the image acquisition and data processing strategies. In this work, measurements with three different gradient-echo EPI BOLD fMRI protocols with a voxel size down to 650 ​μm isotropic were performed at 9. 4 ​T. We estimated how prospective motion correction can help to improve spatial accuracy by reducing the number of spatial resampling steps in postprocessing. In addition, we demonstrate key requirements for accurate geometric distortion correction to ensure that distortion correction maps are properly aligned to the functional data and that strong variations of distortions near large veins can lead to signal overlays which cannot be corrected for during postprocessing. Furthermore, this study illustrates the spatial extent of bias induced by pial and other larger veins in laminar BOLD experiments. Since these issues under investigation affect studies performed with more conventional spatial resolutions, the methods applied in this work may also help to improve the understanding of the BOLD signal more broadly.

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YNICL Journal 2020 Journal Article

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer’s disease spectrum

  • Meret Herdick
  • Martin Dyrba
  • Hans-Christian J. Fritz
  • Slawek Altenstein
  • Tommaso Ballarini
  • Frederic Brosseron
  • Katharina Buerger
  • Arda Can Cetindag

BACKGROUND: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. METHODS: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants. RESULTS: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results. CONCLUSIONS: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.

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YNICL Journal 2019 Journal Article

CACNA1C risk variant affects microstructural connectivity of the amygdala

  • Katharina Koch
  • Sophia Stegmaier
  • Lena Schwarz
  • Michael Erb
  • Mara Thomas
  • Klaus Scheffler
  • Dirk Wildgruber
  • Vanessa Nieratschker

Deficits in perception of emotional prosody have been described in patients with affective disorders at behavioral and neural level. In the current study, we use an imaging genetics approach to examine the impact of CACNA1C, one of the most promising genetic risk factors for psychiatric disorders, on prosody processing on a behavioral, functional and microstructural level. Using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) we examined key areas involved in prosody processing, i.e. the amygdala and voice areas, in a healthy population. We found stronger activation to emotional than neutral prosody in the voice areas and the amygdala, but CACNA1C rs1006737 genotype had no influence on fMRI activity. However, significant microstructural differences (i.e. mean diffusivity) between CACNA1C rs1006737 risk allele carriers and non carriers were found in the amygdala, but not the voice areas. These modifications in brain architecture associated with CACNA1C might reflect a neurobiological marker predisposing to affective disorders and concomitant alterations in emotion perception.

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YNIMG Journal 2019 Journal Article

Dependence of resting-state fMRI fluctuation amplitudes on cerebral cortical orientation relative to the direction of B0 and anatomical axes

  • Olivia Viessmann
  • Klaus Scheffler
  • Marta Bianciardi
  • Lawrence L. Wald
  • Jonathan R. Polimeni

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B 0 -field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B 0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1. 1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i. e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B 0, is about + 70 % at the pial surface at 7T and + 11 % at 3T. The B 0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about − 30 % at the pial surface at 7T and about − 13 % at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI.

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YNIMG Journal 2019 Journal Article

Feasibility of functional MRI at ultralow magnetic field via changes in cerebral blood volume

  • Kai Buckenmaier
  • Anders Pedersen
  • Paul SanGiorgio
  • Klaus Scheffler
  • John Clarke
  • Ben Inglis

We investigate the feasibility of performing functional MRI (fMRI) at ultralow field (ULF) with a Superconducting QUantum Interference Device (SQUID), as used for detecting magnetoencephalography (MEG) signals from the human head. While there is negligible magnetic susceptibility variation to produce blood oxygenation level-dependent (BOLD) contrast at ULF, changes in cerebral blood volume (CBV) may be a sensitive mechanism for fMRI given the five-fold spread in spin-lattice relaxation time (T 1) values across the constituents of the human brain. We undertook simulations of functional signal strength for a simplified brain model involving activation of a primary cortical region in a manner consistent with a blocked task experiment. Our simulations involve measured values of T 1 at ULF and experimental parameters for the performance of an upgraded ULFMRI scanner. Under ideal experimental conditions we predict a functional signal-to-noise ratio of between 3. 1 and 7. 1 for an imaging time of 30 min, or between 1. 5 and 3. 5 for a blocked task experiment lasting 7. 5 min. Our simulations suggest it may be feasible to perform fMRI using a ULFMRI system designed to perform MRI and MEG in situ.

