Stefan Klöppel

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (99)653.35 Total impact

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    ABSTRACT: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI).
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    ABSTRACT: We present in this paper a method to perform a length parameterization of cortical sulcus meshes. Such parameterization allows morphological features to be localized in a normalized way along the length of the sulcus and can be used to perform population studies and group comparisons. Our method uses the second eigenfunction of the Laplace-Beltrami operator, and the resulting parameterization is quasi-isometric. The process is validated on the central sulci of a set of subjects and its efficiency is demonstrated by quantifying morphological differences between left and right-handed subjects.
    IEEE International Symposium on Biomedical Imaging, Brooklyn, USA; 04/2015
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    ABSTRACT: Processing of multiple or bilateral conditions presented simultaneously in both hemifields reflects the natural mode of perception in our multi-target environment, but is not yet completely understood. While region-of-interest based studies in healthy subjects reported single cortical areas as the right inferior parietal lobe (IPL) or temporoparietal junction (TPJ) to process bilateral conditions, studies in extinction patients with reduced ability in this regard suggested the right superior temporal cortex to hold a key role. The present fMRI study on healthy subjects aimed at resolving these discrepancies by contrasting bilateral versus unilateral visual conditions in a paradigm similar to the bed-side test for patients with visual extinction on a whole brain level. Additionally, reduced attentional capacity in spatial processing was investigated in normal aging. Processing of bilateral conditions compared to unilateral ones showed to require stronger activation of not one single cortical region but the entire right-lateralized ventral attention network, bilateral parietal and visual association areas. These results might suggest a conceptual difference between unilateral and bilateral spatial processing with the latter depending on additional anatomical and functional brain resources. Reduced attentional capacity in elderly subjects was associated with compensatory recruitment of contralateral functional homologues [left IPL, TPJ, frontal eye field (FEF)]. These data reveal the functional anatomy of our ability to visually process and respond to the entity of the environment and improve our understanding of neglect and extinction. Moreover, the data demonstrate that a restriction of the attentional capacity is based on processing limitations in the network of high-level cortical areas and not due to restriction in the primary sensory ones. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cortex 03/2015; 66. DOI:10.1016/j.cortex.2015.02.018 · 6.04 Impact Factor
  • Jessica Peter, Stefan Klöppel
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    ABSTRACT: Alzheimer’s disease (AD), the predominant cause of dementia, is characterized by progressive loss of memory and other cognitive functions with advancing age, and both genetic and non-genetic factors modifying disease risk. This chapter provides a summary of the underlying neuropathology, epidemiology, and clinical characteristics of AD. Additionally, recently developed methods of automated diagnosing, novel therapeutic strategies, and possible preventing variables are briefly described.
    Brain Mapping: An Encyclopedic Reference, First Edition edited by Arthur W. Toga, 02/2015: chapter 73; Elsevier., ISBN: 9780123970251
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    ABSTRACT: Deterministic dynamic causal modeling (DCM) for fMRI data is a sophisticated approach to analyse effective connectivity in terms of directed interactions between brain regions of interest. To date it is difficult to know if acquired fMRI data will yield precise estimation of DCM parameters. Focusing on parameter identifiability, an important prerequisite for research questions on directed connectivity, we present an approach inferring if parameters of an envisaged DCM are identifiable based on information from fMRI data. With the freely available "attention to motion" dataset, we investigate identifiability of two DCMs and show how different imaging specifications impact on identifiability. We used the profile likelihood, which has successfully been applied in systems biology, to assess the identifiability of parameters in a DCM with specified scanning parameters. Parameters are identifiable when minima of the profile likelihood as well as finite confidence intervals for the parameters exist. Intermediate epoch duration, shorter TR and longer session duration generally increased the information content in the data and thus improved identifiability. Irrespective of biological factors such as size and location of a region, attention should be paid to densely interconnected regions in a DCM, as those seem to be prone to non-identifiability. Our approach, available in the DCMident toolbox, enables to judge if the parameters of an envisaged DCM are sufficiently determined by underlying data without priors as opposed to primarily reflecting the Bayesian priors in a SPM-DCM. Assessments with the DCMident toolbox prior to a study will lead to improved identifiability of the parameters and thus might prevent suboptimal data acquisition. Thus, the toolbox can be used as a preprocessing step to provide immediate statements on parameter identifiability.
