Biomedical subjects

Thomas Dierks

Publications and source records attributed to Thomas Dierks.

At least 19 recordsLinked to original sources

PubMed2007

Competition for neuronal resources: how hallucinations make themselves heard.

BACKGROUND: Hallucinations are perceptions in the absence of a corresponding external sensory stimulus. However, during auditory verbal hallucinations, activation of the primary auditory cortex has been described. AIMS: The objective of this study was to investigate whether this activation of the auditory cortex contributes essentially to the character of hallucinations and attributes them to alien sources, or whether the auditory activation is a sign of increased general auditory attention to external sounds. METHOD: The responsiveness of the auditory cortex was investigated by auditory evoked potentials (N100) during the simultaneous occurrence of hallucinations and external stimuli. Evoked potentials were computed separately for periods with and without hallucinations; N100 power, topography and brain electrical sources were analysed. RESULTS: Hallucinations lowered the N100 amplitudes and changed the topography, presumably due to a reduced left temporal responsivity. CONCLUSIONS: This finding indicates competition between auditory stimuli and hallucinations for physiological resources in the primary auditory cortex. The abnormal activation of the primary auditory cortex may thus be a constituent of auditory hallucinations.

Adult↗

PubMed2006

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

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.

Acoustic Stimulation↗

PubMed2006

Application and comparison of classification algorithms for recognition of Alzheimer's disease in electrical brain activity (EEG).

The early detection of subjects with probable Alzheimer's disease (AD) is crucial for effective appliance of treatment strategies. Here we explored the ability of a multitude of linear and non-linear classification algorithms to discriminate between the electroencephalograms (EEGs) of patients with varying degree of AD and their age-matched control subjects. Absolute and relative spectral power, distribution of spectral power, and measures of spatial synchronization were calculated from recordings of resting eyes-closed continuous EEGs of 45 healthy controls, 116 patients with mild AD and 81 patients with moderate AD, recruited in two different centers (Stockholm, New York). The applied classification algorithms were: principal component linear discriminant analysis (PC LDA), partial least squares LDA (PLS LDA), principal component logistic regression (PC LR), partial least squares logistic regression (PLS LR), bagging, random forest, support vector machines (SVM) and feed-forward neural network. Based on 10-fold cross-validation runs it could be demonstrated that even tough modern computer-intensive classification algorithms such as random forests, SVM and neural networks show a slight superiority, more classical classification algorithms performed nearly equally well. Using random forests classification a considerable sensitivity of up to 85% and a specificity of 78%, respectively for the test of even only mild AD patients has been reached, whereas for the comparison of moderate AD vs. controls, using SVM and neural networks, values of 89% and 88% for sensitivity and specificity were achieved. Such a remarkable performance proves the value of these classification algorithms for clinical diagnostics.

Aged↗

PubMed2006

Heparan sulfate 6-O-endosulfatases: discrete in vivo activities and functional co-operativity.

HS (heparan sulfate) is essential for normal embryonic development. This requirement is due to the obligatory role for HS in the signalling pathways of many growth factors and morphogens that bind to sulfated domains in the HS polymer chain. The sulfation patterning of HS is determined by a complex interplay of Golgi-located N- and O-sulfotransferases which sulfate the heparan precursor and cell surface endosulfatases that selectively remove 6-O-sulfates from mature HS chains. In the present study we generated single or double knock-out mice for the two murine endosulfatases mSulf1 and mSulf2. Detailed structural analysis of HS from mSulf1-/- fibroblasts showed a striking increase in 6-O-sulfation, which was not seen in mSulf2-/- HS. Intriguingly, the level of 6-O-sulfation in the double mSulf1-/-/2-/- HS was significantly higher than that observed in the mSulf1-/- counterpart. These data imply that mSulf1 and mSulf2 are functionally co-operative. Unlike their avian orthologues, mammalian Sulf activities are not restricted to the highly sulfated S-domains of HS. Mitogenesis assays with FGF2 (fibroblast growth factor 2) revealed that Sulf activity decreases the activating potential of newly-synthesized HS, suggesting an important role for these enzymes in cell growth regulation in embryonic and adult tissues.

Animals↗

PubMed2006

Alterations of white matter connectivity in first episode schizophrenia.