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YNIMG Journal 2018 Journal Article

Chemical exchange saturation transfer MRI contrast in the human brain at 9.4 T

  • Moritz Zaiss
  • Mark Schuppert
  • Anagha Deshmane
  • Kai Herz
  • Philipp Ehses
  • Lars Füllbier
  • Tobias Lindig
  • Benjamin Bender

Purpose The high chemical shift separation at 9. 4 T allows for selective saturation of proton pools in exchange with water protons. For the first time, highly selective and comprehensive chemical exchange saturation transfer (CEST) experiments were performed in the human brain at 9. 4 T. This work provides insight into CEST signals in the human brain in comparison with existing animal studies, as well as with CEST effects in vivo at lower field strengths. Methods A novel snapshot-CEST method for human brain scans at 9. 4 T was optimized and employed for highly-spectrally-resolved (95 offsets) CEST measurements in healthy subjects and one brain tumor patient. Reproducibility and stability between scans was verified in grey and white matter after B0, B1, and motion correction of the acquired 3D CEST volumes. Two-step Lorentzian fitting was used to further improve separation of spectrally discernible signals to create known and novel CEST contrast maps at 9. 4 T. Results At a saturation power of B1 = 0. 5 μT most selective CEST effects could be obtained in the human brain with high inter-scan reproducibility. While contrast behavior of previously measured signals at lower field, namely amide-, guanidyl- and NOE-CEST effects, could be reproduced, novel signals at 2. 7 ppm, and −1. 6 ppm could be verified in healthy subjects and in a brain tumor patient for the first time. Conclusion High spectral resolution chemical exchange saturation transfer at 9. 4 T allows deeper insights into the Z-spectrum structure of the human brain, and provides many different contrasts showing different correlations in healthy tissue and in tumor-affected areas of the brain, generating hypotheses for future investigations of in-vivo-CEST at UHF.

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YNIMG Journal 2018 Journal Article

Human in-vivo brain magnetic resonance current density imaging (MRCDI)

  • Cihan Göksu
  • Lars G. Hanson
  • Hartwig R. Siebner
  • Philipp Ehses
  • Klaus Scheffler
  • Axel Thielscher

Magnetic resonance current density imaging (MRCDI) and MR electrical impedance tomography (MREIT) are two emerging modalities, which combine weak time-varying currents injected via surface electrodes with magnetic resonance imaging (MRI) to acquire information about the current flow and ohmic conductivity distribution at high spatial resolution. The injected current flow creates a magnetic field in the head, and the component of the induced magnetic field ΔBz, c parallel to the main scanner field causes small shifts in the precession frequency of the magnetization. The measured MRI signal is modulated by these shifts, allowing to determine ΔBz, c for the reconstruction of the current flow and ohmic conductivity. Here, we demonstrate reliable ΔBz, c measurements in-vivo in the human brain based on multi-echo spin echo (MESE) and steady-state free precession free induction decay (SSFP-FID) sequences. In a series of experiments, we optimize their robustness for in-vivo measurements while maintaining a good sensitivity to the current-induced fields. We validate both methods by assessing the linearity of the measured ΔBz, c with respect to the current strength. For the more efficient SSFP-FID measurements, we demonstrate a strong influence of magnetic stray fields on the ΔBz, c images, caused by non-ideal paths of the electrode cables, and validate a correction method. Finally, we perform measurements with two different current injection profiles in five subjects. We demonstrate reliable recordings of ΔBz, c fields as weak as 1 nT, caused by currents of 1 mA strength. Comparison of the ΔBz, c measurements with simulated ΔBz, c images based on FEM calculations and individualized head models reveals significant linear correlations in all subjects, but only for the stray field-corrected data. As final step, we reconstruct current density distributions from the measured and simulated ΔBz, c data. Reconstructions from non-corrected ΔBz, c measurements systematically overestimate the current densities. Comparing the current densities reconstructed from corrected ΔBz, c measurements and from simulated ΔBz, c images reveals an average coefficient of determination R2 of 71%. In addition, it shows that the simulations underestimated the current strength on average by 24%. Our results open up the possibility of using MRI to systematically validate and optimize numerical field simulations that play an important role in several neuroscience applications, such as transcranial brain stimulation, and electro- and magnetoencephalography.

