Hans-Jürgen Huppertz

A voxel-based morphometric MRI study in female patients with borderline personality disorder

Subtle prefrontal and limbic structural abnormalities have been reported in borderline personality disorder (BPD). In order to further validate the previously reported findings and to more precisely describe the nature of the structural change we performed a voxel-based morphometric (VBM) study in patients with BPD. Twenty female patients with BPD and 21 female healthy controls were investigated. High-resolution 3-D datasets were acquired and analyzed following an optimized protocol of VBM in the framework of statistical parametric mapping (SPM99). Gray matter volume loss was found in the left amygdala. No other differences in gray or white matter volume or density were found anywhere else in the brain. Our findings support the hypothesis that temporolimbic abnormalities play a role in the pathophysiology of BPD. Prefrontal structural alterations in BPD were not observed in this study.

Enhanced visualization of blurred gray–white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis

PURPOSE Focal cortical dysplasia (FCD), a frequent cause of partial epilepsy, is often associated with blurring of the gray-white matter junction in magnetic resonance images (MRI). To improve the recognition and delineation of FCD we developed a novel voxel-based image post-processing method for enhanced visualization of blurred gray-white matter junctions. METHODS Using standard algorithms of statistical parametric mapping software (SPM99) a T1-weighted MRI volume data set is normalized and segmented. The distribution of gray and white matter is analyzed on a voxelwise basis and compared with a normal database. Based on this analysis, a three-dimensional feature map is created which highlights brain areas with blurred gray-white matter transition. This method was applied to the MRI data of 25 epilepsy patients with histologically proven FCD. RESULTS In 18/25 patients the new feature maps clearly showed that the dysplastic lesions were accompanied by blurring of the gray-white matter junction. Combined with a formerly published method of voxel-based 3D MRI analysis, 21/25 FCD lesions were shown to be associated with either blurring or abnormal extension of gray matter beyond the normal cortical ribbon, including four cases with lesions not or incompletely recognized on conventional MRI. CONCLUSIONS The MRI post-processing presented here improves the visualization of FCD and may increase the diagnostic yield of MRI. Thereby, it provides a valuable additional diagnostic tool in the presurgical evaluation of epilepsy patients.

Global brain atrophy and corticospinal tract alterations in ALS, as investigated by voxel‐based morphometry of 3‐D MRI

In ALS, advanced magnetic resonance imaging (MRI) techniques are increasingly used to investigate the underlying pathology. In this study, the technique of voxel‐based morphometry (VBM) was applied to 3‐D MRI data in ALS patients to localize regional grey and white matter changes. Twenty‐two ALS patients (mean age 58±9 years) with clinically definite ALS by revised El Escorial criteria were studied. None of the patients had any signs of associated frontotemporal dementia. High‐resolution 3‐D MRI data sets of the whole brain, collected on a 1.5 T scanner, were analysed by statistical parametric mapping (SPM) and VBM in comparison to an age‐matched normal data base consisting of 22 healthy volunteers (mean age 59±11 years), for grey matter and white matter segments separately. Global brain atrophy was assessed by calculation of brain parenchymal fractions (BPF). In ALS patients, BPF were significantly reduced compared to controls (p = 0.0003), indicating global brain atrophy. Regional decreases of grey matter density were found in the ALS patients at corrected p<0.01 in the right‐hemispheric primary motor cortex (area of the highest Z‐score) and in the left medial frontal gyrus. Furthermore, regional white matter alterations were observed along the corticospinal tracts bilaterally and in multiple smaller areas including corpus callosum, cerebellum, frontal and occipital subcortical regions. Besides considerable global atrophy in ALS, the topography of ALS‐associated cerebral morphological changes could be mapped using VBM, in particular white matter signal changes along the bilateral corticospinal tracts, but also in extra‐motor areas. VBM might be a potential tool to visualize disease progression in future longitudinal studies.

Automated detection of gray matter malformations using optimized voxel-based morphometry: a systematic approach.

Malformations of cortical development (MCD) are a recognized cause of epilepsy. Their special significance lies in the fact that, once detected and delineated, they are amenable to surgical removal. However, diagnosis from high-resolution MRI is still difficult, time-consuming, and highly dependent on individual expertise. We have recently proposed a simple procedure to detect cortical dysplasias, using automated procedures available within SPM99 (Wellcome Department, University College London, UK). Here, we aimed to systematically determine the best combination of processing parameters, using an optimized voxel-based morphometry approach. We included 20 patients with a known MCD and compared them to a normal database of 53 healthy, age- and gender-matched controls. The approaches taken during spatial normalization and a number of other parameters were systematically altered in order to find the best combination of parameters. Overall, 99 different approaches were evaluated in different ways. As far as possible, automatic processing and evaluation steps were used. With the number of candidate regions for MCD limited to five per patient, the best approaches resulted in the correct identification of up to 16 of 20 malformations. However, a number of approaches failed to perform well. The reasons for these failures and the implications this has for other studies are discussed. We conclude that voxel-based morphometry is able to detect cortical malformations with a high degree of accuracy. However, specific problems seem to arise when using an optimized protocol for voxel-based morphometry, indicating that this protocol may not be optimal for all voxel-based studies on brain morphology. Our approach, involving systematic alterations of parameters and evaluation, may be useful for other studies.

