Juergen Reichenbach

Nonnvasive assessment of vascular architecture and function during modulated blood oxygenation using susceptibility weighted magnetic resonance imaging.

Susceptibility weighted imaging (SWI) is a BOLD‐sensitive method for visualizing anatomical features such as small cerebral veins in high detail. The purpose of this study was to evaluate high‐resolution SWI in combination with a modulation of blood oxygenation by breathing of air, carbogen, and oxygen and to directly visualize the effects of changing blood oxygenation on the magnetic field inside and around venous blood vessels. Signal changes associated with the response to carbogen and oxygen breathing were evaluated in different anatomic regions in healthy volunteers and in two patients with brain tumors. In the magnitude images inhalation of carbogen led to significant signal intensity changes ranging from +4.4 ± 1.9% to +9.5 ± 1.4% in gray matter and no significant changes in thalamus, putamen, and white matter. During oxygen breathing mean signal changes were smaller than during carbogen breathing. The method is capable of producing high‐resolution functional maps of BOLD response to carbogen and oxygen breathing as well as high‐resolution images of venous vasculature. Its sensitivity to changes in blood oxygenation was demonstrated by in vivo visualization of the BOLD effect via phase imaging. Magn Reson Med 54:87–95, 2005.

Fronto-Cingulate Effective Connectivity in Obsessive Compulsive Disorder: A Study With fMRI and Dynamic Causal Modeling

Evidence suggests that obsessive compulsive disorder (OCD) is associated with an overactive error control system. A key role in error detection and control has been ascribed to the fronto‐cingulate system. However, the exact functional interplay between the single components of this network in OCD is largely unknown. Therefore, the present study combined a univariate data analysis and effective connectivity analysis using dynamic causal modeling (DCM) to examine error control in 21 patients with OCD and 21 matched healthy controls. All subjects performed an adapted version of the Stroop color‐word task while undergoing fMRI scans. Enhanced activation in the fronto‐cingulate system could be detected in OCD patients during the incongruent task condition. Additionally, task‐related modulation of effective connectivity from the dorsal ACC to left DLPFC was significantly stronger in OCD patients. These findings are consistent with an overactive error control system in OCD subserving suppression of prepotent responses during decision‐making. Hum Brain Mapp, 2010.

Improved elimination of phase effects from background field inhomogeneities for susceptibility weighted imaging at high magnetic field strengths

To enhance susceptibility-related contrast of magnetic resonance images, the phase of susceptibility weighted data needs to be corrected for background inhomogeneities and phase wraps caused by them. Current methods either use homodyne filtering or a combination of phase unwrapping and high pass filtering. The drawback of homodyne filtering is incomplete elimination of phase wraps in areas with steep phase topography produced by background inhomogeneities of the static magnetic field. The disadvantage of phase unwrapping is that it requires subsequent high pass filtering, which introduces artifacts in areas with very steep transitions, such as areas near interfaces between parenchyma and bone or air. A method is proposed that reduces the artifacts associated with high pass filtering without sacrificing the advantages of phase unwrapping. This technique is demonstrated with phantom data at 1.5 T and with human data at 1.5, 3 and 7 T.

Antipsychotic drug effects on left prefrontal phospholipid metabolism: A follow-up 31P-2D-CSI study of haloperidol and risperidone in acutely ill chronic schizophrenia patients

INTRODUCTION ³¹Phosphorous magnetic resonance spectroscopy (2D chemical shift imaging, CSI) allows multiregional study of membrane phospholipids and high-energy phosphates in vivo. Increased membrane lipid turnover and impaired energy supply have repeatedly been shown in first-episode schizophrenia patients, and might be a target of drug actions other than dopamine receptors. Here, we explored differential metabolic effects of a typical vs. an atypical antipsychotic on brain phospholipids. METHODS We applied 2D-CSI MR spectroscopy in 17 recurrent-episode schizophrenia patients off antipsychotics at baseline and at follow-up after 6 weeks, during which 7 patients were treated with haloperidol (10-16 mg/d) and 10 with risperidone (4-6 mg/d). Psychopathology changes were assessed using PANSS, BPRS and CGI scores. RESULTS Follow-up analysis using repeated measure ANOVA revealed different effects of both antipsychotic agents: while risperidone generally increased metabolite levels, haloperidol showed a tendency to decrease them. This diverging effect was significant for ATP levels in the left lateral frontal cortex. Furthermore, risperidone increased ATP in the left dorsolateral prefrontal cortex, left anterior temporal cortex and left insular cortex, basal ganglia, and anterior cerebellum, along with left frontal and prefrontal increase of PCr, PDE and PME in these brain regions. CONCLUSION Risperidone seems to stimulate neuronal and synaptic phospholipid remodeling in left frontal and prefrontal regions, and to a lesser extent also in temporal and insular cortices. We discuss these effects with respect to clinical effects on negative and cognitive symptoms, as well as interaction of phospholipid metabolism with glutamatergic neurotransmission.