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YNIMG Journal 2018 Journal Article

In-vivo quantitative structural imaging of the human midbrain and the superior colliculus at 9.4T

  • Joana R. Loureiro
  • Marc Himmelbach
  • Thomas Ethofer
  • Rolf Pohmann
  • Pascal Martin
  • Jonas Bause
  • Wolfgang Grodd
  • Klaus Scheffler

We explored anatomical details of the superior colliculus (SC) by in vivo magnetic resonance imaging (MRI) at 9. 4T. The high signal-to-noise ratio allowed the acquisition of high resolution, multi-modal images with voxel sizes ranging between 176 × 132 × 600 μm and (800)3μm. Quantitative mapping of the longitudinal relaxation rate R1, the effective transverse relaxation rate R2*, and the magnetic susceptibility QSM was performed in 14 healthy volunteers. The images were analyzed in native space as well as after normalization to a common brain space (MNI). The coefficient-of-variation (CoV) across subjects was evaluated in prominent regions of the midbrain, reaching the best reproducibility (CoV of 5%) in the R2* maps of the SC in MNI space, while the CoV in the QSM maps remained high regardless of brain-space. To investigate whether more complex neurobiological architectural features could be detected, depth profiles through the SC layers towards the red nucleus (RN) were evaluated at different levels of the SC along the rostro-caudal axis. This analysis revealed alterations of the quantitative MRI parameters concordant with previous post mortem histology studies of the cyto- and myeloarchitecture of the SC. In general, the R1 maps were hyperintense in areas characterized by the presence of abundant myelinated fibers, and likely enabled detection of the deep white layer VII of the SC adjacent to the periaqueductal gray. While R1 maps failed to reveal finer details, possibly due to the relatively coarse spatial sampling used for this modality, these could be recovered in R2* maps and in QSM. In the central part of the SC along its rostro-caudal axis, increased R2* values and decreased susceptibility values were observed 2 mm below the SC surface, likely reflecting the myelinated fibers in the superficial optic layer (layer III). Towards the deeper layers, a second increase in R2* was paralleled by a paramagnetic shift in QSM suggesting the presence of an iron-rich layer about 3 mm below the surface of the SC, attributed to the intermediate gray layer (IV) composed of multipolar neurons. These results dovetail observations in histological specimens and animal studies and demonstrate that high-resolution multi-modal MRI at 9. 4T can reveal several microstructural features of the SC in vivo.

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YNIMG Journal 2017 Journal Article

Functional anatomy of the human thalamus at rest

  • Vinod Jangir Kumar
  • Erik van Oort
  • Klaus Scheffler
  • Christian F. Beckmann
  • Wolfgang Grodd

In the present work, we used resting state-fMRI to investigate the functional anatomy of the thalamus at rest by applying an Independent Component Analysis to delineate thalamic substructures into stable and reproducible parcels for the left and right thalamus. We determined 15 functionally distinct thalamic parcels, which differed in laterality and size but exhibited a correspondence with 18 cytoarchitectonally defined nuclei. We characterized their structural connectivity in determining DWI based cortical fiber pathways and found selected projections to different cortical areas. In contrast, the functional connections of these parcels were not confined to certain cortical areas or lobes. We, finally evaluated cortical projections and found particular subcortical and cortical pattern for each parcel, which partly exhibited a correspondence with the thalamo-cortical connectivity maps of the mouse.

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YNIMG Journal 2017 Journal Article

The impact of vessel size, orientation and intravascular contribution on the neurovascular fingerprint of BOLD bSSFP fMRI

  • Mario Gilberto Báez-Yánez
  • Philipp Ehses
  • Christian Mirkes
  • Philbert S. Tsai
  • David Kleinfeld
  • Klaus Scheffler

Monte Carlo simulations have been used to analyze oxygenation-related signal changes in pass-band balanced steady state free precession (bSSFP) as well as in gradient echo (GE) and spin echo (SE) sequences. Signal changes were calculated for artificial cylinders and neurovascular networks acquired from the mouse parietal cortex by two-photon laser scanning microscopy at 1 μm isotropic resolution. Signal changes as a function of vessel size, blood volume, vessel orientation to the main magnetic field B0 as well as relations of intra- and extravascular and of micro- and macrovascular contributions have been analyzed. The results show that bSSFP is highly sensitive to extravascular and microvascular components. Furthermore, GE and bSSFP, and to a lesser extent SE, exhibit a strong dependence of their signal change on the orientation of the vessel network to B0.