    Frontiers in Neuroscience 02/2015; 9:43. DOI:10.3389/fnins.2015.00043
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    ABSTRACT: Voxel-based morphometry from conventional T1-weighted images has proved effective to quantify Alzheimer's disease (AD) related brain atrophy and to enable fairly accurate automated classification of AD patients, mild cognitive impaired patients (MCI) and elderly controls. Little is known, however, about the classification power of volume-based morphometry, where features of interest consist of a few brain structure volumes (e.g. hippocampi, lobes, ventricles) as opposed to hundreds of thousands of voxel-wise gray matter concentrations. In this work, we experimentally evaluate two distinct volume-based morphometry algorithms (FreeSurfer and an in-house algorithm called MorphoBox) for automatic disease classification on a standardized data set from the Alzheimer's Disease Neuroimaging Initiative. Results indicate that both algorithms achieve classification accuracy comparable to the conventional whole-brain voxel-based morphometry pipeline using SPM for AD vs elderly controls and MCI vs controls, and higher accuracy for classification of AD vs MCI and early vs late AD converters, thereby demonstrating the potential of volume-based morphometry to assist diagnosis of mild cognitive impairment and Alzheimer's disease.
    11/2014; 7. DOI:10.1016/j.nicl.2014.11.001
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    ABSTRACT: Several models of neural compensation in healthy aging have been suggested to explain brain activity that aids to sustain cognitive function. Applying recently suggested criteria of "attempted" and "successful" compensation, we reviewed existing literature on compensatory mechanisms in preclinical Huntington's disease (HD) and amnestic mild cognitive impairment (aMCI). Both disorders constitute early stages of neurodegeneration ideal for examining compensatory mechanisms and developing targeted interventions. We strived to clarify whether compensation criteria derived from healthy aging populations can be applied to early neurodegeneration. To concentrate on the close coupling of cognitive performance and brain activity, we exclusively addressed task fMRI studies. First, we found evidence for parallels in compensatory mechanisms between healthy aging and neurodegenerative disease. Several studies fulfilled criteria of attempted compensation, while reports of successful compensation were largely absent, which made it difficult to conclude on. Second, comparing working memory studies in preclinical HD and aMCI, we identified similar compensatory patterns across neurodegenerative disorders in lateral and medial prefrontal cortex. Such patterns included an inverted U-shaped relationship of neurodegeneration and compensatory activity spanning from preclinical to manifest disease. Due to the lack of studies systematically targeting all criteria of compensation, we propose an exemplary study design, including the manipulation of compensating brain areas by brain stimulation. Furthermore, we delineate the benefits of targeted interventions by non-invasive brain stimulation, as well as of unspecific interventions such as physical activity or cognitive training. Unambiguously detecting compensation in early neurodegenerative disease will help tailor interventions aiming at sustained overall functioning and delayed clinical disease onset.
    Frontiers in Psychiatry 09/2014; 5:132. DOI:10.3389/fpsyt.2014.00132
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    ABSTRACT: Visual neglect results from dysfunction within the spatial attention network. The structural connectivity in undamaged brain tissue in neglect has barely been investigated until now. In the present study, we explored the microstructural white matter characteristics of the contralesional hemisphere in relation to neglect severity and recovery in acute stroke patients. We compared age-matched healthy subjects and three groups of acute stroke patients (9 ± 0.5 days after stroke): (i) patients with nonrecovered neglect (n = 12); (ii) patients with rapid recovery from initial neglect (within the first week post-stroke, n = 7), (iii) stroke patients without neglect (n = 17). We analyzed the differences between groups in grey and white matter density and fractional anisotropy (FA) and used fiber tracking to identify the affected fibers. Patients with nonrecovered neglect differed from those with rapid recovery by FA-reduction in the left inferior parietal lobe. Fibers passing through this region connect the left-hemispheric analogues of the ventral attention system. Compared with healthy subjects, neglect patients with persisting neglect had FA-reduction in the left superior parietal lobe, optic radiation, and left corpus callosum/cingulum. Fibers passing through these regions connect centers of the left dorsal attention system. FA-reduction in the identified regions correlated with neglect severity. The study shows for the first time white matter changes within the spatial attention system remote from the lesion and correlating with the extent and persistence of neglect. The data support the concept of neglect as disintegration within the whole attention system and illustrate the dynamics of structural-functional correlates in acute stroke. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2014; 35(9). DOI:10.1002/hbm.22503 · 6.92 Impact Factor
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    ABSTRACT: Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level.