Cerebral disconnectivity due to white matter alterations in patients with chronic schizophrenia assessed by diffusion tensor imaging has been reported previously. The aim of this preliminary study is to investigate whether cerebral disconnectivity can be detected as early as the first episode of schizophrenia. Intervoxel coherence values were compared by voxel-based t test in 12 patients with first episode schizophrenia and 12 age- and gender-matched control groups. We detected 14 circumscribed significant clusters (P < 0.02), 3 of them with higher, and 11 of them with lower IC values for patients with schizophrenia than for healthy control groups. We interpret these white matter alterations in different regions to be disconnected fiber tracts already present early in schizophrenic disease progression.

Adolescent↗

PubMed2006

Increased sensitivity in mapping task demand in visuospatial processing using reaction-time-dependent hemodynamic response predictors in rapid event-related fMRI.

Searching for the neural correlates of visuospatial processing using functional magnetic resonance imaging (fMRI) is usually done in an event-related framework of cognitive subtraction, applying a paradigm comprising visuospatial cognitive components and a corresponding control task. Besides methodological caveats of the cognitive subtraction approach, the standard general linear model with fixed hemodynamic response predictors bears the risk of being underspecified. It does not take into account the variability of the blood oxygen level-dependent signal response due to variable task demand and performance on the level of each single trial. This underspecification may result in reduced sensitivity regarding the identification of task-related brain regions. In a rapid event-related fMRI study, we used an extended general linear model including single-trial reaction-time-dependent hemodynamic response predictors for the analysis of an angle discrimination task. In addition to the already known regions in superior and inferior parietal lobule, mapping the reaction-time-dependent hemodynamic response predictor revealed a more specific network including task demand-dependent regions not being detectable using the cognitive subtraction method, such as bilateral caudate nucleus and insula, right inferior frontal gyrus and left precentral gyrus.

Adult↗

PubMed2006

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

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.

Acoustic Stimulation↗

PubMed2006

Motion standstill leads to activation of inferior parietal lobe.

Previous studies on motion perception revealed motion-processing brain areas sensitive to changes in luminance and texture (low-level) and changes in salience (high-level). The present functional magnetic resonance imaging (fMRI) study focused on motion standstill. This phenomenon, occurring at fast presentation frequencies of visual moving objects that are perceived as static, has not been previously explored by neuroimaging techniques. Thirteen subjects were investigated while perceiving apparent motion at 4 Hz, at 30 Hz (motion standstill), isoluminant static and flickering stimuli, fixation cross, and blank screen, presented randomly and balanced for rapid event-related fMRI design. Blood oxygenation level-dependent (BOLD) signal in the occipito-temporal brain region MT/V5 increased during apparent motion perception. Here we could demonstrate that brain areas like the posterior part of the right inferior parietal lobule (IPL) demonstrated higher BOLD-signal during motion standstill. These findings suggest that the activation of higher-order motion areas is elicited by apparent motion at high presentation rates (motion standstill). We interpret this observation as a manifestation of an orienting reaction in IPL towards stimulus motion that might be detected but not resolved by other motion-processing areas (i.e., MT/V5).

Adult↗

PubMed2006

Facial affect recognition training in autism: can we animate the fusiform gyrus?

One of the most consistent findings in the neuroscience of autism is hypoactivation of the fusiform gyrus (FG) during face processing. In this study the authors examined whether successful facial affect recognition training is associated with an increased activation of the FG in autism. The effect of a computer-based program to teach facial affect identification was examined in 10 individuals with high-functioning autism. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) changes in the FG and other regions of interest, as well as behavioral facial affect recognition measures, were assessed pre- and posttraining. No significant activation changes in the FG were observed. Trained participants showed behavioral improvements, which were accompanied by higher BOLD fMRI signals in the superior parietal lobule and maintained activation in the right medial occipital gyrus.

Adult↗

PubMed2005

A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme.

The formylglycine (FGly)-generating enzyme (FGE) uses molecular oxygen to oxidize a conserved cysteine residue in all eukaryotic sulfatases to the catalytically active FGly. Sulfatases degrade and remodel sulfate esters, and inactivity of FGE results in multiple sulfatase deficiency, a fatal disease. The previously determined FGE crystal structure revealed two crucial cysteine residues in the active site, one of which was thought to be implicated in substrate binding. The other cysteine residue partakes in a novel oxygenase mechanism that does not rely on any cofactors. Here, we present crystal structures of the individual FGE cysteine mutants and employ chemical probing of wild-type FGE, which defined the cysteines to differ strongly in their reactivity. This striking difference in reactivity is explained by the distinct roles of these cysteine residues in the catalytic mechanism. Hitherto, an enzyme-substrate complex as an essential cornerstone for the structural evaluation of the FGly formation mechanism has remained elusive. We also present two FGE-substrate complexes with pentamer and heptamer peptides that mimic sulfatases. The peptides isolate a small cavity that is a likely binding site for molecular oxygen and could host reactive oxygen intermediates during cysteine oxidation. Importantly, these FGE-peptide complexes directly unveil the molecular bases of FGE substrate binding and specificity. Because of the conserved nature of FGE sequences in other organisms, this binding mechanism is of general validity. Furthermore, several disease-causing mutations in both FGE and sulfatases are explained by this binding mechanism.