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YNIMG Journal 2016 Journal Article

Neurobiology of knowledge and misperception of lyrics

  • Claudia Beck Lidén
  • Oliver Krüger
  • Lena Schwarz
  • Michael Erb
  • Bernd Kardatzki
  • Klaus Scheffler
  • Thomas Ethofer

We conducted two functional magnetic resonance imaging (fMRI) experiments to investigate the neural underpinnings of knowledge and misperception of lyrics. In fMRI experiment 1, a linear relationship between familiarity with lyrics and activation was found in left-hemispheric speech-related as well as bilateral striatal areas which is in line with previous research on generation of lyrics. In fMRI experiment 2, we employed so called Mondegreens and Soramimi to induce misperceptions of lyrics revealing a bilateral network including middle temporal and inferior frontal areas as well as anterior cingulate cortex (ACC) and mediodorsal thalamus. ACC activation also correlated with the extent to which misperceptions were judged as amusing corroborating previous neuroimaging results on the role of this area in mediating the pleasant experience of chills during music perception. Finally, we examined the areas engaged during misperception of lyrics using diffusion-weighted imaging (DWI) to determine their structural connectivity. These combined fMRI/DWI results could serve as a neurobiological model for future studies on other types of misunderstanding which are events with potentially strong impact on our social life.

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YNIMG Journal 2016 Journal Article

Specific white matter tissue microstructure changes associated with obesity

  • Stephanie Kullmann
  • Martina F. Callaghan
  • Martin Heni
  • Nikolaus Weiskopf
  • Klaus Scheffler
  • Hans-Ulrich Häring
  • Andreas Fritsche
  • Ralf Veit

Obesity-related structural brain alterations point to a consistent reduction in gray matter with increasing body mass index (BMI) but changes in white matter have proven to be more complex and less conclusive. Hence, more recently diffusion tensor imaging (DTI) has been employed to investigate microstructural changes in white matter structure. Altogether, these studies have mostly shown a loss of white matter integrity with obesity-related factors in several brain regions. However, the variety of these obesity-related factors, including inflammation and dyslipidemia, resulted in competing influences on the DTI indices. To increase the specificity of DTI results, we explored specific brain tissue properties by combining DTI with quantitative multi-parameter mapping in lean, overweight and obese young adults. By means of multi-parameter mapping, white matter structures showed differences in MRI parameters consistent with reduced myelin, increased water and altered iron content with increasing BMI in the superior longitudinal fasciculus, anterior thalamic radiation, internal capsule and corpus callosum. BMI-related changes in DTI parameters revealed mainly alterations in mean and axial diffusivity with increasing BMI in the corticospinal tract, anterior thalamic radiation and superior longitudinal fasciculus. These alterations, including mainly fiber tracts linking limbic structures with prefrontal regions, could potentially promote accelerated aging in obese individuals leading to an increased risk for cognitive decline.

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YNIMG Journal 2014 Journal Article

Functional quantitative susceptibility mapping (fQSM)

  • Dávid Z. Balla
  • Rosa M. Sanchez-Panchuelo
  • Samuel J. Wharton
  • Gisela E. Hagberg
  • Klaus Scheffler
  • Susan T. Francis
  • Richard Bowtell

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is a powerful technique, typically based on the statistical analysis of the magnitude component of the complex time-series. Here, we additionally interrogated the phase data of the fMRI time-series and used quantitative susceptibility mapping (QSM) in order to investigate the potential of functional QSM (fQSM) relative to standard magnitude BOLD fMRI. High spatial resolution data (1mm isotropic) were acquired every 3seconds using zoomed multi-slice gradient-echo EPI collected at 7T in single orientation (SO) and multiple orientation (MO) experiments, the latter involving 4 repetitions with the subject's head rotated relative to B0. Statistical parametric maps (SPM) were reconstructed for magnitude, phase and QSM time-series and each was subjected to detailed analysis. Several fQSM pipelines were evaluated and compared based on the relative number of voxels that were coincidentally found to be significant in QSM and magnitude SPMs (common voxels). We found that sensitivity and spatial reliability of fQSM relative to the magnitude data depended strongly on the arbitrary significance threshold defining “activated” voxels in SPMs, and on the efficiency of spatio-temporal filtering of the phase time-series. Sensitivity and spatial reliability depended slightly on whether MO or SO fQSM was performed and on the QSM calculation approach used for SO data. Our results present the potential of fQSM as a quantitative method of mapping BOLD changes. We also critically discuss the technical challenges and issues linked to this intriguing new technique.