    BioMedical Engineering OnLine 09/2014; 13(1):128. DOI:10.1186/1475-925X-13-128 · 1.75 Impact Factor
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    Alzheimer's Association International Conference, Copenhagen; 07/2014
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    Alzheimer's and Dementia 07/2014; 10(4):P541-P542. DOI:10.1016/j.jalz.2014.05.868 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P846. DOI:10.1016/j.jalz.2014.05.1672 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P824. DOI:10.1016/j.jalz.2014.05.1624 · 17.47 Impact Factor
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    ABSTRACT: Although episodic memory impairment is usually the earliest sign of Alzheimer's disease (AD), there are up to 15% of patients presenting with early impairment in non-memory cognitive functions (i.e., atypical AD). Stratifying patients with AD may aid clinical trials. Previous studies divided patients by cognitive profile, focusing on cross-sectional analyses without testing stability of clusters over time. We used principal component analysis followed by cluster analyses in 127 patients with AD based on 24 cognitive scores at 0, 6, 12, and 24 months follow-up. We investigated the definition of clusters and their stability over time as well as interactions of cluster assignment and disease severity. At each time point, six distinct factors and four distinct clusters were extracted that did not differ substantially between time points. Clusters were defined by cognitive profile rather than disease severity. 85% of patients fell into the same cluster twice, 42% three times, and 17% four times. Subjects with focal semantic impairment progressed significantly faster than the other cluster. Longitudinally, focal deficits increased relatively rather than tending toward average disease severity. The observed similar cluster definitions at each time point indicate the validity of the approach. Cluster-specific longitudinal increases of focal impairments and significant between-cluster differences in disease progression make this approach useful for stratified inclusions into clinical trials.
    Journal of Alzheimer's disease: JAD 06/2014; 42(2). DOI:10.3233/JAD-140261 · 3.61 Impact Factor
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    ABSTRACT: Long-term potentiation (LTP) is a key element of synaptic plasticity. At the macroscopic level, similar effects can be induced in the human brain using repetitive stimulation with identical stimuli. High-frequency stimulation (HFS) can increase neuronal responses whereas low-frequency stimulation may produce the opposite effect. Optimal stimulation frequencies and characteristics for inducing stimulus-specific response modification differ substantially from those applied to brain tissue slices but have been explored in recent studies. In contrast, the individual manifestation of this effect in terms of its spatial location and extent are unclear. Using functional MRI (fMRI) in 18 subjects (mean age 25.3 years), we attempted to induce LTP-like effects by HFS with checkerboard flashes at 9 Hz for 120 seconds. As expected, flashes induced strong activation in primary and secondary visual cortices. Contrary to our expectations, we found clusters of decreased activations induced by pattern flashes after HFS at the border between primary and secondary visual cortices.. On the level of the individual subject, some showed significantly increased activations in the post-HFS session while the majority showed significant decreases. The locations of areas showing altered activations before and after HFS were only partly overlapping. No association between location, extent and direction of the HFS-effect was observed. The findings are unexpected in the light of existing HFS-studies, but mirror the high inter-subject variability, concerning even the directionality of the induced effects shown for other indices of LTP-like plasticity in the human brain. As this variability is not observed in LTP at the cellular level, a better understanding of LTP-like mechanisms on the macroscopic level is essential for establishing tools to quantify individual synaptic plasticity in-vivo.
    Frontiers in Human Neuroscience 06/2014; 8(695). DOI:10.3389/fnhum.2014.00695 · 2.90 Impact Factor
  • Joint Congress of European Neurology; 05/2014
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    ABSTRACT: Automated analysis of structural magnetic resonance images is a promising way to improve early detection of neurodegenerative brain diseases. Clinical applications of such methods involve multiple scanners with potentially different hardware and/or acquisition sequences and demographically heterogeneous groups. To improve classification performance, we propose to correct effects of subject-specific covariates (such as age, total intracranial volume, and sex) as well as effects of scanner by using a non-linear Gaussian process model. To test the efficacy of the correction, we performed classification of carriers of the genetic mutation leading to Huntington's disease (HD) versus healthy controls. Half of the HD carriers were free of typical HD symptoms and had an estimated 5 to 20 years before onset of clinical symptoms, thus providing a model for preclinical diagnosis of a neurodegenerative disease.