Automated modeling of tubular blood vessels in 3D MR angiography images

An algorithm is developed for automated modeling of tubular blood vessel segments, based on their noisy 3D raster image. The approach is based on continuous-function approximation of binary skeleton lines extracted from thresholded multiscale vesselness images. The continuous centerline functions allow robust computation of tangent vectors, to define normal planes and 3D image cross-sections on those planes. A vessel intensity profile model is next least-squares fitted to the image cross-section along straight lines segments - anchored at centerline and extended toward vessel walls, at a number of directions covering the full angle. Vessel parameters, such as local radius for circular vessels, distances between the centerline and edges for non-circular shapes or intensity profile corresponding to blood velocity distribution, are estimated through the model fitting. Subvoxel accuracy vessel representation, robustness to noise and image inhomogeneity are of primary concern. The algorithm is applied to 3D synthetic and real-life magnetic resonance images. It is demonstrated that the proposed method facilitates automated extraction of geometric vessel-tree models from images and outperforms the well-known Hessian vector approach in terms of accurate estimation of the centerline local direction in noisy images.

Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica – A Pilot Study

Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman’s rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p<0.01; d>0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s-1). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding.

Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naïve first-episode psychosis patients

BACKGROUND Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naïve individuals with first acute episode of psychosis (FEP). METHOD The study involved 27 drug-naïve FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T1-weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). RESULTS (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). CONCLUSION Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms.

Detection of multiple intracranial hemorrhages in a child with acute lymphocytic leukemia (ALL) by susceptibility weighted imaging (SWI).

Susceptibility weighted imaging (SWI) combines magnitude and phase information from a high-resolution, fully velocity compensated, three-dimensional (3D) gradient echo sequence. We report on the use of this MRI technique in a young patient with acute lymphocytic leukemia (ALL) and demonstrate a higher detection rate of hemorrhagic lesion in comparison with other T2*-weighted sequences.

F9. ALTERATIONS OF NEURONAL METABOLISM IN PATIENT SUBGROUPS AT ULTRA-HIGH RISK FOR PSYCHOSIS ACCORDING TO PACE CRITERIA – A 1H/31P-MR-SPECTROSCOPY STUDY