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YNIMG Journal 2014 Journal Article

Ultra-high resolution imaging of the human brain using acquisition-weighted imaging at 9.4T

  • Juliane Budde
  • G. Shajan
  • Klaus Scheffler
  • Rolf Pohmann

One of the main goals of ultra-high field MRI is to increase the spatial resolution reached in structural and functional images. Here, the possibility to obtain in vivo images of the human brain with voxel volumes below 0. 02mm3 is shown at 9. 4T. To optimize SNR and suppress ringing artifacts, an acquisition-weighted 3D gradient-echo sequence is used, which acquires more averages in the center than in the outer regions of k-space. The weighting function is adjusted to avoid losses in spatial resolution and scan duration compared to a conventional experiment with an equal number of scans and otherwise identical parameters. Spatial resolution and SNR of the weighted sequence are compared to conventionally acquired images by means of phantom and in vivo measurements, and show improved image quality with unchanged spatial resolution and an SNR increase of up to 36% in phantoms and 20%±5% in vivo. Ultra-high resolution images with a voxel volume of 0. 014mm3 (0. 13×0. 13×0. 8mm3) from the human brain have sufficient SNR and show fine intracortical detail, demonstrating the potential of the technique. The combination of acquisition-weighted imaging and highly sensitive array coils at ultra-high fields thus makes it possible to obtain images with ultra-high spatial resolutions within acceptable scan times.

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YNIMG Journal 2013 Journal Article

Dynamic reconfiguration of human brain functional networks through neurofeedback

  • Sven Haller
  • Rotem Kopel
  • Permi Jhooti
  • Tanja Haas
  • Frank Scharnowski
  • Karl-Olof Lovblad
  • Klaus Scheffler
  • Dimitri Van De Ville

Recent fMRI studies demonstrated that functional connectivity is altered following cognitive tasks (e. g. , learning) or due to various neurological disorders. We tested whether real-time fMRI-based neurofeedback can be a tool to voluntarily reconfigure brain network interactions. To disentangle learning-related from regulation-related effects, we first trained participants to voluntarily regulate activity in the auditory cortex (training phase) and subsequently asked participants to exert learned voluntary self-regulation in the absence of feedback (transfer phase without learning). Using independent component analysis (ICA), we found network reconfigurations (increases in functional network connectivity) during the neurofeedback training phase between the auditory target region and (1) the auditory pathway; (2) visual regions related to visual feedback processing; (3) insula related to introspection and self-regulation and (4) working memory and high-level visual attention areas related to cognitive effort. Interestingly, the auditory target region was identified as the hub of the reconfigured functional networks without a-priori assumptions. During the transfer phase, we again found specific functional connectivity reconfiguration between auditory and attention network confirming the specific effect of self-regulation on functional connectivity. Functional connectivity to working memory related networks was no longer altered consistent with the absent demand on working memory. We demonstrate that neurofeedback learning is mediated by widespread changes in functional connectivity. In contrast, applying learned self-regulation involves more limited and specific network changes in an auditory setup intended as a model for tinnitus. Hence, neurofeedback training might be used to promote recovery from neurological disorders that are linked to abnormal patterns of brain connectivity.

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YNIMG Journal 2012 Journal Article

Recovery of the default mode network after demanding neurofeedback training occurs in spatio-temporally segregated subnetworks

  • Dimitri Van De Ville
  • Permi Jhooti
  • Tanja Haas
  • Rotem Kopel
  • Karl-Olof Lovblad
  • Klaus Scheffler
  • Sven Haller

The default mode (DM) network is a major large-scale cerebral network that can be identified with functional magnetic resonance imaging (fMRI) during resting state. Most studies consider functional connectivity networks as stationary phenomena. Consequently, the transient behavior of the DM network and its subnetworks is still largely unexplored. Most functional connectivity fMRI studies assess the steady state of resting without any task. To specifically investigate the recovery of the DM network during the transition from activation to rest, we implemented a cognitively demanding real-time fMRI neurofeedback task that targeted down-regulation of the primary auditory cortex. Each of twelve healthy subjects performed 16 block-design fMRI runs (4 runs per day repeated on 4days) resulting 192 runs in total. The analysis included data-driven independent component analysis (ICA) and high-resolution latency estimation between the four components that corresponded to subnetworks of the DM network. These different subnetworks reemerged after regulation with an average time lag or 3. 3s and a time lag of 4. 4s between the first and fourth components; i. e. , the DM recovery first shifts from anterior to posterior, and then gradually focuses on the ventral part of the posterior cingulate cortex, which is known to be implicated in internally directed cognition. In addition, we found less reactivation in the early anterior subnetwork as regulation strength increased, but more reactivation with larger regulation for the late subnetwork that encompassed the ventral PCC. This finding confirms that the level of task engagement influences inversely the subsequent recovery of regions related to attention compared to those related to internally directed cognition.