    NeuroImage 04/2014; 98. DOI:10.1016/j.neuroimage.2014.04.057 · 6.36 Impact Factor
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    ABSTRACT: Diffusion tensor imaging (DTI) allows the simultaneously measurement of several diffusion indices that provide complementary information on the substrate of white matter alterations in neurodegenerative diseases. These indices include fractional anisotropy (FA) as measure of fiber tract integrity, and the mode of anisotropy (Mode) reflecting differences in the shape of the diffusion tensor. We used a multivariate approach based on joint independent component analysis of FA and Mode in a large sample of 138 subjects with Alzheimer's disease (AD) dementia, 37 subjects with cerebrospinal fluid biomarker positive mild cognitive impairment (MCI-AD), and 153 healthy elderly controls from the European DTI Study on Dementia to comprehensively study alterations of microstructural white matter integrity in AD dementia and predementia AD. We found a parallel decrease of FA and Mode in intracortically projecting fiber tracts, and a parallel increase of FA and Mode in the corticospinal tract in AD patients compared to controls. Subjects with MCI-AD showed a similar, but spatially more restricted pattern of diffusion changes. Our findings suggest an early axonal degeneration in intracortical projecting fiber tracts in dementia and predementia stages of AD. An increase of Mode, parallel to an increase of FA, in the corticospinal tract suggests a more linear shape of diffusion due to loss of crossing fibers along relatively preserved cortico-petal and cortico-fugal fiber tracts in AD. Supporting this interpretation, we found three populations of fiber tracts, namely cortico-petal and cortico-fugal, commissural, and intrahemispherically projecting fiber tracts, in the peak area of parallel FA and Mode increase.
    Journal of Alzheimer's disease: JAD 02/2014; 41(1). DOI:10.3233/JAD-131829 · 3.61 Impact Factor
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    ABSTRACT: Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.
    Journal of Alzheimer's disease: JAD 02/2014; 40(3). DOI:10.3233/JAD-132345 · 3.61 Impact Factor
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    ABSTRACT: The early, preferably pre-clinical, identification of neurodegenerative diseases is important as treatment will be most successful before substantial neuronal loss. Here, we reasoned that functional brain changes as measured using functional magnetic resonance imaging (fMRI) will precede neurodegeneration. Three independent cohorts of patients with the genetic mutation leading to Huntington's Disease (HD) but without any clinical symptoms and matched controls performed three different fMRI tasks: Sequential finger tapping engaged the motor system, which is primarily affected by HD, whereas a working-memory task and a task aiming to induce irritation represented the range of low- and high-level cognitive functions also affected by HD. Each diagnostic group of every cohort included 11-16 subjects. After segmentation into 76 cortical and 14 subcortical regions, we extracted functional connectivity patterns through pairwise correlation between the signals in the regions. The resulting coefficients were directly embedded as input to a pattern classifier aiming to separate controls from gene mutation carriers. Alternatively, graph-theory measures such as degree and clustering coefficient were used as features for the discrimination. Classification accuracy never outperformed the accuracy of a grouping based on parameter estimates from a general-linear model approach or a grouping based on features extracted from anatomical images as reported in a previous analysis. Despite good within-subject stability between two runs of the same task, a high between-subject variability led to chance-level accuracy. These results indicate that standard graph-metrics are insufficient to detect subtle disease related changes when within-group variability is high. Developing methods that reduce variability related to noise should be the focus of future studies.
    10/2013; 214(3). DOI:10.1016/j.pscychresns.2013.09.009

Publication Stats

2k Citations
653.35 Total Impact Points

Institutions

  • 2011–2015
    • Universitätsklinikum Freiburg
      • Department of Psychiatry and Psychotherapy
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2007–2014
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • University of Hamburg
      Hamburg, Hamburg, Germany
    • University College London
      • Wellcome Department of Imaging Neuroscience
      London, ENG, United Kingdom
  • 2005
    • University Medical Center Hamburg - Eppendorf
      • Department of Systems Neuroscience
      Hamburg, Hamburg, Germany