Abstract Background Glutamatergic dysfunction, deregulated mitochondrial metabolism and alterations of membrane phospholipids have been extensively investigated in schizophrenic illness by using in vivo magnetic resonance spectroscopy (MRS). Findings in the ultra-high risk (UHR) phase of psychotic illness, however, are still rare and inconsistent. Combining both 1H- and 31P-MRS, this study investigates these aspects in the different UHR patient subgroups as defined by PACE (Personal Assessment and Crisis Evaluation) criteria. Methods We applied 3 T chemical shift imaging (3D 31P-MRS, 2D 1H-MRS) and hippocampal single-voxel MRS in 69 neuroleptic-naïve UHR patients (age: 26.2 ± 6.2y; males 59.4% 41/69, attenuated symptoms (AS) n=50, BLIPS n=5, genetic risk (GR) n=8, AS+GR n=6; transition rate 17.2%, all transitions in the AS or BLIPS group) and 61 healthy controls (age: 25.2 ± 4.8y; males 54.1% 33/61). 11 metabolite markers were investigated (neuronal/mitochondrial metabolism: glutamate (Glu), N-acetyl-aspartate (NAA), phosphocreatine (PCr), and adenosine triphosphate (ATP); phospholipid synthesis: phosphomonoester/-metabolites (PME, Peth, Pch); phospholipids breakdown: phosphodiester/-metabolites (PDE, Gpeth, Gpch); astrocyte activation: myo-Inositol (mI)) in 5 brain regions (dorsolateral prefrontal cortex, DLPFC; dorsomedial prefrontal cortex, DMPFC; dorsal anterior cingulate cortex, dACC; mediodorsal thalamus, Th; and hipoocampus, Hip). Psychopathology was assessed using the CAARMS-Interview as well as PANSS, BPRS-E and SCL-90-R ratings. Statistical analysis included multi-and univariate ANOVA, Kruskal-Wallis-tests and correlation analysis. Results (i) In all UHR individuals (and also in the AS and BLIPS subgroup), NAA was reduced in the left Th. There was no alteration of Glu. While PCr was increased in the left DLPFC, left dACC (right trend) and in the right Hip, ATP was not different from controls. PME were decreased in the right Hip, PDE did not differ from controls. mI was found increased in the left Hip. (ii) In the GR subgroup PCr was increased in the bilateral Th. The PME metabolite Peth was decreased in the right Th. PDE were increased in the left dACC. mI was increased in the left Th. Discussion While the observed pattern of metabolite abnormalities in the AS and BLIPS risk group suggests a pathology that affects the left thalamus (NAA decrease), left DLPFC, dACC and bilateral Hip (left: PCr increase, PME decrease; right mI increase), the pathology of the GR group appears more focussed on the bilateral Th (bil. PCr increase, right PME decrease, left mI increase) and left dACC (PDE increase). The results suggest a functional disturbance of networks including the left DLPFC, dACC, bilateral Hip and Th, whereby the latter might be more an expression of a genetic risk profile.

T23. DYNAMICS OF NEURONAL METABOLISM AFTER THE ACUTE ONSET OF PSYCHOSIS – A TWO YEARS FOLLOW-UP 1H/31P-MR-SPECTROSCOPY STUDY IN NEUROLEPTIC NAïVE UHR TRANSITION PATIENTS

Abstract Background Glutamatergic dysfunction, deregulated mitochondrial metabolism and alterations of membrane phospholipids are considered as core pathology of psychosis, and have been studied in schizophrenic illness using magnetic resonance spectroscopy (MRS). Combining 1H- and 31P-MRS, this study investigates these aspects in Ultra-high risk (UHR-T) patients right after transition to psychosis (T0) and after a two years interval (T1) in a naturalistic longitudinal design, including treatment as usual by cognitive-behavioral therapy (CBT) and pharmacotherapy with second generation antipsychotics. Methods We applied 3 T chemical shift imaging (3D 31P-MRS, 2D 1H-MRS) and hippocampal single-voxel 1H-MRS in 29 neuroleptic-naïve UHR-T patients and 27 healthy controls matched for age and gender. Glutamate (Glu) and N-acetyl-aspartate (NAA) reflect neuronal functioning, phosphocreatine (PCr), adenosine triphosphate (ATP) and NAA indicate mitochondrial function and energy metabolism, and phosphomono- and diester indicate the balance of phospholipid synthesis (PME) and -breakdown (PDE). Psychopathology was assessed using the CAARMS, BPRS-E and SCL-90-R. Generalized linear mixed models were used to examine case-control differences in metabolite changes over time, and associations with clinical improvement. Results At T0, cross-sectional analysis revealed decreased NAA, Glu and PME levels in the left dorsolateral prefrontal cortex (DLPFC) and thalamus of UHR-T patients as well as higher PCr and lower PDE levels in the right hippocampus. (ii) Follow-up analysis (T1) showed in patients a significant increase of Glu in the bilateral DLPFC and the right thalamus, while a decrease of PCr was observed in the right hippocampus. Discussion The observed metabolite pattern at T0 likely reflects a hypofunction of glutamatergic neurons and a disturbance of membrane phospholipid turnover in fronto-thalamo-hippocampal networks during the first acute onset phase of psychotic illness. The pattern of changes at T1 is suggestive for an improvement of neuronal functioning in these networks that is caused by therapy, and presumably underlies the observed clinical improvement in terms of negative symptoms and cognitive impairment.