Morphometric MRI analysis improves detection of focal cortical dysplasia type II

Focal cortical dysplasias type II (FCD II) are highly epileptogenic lesions frequently causing pharmacoresistant epilepsy. Detection of these lesions on MRI is still challenging as FCDs may be very subtle in appearance and might escape conventional visual analysis. Morphometric MRI analysis is a voxel-based post-processing method based on algorithms of the statistical parametric mapping software (SPM5). It creates three dimensional feature maps highlighting brain areas with blurred grey-white matter junction and abnormal gyration, and thereby may help to detect FCD. In this study, we evaluated the potential diagnostic value of morphometric analysis as implemented in a morphometric analysis programme, compared with conventional visual analysis by an experienced neuroradiologist in 91 patients with histologically proven FCD II operated on at the University Hospital of Bonn between 2000 and 2010 (FCD IIa, n = 17; IIb, n = 74). All preoperative MRI scans were evaluated independently (i) based on conventional visual analysis by an experienced neuroradiologist and (ii) using morphometric analysis. Both evaluators had the same clinical information (electroencephalography and semiology), but were blinded to each others results. The detection rate of FCD using morphometric analysis was superior to conventional visual analysis in the FCD IIa subgroup (82% versus 65%), while no difference was found in the FCD IIb subgroup (92% versus 91%). However, the combination of conventional visual analysis and morphometric analysis provided complementary information and detected 89 out of all 91 FCDs (98%). The combination was significantly superior to conventional visual analysis alone in both subgroups resulting in a higher diagnostic sensitivity (94% versus 65%, P = 0.031 for FCD IIa; 99% versus 91%, P = 0.016 for FCD IIb). In conclusion, the additional application of morphometric MRI analysis increases the diagnostic sensitivity for FCD II in comparison with conventional visual analysis alone. Since detection of FCDs on MRI during the presurgical evaluation markedly improves the chance of becoming seizure free postoperatively, we apply morphometric analysis in all patients who are MRI-negative after conventional visual analysis at our centre.

Detection and Localization of Focal Cortical Dysplasia by Voxel-based 3-D MRI Analysis

Summary:  Purpose: Focal cortical dysplasia (FCD) is a frequent cause of partial epilepsy. Its diagnosis by visual evaluation of magnetic resonance images (MRIs) remains difficult. The purpose of this study was to apply a novel automated and observer‐independent voxel‐based technique for the analysis of 3‐dimensional (3‐D) MRI to detect and localize FCD.

Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial.

It is believed that glycogen synthase kinase‐3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase‐3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double‐blind, placebo‐controlled trial in patients with mild‐to‐moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52‐week MRI. Automated, observer‐independent, atlas‐based, and mask‐based volumetry was done on high‐resolution, T1‐weighted, three‐dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: −1.3% ± 1.4% vs. −3.1% ± 2.3%, respectively), cerebrum (−1.3% ± 1.5% vs. −3.2% ± 2.1%, respectively), parietal lobe (−1.6% ± 1.9% vs. −4.1% ± 3.0%, respectively), and occipital lobe (−0.3% ± 1.8% vs. −2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.

Intra- and interscanner variability of automated voxel-based volumetry based on a 3D probabilistic atlas of human cerebral structures

The intra- and inter-scanner variability of an automated method for MRI-based volumetry was investigated. Using SPM5 algorithms and predefined masks derived from a probabilistic whole-brain atlas, this method allows to determine the volumes of various brain structures (e.g., hemispheres, lobes, cerebellum, basal ganglia, grey and white matter etc.) in single subjects in an observer-independent fashion. A healthy volunteer was scanned three times at six different MRI scanners (including different vendors and field strengths) to calculate intra- and inter-scanner volumetric coefficients of variation (CV). The mean intra-scanner CV values per brain structure ranged from 0.50% to 4.4% (median, 0.89%), while the inter-scanner CV results varied between 0.66% and 14.7% (median, 4.74%). The overall (=combined intra- and inter-scanner) variability of measurements was only marginally higher, with CV results of 0.87-15.1% (median, 4.80%). Furthermore, the minimum percentage volume difference for detecting a significant volume change between two volume measurements in the same subject was calculated for each substructure. For example, for the total brain volume, mean intra-scanner, inter-scanner, and overall CV results were 0.50%, 3.78%, and 3.80%, respectively, and the cut-offs for significant volume changes between two measurements in the same subject amounted to 1.4% for measurements on the same scanner and 10.5% on different scanners. These findings may be useful for planning and assessing volumetric studies in neurological diseases, for the differentiation of certain patterns of atrophy, or for longitudinal studies monitoring the course of a disease and potential therapeutic effects.

Myoclonus in Epilepsy Patients with Anticonvulsive Add-On Therapy with Pregabalin

Summary:  Purpose: To report on the occurrence of myoclonus in patients receiving pregabalin (PGB) for the treatment of focal epilepsy.

Localization of Interictal Delta and Epileptiform EEG Activity Associated with Focal Epileptogenic Brain Lesions

The present study was aimed at investigating the accuracy of electric source reconstruction in the presurgical evaluation of epilepsy patients. Spontaneous EEG activity of 14 patients with focal intracerebral epileptogenic lesions was analyzed by source reconstruction based on high-resolution EEG (64-channel system) and a boundary element method head model accounting for the individual head anatomy. Equivalent dipole modeling was applied to focal delta and interictal epileptiform activity. The localization results were validated quantitatively by comparison with the sites of the structural lesions. In 6 of 9 patients with focal delta activity, the maximum of dipole concentration was closer than 10 mm to the nearest lesion margin and mostly at the border or within pathologically altered cortical tissue. In all 11 patients showing interictal epileptiform activity, the localization results were found in the same lobe as the lesion. In almost half of them, they were closer than 10 mm to the lesion margin. Patients with larger distances (22-36 mm) mostly had hippocampal atrophy or sclerosis. Their dipole locations did not appear in the affected hippocampus, but in the adjacent temporal neocortex. In conclusion, electric source reconstruction applied to both abnormal slow and interictal epileptiform EEG activity seems to be a valuable additional noninvasive component in the multimodal presurgical evaluation of epilepsy patients.