Alanine↗

PubMed2005

Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.

Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate.

Alanine↗

PubMed2005

Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme.

pFGE is the paralog of the formylglycine-generating enzyme (FGE), which catalyzes the oxidation of a specific cysteine to Calpha-formylglycine, the catalytic residue in the active site of sulfatases. The enzymatic activity of sulfatases depends on this posttranslational modification, and the genetic defect of FGE causes multiple sulfatase deficiency. The structural and functional properties of pFGE were analyzed. The comparison with FGE demonstrates that both share a tissue-specific expression pattern and the localization in the lumen of the endoplasmic reticulum. Both are retained in the endoplasmic reticulum by a saturable mechanism. Limited proteolytic cleavage at similar sites indicates that both also share a similar three-dimensional structure. pFGE, however, is lacking the formylglycine-generating activity of FGE. Although overexpression of FGE stimulates the generation of catalytically active sulfatases, overexpression of pFGE has an inhibitory effect. In vitro pFGE interacts with sulfatase-derived peptides but not with FGE. The inhibitory effect of pFGE on the generation of active sulfatases may therefore be caused by a competition of pFGE and FGE for newly synthesized sulfatase polypeptides.

Alanine↗

PubMed2005

Crystal structure of human pFGE, the paralog of the Calpha-formylglycine-generating enzyme.

In eukaryotes, sulfate esters are degraded by sulfatases, which possess a unique Calpha-formylglycine residue in their active site. The defect in post-translational formation of the Calpha-formylglycine residue causes a severe lysosomal storage disorder in humans. Recently, FGE (formylglycine-generating enzyme) has been identified as the protein required for this specific modification. Using sequence comparisons, a protein homologous to FGE was found and denoted pFGE (paralog of FGE). pFGE binds a sulfatase-derived peptide bearing the FGE recognition motif, but it lacks formylglycine-generating activity. Both proteins belong to a large family of pro- and eukaryotic proteins containing the DUF323 domain, a formylglycine-generating enzyme domain of unknown three-dimensional structure. We have crystallized the glycosylated human pFGE and determined its crystal structure at a resolution of 1.86 A. The structure reveals a novel fold, which we denote the FGE fold and which therefore serves as a paradigm for the DUF323 domain. It is characterized by an asymmetric partitioning of secondary structure elements and is stabilized by two calcium cations. A deep cleft on the surface of pFGE most likely represents the sulfatase polypeptide binding site. The asymmetric unit of the pFGE crystal contains a homodimer. The putative peptide binding site is buried between the monomers, indicating a biological significance of the dimer. The structure suggests the capability of pFGE to form a heterodimer with FGE.

Amino Acid Motifs↗

PubMed2005

Molecular characterization of the human Calpha-formylglycine-generating enzyme.

Calpha-formylglycine (FGly) is the catalytic residue in the active site of sulfatases. In eukaryotes, it is generated in the endoplasmic reticulum by post-translational modification of a conserved cysteine residue. The FGly-generating enzyme (FGE), performing this modification, is an endoplasmic reticulum-resident enzyme that upon overexpression is secreted. Recombinant FGE was purified from cells and secretions to homogeneity. Intracellular FGE contains a high mannose type N-glycan, which is processed to the complex type in secreted FGE. Secreted FGE shows partial N-terminal trimming up to residue 73 without loosing catalytic activity. FGE is a calcium-binding protein containing an N-terminal (residues 86-168) and a C-terminal (residues 178-374) protease-resistant domain. The latter is stabilized by three disulfide bridges arranged in a clamp-like manner, which links the third to the eighth, the fourth to the seventh, and the fifth to the sixth cysteine residue. The innermost cysteine pair is partially reduced. The first two cysteine residues are located in the sequence preceding the N-terminal protease-resistant domain. They can form intramolecular or intermolecular disulfide bonds, the latter stabilizing homodimers. The C-terminal domain comprises the substrate binding site, as evidenced by yeast two-hybrid interaction assays and photocross-linking of a substrate peptide to proline 182. Peptides derived from all known human sulfatases served as substrates for purified FGE indicating that FGE is sufficient to modify all sulfatases of the same species.