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YNIMG Journal 2007 Journal Article

BOLD correlates of edge detection in human auditory cortex

  • Marcus Herdener
  • Fabrizio Esposito
  • Francesco Di Salle
  • Christoph Lehmann
  • Dominik R. Bach
  • Klaus Scheffler
  • Erich Seifritz

Edges are important cues defining coherent auditory objects. As a model of auditory edges, sound on- and offset are particularly suitable to study their neural underpinnings because they contrast a specific physical input against no physical input. Change from silence to sound, that is onset, has extensively been studied and elicits transient neural responses bilaterally in auditory cortex. However, neural activity associated with sound onset is not only related to edge detection but also to novel afferent inputs. Edges at the change from sound to silence, that is offset, are not confounded by novel physical input and thus allow to examine neural activity associated with sound edges per se. In the first experiment, we used silent acquisition functional magnetic resonance imaging and found that the offset of pulsed sound activates planum temporale, superior temporal sulcus and planum polare of the right hemisphere. In the planum temporale and the superior temporal sulcus, offset response amplitudes were related to the pulse repetition rate of the preceding stimulation. In the second experiment, we found that these offset-responsive regions were also activated by single sound pulses, onset of sound pulse sequences and single sound pulse omissions within sound pulse sequences. However, they were not active during sustained sound presentation. Thus, our data show that circumscribed areas in right temporal cortex are specifically involved in identifying auditory edges. This operation is crucial for translating acoustic signal time series into coherent auditory objects.

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YNIMG Journal 2007 Journal Article

Dissociated lateralization of transient and sustained blood oxygen level-dependent signal components in human primary auditory cortex

  • Christoph Lehmann
  • Marcus Herdener
  • Peter Schneider
  • Andrea Federspiel
  • Dominik R. Bach
  • Fabrizio Esposito
  • Francesco Di Salle
  • Klaus Scheffler

Among other auditory operations, the analysis of different sound levels received at both ears is fundamental for the localization of a sound source. These so-called interaural level differences, in animals, are coded by excitatory–inhibitory neurons yielding asymmetric hemispheric activity patterns with acoustic stimuli having maximal interaural level differences. In human auditory cortex, the temporal blood oxygen level-dependent (BOLD) response to auditory inputs, as measured by functional magnetic resonance imaging (fMRI), consists of at least two independent components: an initial transient and a subsequent sustained signal, which, on a different time scale, are consistent with electrophysiological human and animal response patterns. However, their specific functional role remains unclear. Animal studies suggest these temporal components being based on different neural networks and having specific roles in representing the external acoustic environment. Here we hypothesized that the transient and sustained response constituents are differentially involved in coding interaural level differences and therefore play different roles in spatial information processing. Healthy subjects underwent monaural and binaural acoustic stimulation and BOLD responses were measured using high signal-to-noise-ratio fMRI. In the anatomically segmented Heschl’s gyrus the transient response was bilaterally balanced, independent of the side of stimulation, while in opposite the sustained response was contralateralized. This dissociation suggests a differential role at these two independent temporal response components, with an initial bilateral transient signal subserving rapid sound detection and a subsequent lateralized sustained signal subserving detailed sound characterization.

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YNIMG Journal 2006 Journal Article

A multivariate approach for processing magnetization effects in triggered event-related functional magnetic resonance imaging time series

  • Fabrizio Esposito
  • Francesco Di Salle
  • Franciszek Hennel
  • Ornella Santopaolo
  • Marcus Herdener
  • Klaus Scheffler
  • Rainer Goebel
  • Erich Seifritz

Triggered event-related functional magnetic resonance imaging requires sparse intervals of temporally resolved functional data acquisitions, whose initiation corresponds to the occurrence of an event, typically an epileptic spike in the electroencephalographic trace. However, conventional fMRI time series are greatly affected by non-steady-state magnetization effects, which obscure initial blood oxygen level-dependent (BOLD) signals. Here, conventional echo-planar imaging and a post-processing solution based on principal component analysis were employed to remove the dominant eigenimages of the time series, to filter out the global signal changes induced by magnetization decay and to recover BOLD signals starting with the first functional volume. This approach was compared with a physical solution using radiofrequency preparation, which nullifies magnetization effects. As an application of the method, the detectability of the initial transient BOLD response in the auditory cortex, which is elicited by the onset of acoustic scanner noise, was used to demonstrate that post-processing-based removal of magnetization effects allows to detect brain activity patterns identical with those obtained using the radiofrequency preparation. Using the auditory responses as an ideal experimental model of triggered brain activity, our results suggest that reducing the initial magnetization effects by removing a few principal components from fMRI data may be potentially useful in the analysis of triggered event-related echo-planar time series. The implications of this study are discussed with special caution to remaining technical limitations and the additional neurophysiological issues of the triggered acquisition.