Amino Acid Sequence↗

PubMed2005

The neurophysiological time pattern of illusionary visual perceptual transitions: a simultaneous EEG and fMRI study.

Several divergent cortical mechanisms generating multistability in visual perception have been suggested. Here, we investigated the neurophysiologic time pattern of multistable perceptual changes by means of a simultaneous recording with electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Volunteers responded to the subjective perception of a sudden change between stable patterns of illusionary motion (multistable transition) during a stroboscopic paradigm. We found a global deceleration of the EEG frequency prior to a transition and an occipital-accentuated acceleration after a transition, as obtained by low-resolution electromagnetic tomography analysis (LORETA) analysis. A decrease in BOLD response was found in the prefrontal cortex before, and an increase after the transitions was observed in the right anterior insula, the MT/V5 regions and the SMA. The thalamus and left superior temporal gyrus showed a pattern of decrease before and increase after transitions. No such temporal course was found in the control condition. The multimodal approach of data acquisition allows us to argue that the top-down control of illusionary visual perception depends on selective attention, and that a diminution of vigilance reduces selective attention. These are necessary conditions to allow for the occurrence of a perception discontinuity in absence of a physical change of the stimulus.

Adolescent↗

PubMed2005

The spatiotemporal pattern of auditory cortical responses during verbal hallucinations.

Functional magnetic resonance imaging (fMRI) studies can provide insight into the neural correlates of hallucinations. Commonly, such studies require self-reports about the timing of the hallucination events. While many studies have found activity in higher-order sensory cortical areas, only a few have demonstrated activity of the primary auditory cortex during auditory verbal hallucinations. In this case, using self-reports as a model of brain activity may not be sensitive enough to capture all neurophysiological signals related to hallucinations. We used spatial independent component analysis (sICA) to extract the activity patterns associated with auditory verbal hallucinations in six schizophrenia patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. The resulting activity patterns from auditory and sensorimotor components were further analyzed in a single-subject fashion using a visualization tool that allows for easy inspection of the variability of regional brain responses. We found bilateral auditory cortex activity, including Heschl's gyrus, during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. However, the average of the time courses during hallucinations showed a clear association with this clinical phenomenon. We suggest that detection of this activity may be facilitated by examining hallucination epochs of sufficient length, in combination with a data-driven approach.

Acoustic Stimulation↗

PubMed2004

Volumetry and diffusion tensor imaging of hippocampal subregions in schizophrenia.

Previous MRI-volumetric studies in schizophrenic psychoses have demonstrated more or less pronounced volume reductions of the hippocampus in patients. Correspondingly, neuropathological examinations on the brains of schizophrenics showed diverse structural changes of the hippocampus. Employing a high-resolution 3D-MPRAGE sequence, we found volume reductions in most hippocampal subregions of schizophrenic patients, which, however, did not reach significant levels. An analysis of co-registered diffusion tensor imaging (DTI) data revealed significant alterations of the inter-voxel coherences in single hippocampal subdivisions of these patients, supporting the assumption of characteristic microstructural tissue changes relevant for the pathogenesis of schizophrenic psychoses. Our results argue for the usage of additional MRI modalities like DTI in order to detect subtle regional alterations of hippocampal structure in schizophrenics.

Adult↗

PubMed2004

Crystal structure of the alkylsulfatase AtsK: insights into the catalytic mechanism of the Fe(II) alpha-ketoglutarate-dependent dioxygenase superfamily.

The alkylsulfatase AtsK from Pseudomonas putida S-313 belongs to the widespread and versatile non-heme iron(II) alpha-ketoglutarate-dependent dioxygenase superfamily and catalyzes the oxygenolytic cleavage of a variety of different alkyl sulfate esters to the corresponding aldehyde and sulfate. The enzyme is only expressed under sulfur starvation conditions, providing a selective advantage for bacterial growth in soils and rhizosphere. Here we describe the crystal structure of AtsK in the apo form and in three complexes: with the cosubstrate alpha-ketoglutarate, with alpha-ketoglutarate and iron, and finally with alpha-ketoglutarate, iron, and an alkyl sulfate ester used as substrate in catalytic studies. The overall fold of the enzyme is closely related to that of the taurine/alpha-ketoglutarate dioxygenase TauD and is similar to the fold observed for other members of the enzyme superfamily. From comparison of these structures with the crystal structure of AtsK and its complexes, we propose a general mechanism for the catalytic cycle of the alpha-ketoglutarate-dependent dioxygenase superfamily.

Amino Acid Motifs↗