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YNIMG Journal 2006 Journal Article

Differential patterns of multisensory interactions in core and belt areas of human auditory cortex

  • Christoph Lehmann
  • Marcus Herdener
  • Fabrizio Esposito
  • Daniela Hubl
  • Francesco Di Salle
  • Klaus Scheffler
  • Dominik R. Bach
  • Andrea Federspiel

The auditory cortex is anatomically segregated into a central core and a peripheral belt region, which exhibit differences in preference to bandpassed noise and in temporal patterns of response to acoustic stimuli. While it has been shown that visual stimuli can modify response magnitude in auditory cortex, little is known about differential patterns of multisensory interactions in core and belt. Here, we used functional magnetic resonance imaging and examined the influence of a short visual stimulus presented prior to acoustic stimulation on the spatial pattern of blood oxygen level-dependent signal response in auditory cortex. Consistent with crossmodal inhibition, the light produced a suppression of signal response in a cortical region corresponding to the core. In the surrounding areas corresponding to the belt regions, however, we found an inverse modulation with an increasing signal in centrifugal direction. Our data suggest that crossmodal effects are differentially modulated according to the hierarchical core-belt organization of auditory cortex.

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YNIMG Journal 2006 Journal Article

Enhancing BOLD response in the auditory system by neurophysiologically tuned fMRI sequence

  • Erich Seifritz
  • Francesco Di Salle
  • Fabrizio Esposito
  • Marcus Herdener
  • John G. Neuhoff
  • Klaus Scheffler

Auditory neuroscience has not tapped fMRI's full potential because of acoustic scanner noise emitted by the gradient switches of conventional echoplanar fMRI sequences. The scanner noise is pulsed, and auditory cortex is particularly sensitive to pulsed sounds. Current fMRI approaches to avoid stimulus–noise interactions are temporally inefficient. Since the sustained BOLD response to pulsed sounds decreases with repetition rate and becomes minimal with unpulsed sounds, we developed an fMRI sequence emitting continuous rather than pulsed gradient sound by implementing a novel quasi-continuous gradient switch pattern. Compared to conventional fMRI, continuous-sound fMRI reduced auditory cortex BOLD baseline and increased BOLD amplitude with graded sound stimuli, short sound events, and sounds as complex as orchestra music with preserved temporal resolution. Response in subcortical auditory nuclei was enhanced, but not the response to light in visual cortex. Finally, tonotopic mapping using continuous-sound fMRI demonstrates that enhanced functional signal-to-noise in BOLD response translates into improved spatial separability of specific sound representations.

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YNIMG Journal 2003 Journal Article

Sustained blood oxygenation and volume response to repetition rate-modulated sound in human auditory cortex

  • Erich Seifritz
  • Francesco Di Salle
  • Fabrizio Esposito
  • Deniz Bilecen
  • John G Neuhoff
  • Klaus Scheffler

The blood oxygen level-dependent (BOLD) signal time course in the auditory cortex is characterized by two components, an initial transient peak and a subsequent sustained plateau with smaller amplitude. Because the T2 * signal detected by functional magnetic resonance imaging (fMRI) depends on at least two counteracting factors, blood oxygenation and volume, we examined whether the reduction in the sustained BOLD signal results from decreased levels of oxygenation or from increased levels of blood volume. We used conventional fMRI to quantify the BOLD signal and fMRI in combination with superparamagnetic contrast agent to quantify blood volume and employed repetition rate-modulated sounds in a silent background to manipulate the response amplitude in the auditory cortex. In the BOLD signal, the initial peak reached 3. 3% with pulsed sound and 1. 9% with continuous sound, whereas the sustained BOLD signal fell to 2. 2% with pulsed sound and to 0. 5% with continuous sound, respectively. The repetition rate-dependent reduction in the sustained BOLD amplitude was accompanied by concordant changes in sustained blood volume levels, which, compared to silence, increased by ∼30% with pulsed and by ∼10% with continuous sound. Thus, our data suggest that the reduced amplitude of the sustained BOLD signal reflects stimulus-dependent modulation of blood oxygenation rather than blood volume-related effects.

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YNIMG Journal 2003 Journal Article

Temporal integration of sequential auditory events: silent period in sound pattern activates human planum temporale

  • Henrietta Mustovic
  • Klaus Scheffler
  • Francesco Di Salle
  • Fabrizio Esposito
  • John G Neuhoff
  • Jürgen Hennig
  • Erich Seifritz

Temporal integration is a fundamental process that the brain carries out to construct coherent percepts from serial sensory events. This process critically depends on the formation of memory traces reconciling past with present events and is particularly important in the auditory domain where sensory information is received both serially and in parallel. It has been suggested that buffers for transient auditory memory traces reside in the auditory cortex. However, previous studies investigating “echoic memory” did not distinguish between brain response to novel auditory stimulus characteristics on the level of basic sound processing and a higher level involving matching of present with stored information. Here we used functional magnetic resonance imaging in combination with a regular pattern of sounds repeated every 100 ms and deviant interspersed stimuli of 100-ms duration, which were either brief presentations of louder sounds or brief periods of silence, to probe the formation of auditory memory traces. To avoid interaction with scanner noise, the auditory stimulation sequence was implemented into the image acquisition scheme. Compared to increased loudness events, silent periods produced specific neural activation in the right planum temporale and temporoparietal junction. Our findings suggest that this area posterior to the auditory cortex plays a critical role in integrating sequential auditory events and is involved in the formation of short-term auditory memory traces. This function of the planum temporale appears to be fundamental in the segregation of simultaneous sound sources.

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YNIMG Journal 2002 Journal Article

Amplitopicity of the Human Auditory Cortex: An fMRI Study

  • Deniz Bilecen
  • Erich Seifritz
  • Klaus Scheffler
  • Jürgen Henning
  • Anja-Carina Schulte

Whereas specialized frequency-encoding patterns in the human auditory cortex are generally accepted, termed tonotopicity, a similar principle of intensity encoding—amplitopicity—is debated controversially. This functional magnetic resonance imaging study describes the relationship of the activation volume and the spatial distribution of activated clusters under different sound pressure levels (SPL) across the temporal plane including the transverse temporal gyrus (TTG). Nine healthy subjects with no hearing deficiencies were investigated using an echo-planar imaging technique at 1. 5 T. A boxcar stimulation paradigm was applied with a 5-Hz pulsed sine tone of 1000 Hz frequency at three SPLs of 70, 82, and 90 dB. Linear cross-correlation analysis (correlation coefficient > 0. 3 corresponding to P < 0. 08) of the functional data set revealed bilateral BOLD response within the auditory cortex of the nine subjects with moderate increase of activation volume for higher sound pressure levels. With increasing sound pressure a two-dimensional drift of cortical activation was observed (a) from the ventral to the dorsal edge and (b) from lateral to medial parts of TTG. This latero-medial drift therefore mimics the well-accepted principle of tonotopy for frequency-encoding neurons. This study demonstrates the existence of an amplitopic pattern of intensity-encoding neuronal clusters that in part resembles the tonotopic distribution of frequency-encoding neurons. This finding has to be integrated into the understanding of the auditory organization for the interpretation of higher auditory functions such as sound perception or speech.

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YNIMG Journal 2001 Journal Article

Functional Fields in Human Auditory Cortex Revealed by Time-Resolved fMRI without Interference of EPI Noise

  • Francesco Di Salle
  • Elia Formisano
  • Erich Seifritz
  • David E.J. Linden
  • Klaus Scheffler
  • Claudio Saulino
  • Gioacchino Tedeschi
  • Friedhelm E. Zanella

The gradient switching during fast echoplanar functional magnetic resonance imaging (EPI-fMRI) produces loud noises that may interact with the functional activation of the central auditory system induced by experimental acoustic stimuli. This interaction is unpredictable and is likely to confound the interpretation of functional maps of the auditory cortex. In the present study we used an experimental design which does not require the presentation of stimuli during EPI acquisitions and allows for mapping of the auditory cortex without the interference of scanner noise. The design relies on the physiological delays between the onset, or the end, of stimulation and the corresponding hemodynamic response. Owing to these delays and through a time-resolved acquisition protocol it is possible to analyze the decay of the stimulus-specific signal changes after the cessation of the stimulus itself and before the onset of the EPI-acoustic noise related activation (decay-sampling technique). This experimental design, which might permit a more detailed insight in the auditory cortex, has been applied to the study of the cortical responses to pulsed 1000 Hz sine tones. Distinct activation clusters were detected in the Heschl's gyri and the planum temporale, with an increased extension compared to a conventional block-design paradigm. Furthermore, the comparison of the hemodynamic response of the most anterior and the posterior clusters of activation highlighted differential response patterns to the sound stimulation and to the EPI-noise. These differences, attributable to reciprocal saturation effects unevenly distributed over the superior temporal cortex, provided evidence for functionally distinct auditory fields.

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v2026.09.13