Matthias J. Koepp

Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe

Probabilistic atlases of neuroanatomy are more representative of population anatomy than single brain atlases. They allow anatomical labeling of the results of group studies in stereotaxic space, automated anatomical labeling of individual brain imaging datasets, and the statistical assessment of normal ranges for structure volumes and extents. No such manually constructed atlas is currently available for the frequently studied group of young adults. We studied 20 normal subjects (10 women, median age 31 years) with high‐resolution magnetic resonance imaging (MRI) scanning. Images were nonuniformity corrected and reoriented along both the anterior‐posterior commissure (AC–PC) line horizontally and the midsagittal plane sagittally. Building on our previous work, we have expanded and refined existing algorithms for the subdivision of MRI datasets into anatomical structures. The resulting algorithm is presented in the Appendix . Forty‐nine structures were interactively defined as three‐dimensional volumes‐of‐interest (VOIs). The resulting 20 individual atlases were spatially transformed (normalized) into standard stereotaxic space, using SPM99 software and the MNI/ICBM 152 template. We evaluated volume data for all structures both in native space and after spatial normalization, and used the normalized superimposed atlases to create a maximum probability map in stereotaxic space, which retains quantitative information regarding inter‐subject variability. Its potential applications range from the automatic labeling of new scans to the detection of anatomical abnormalities in patients. Further data can be extracted from the atlas for the detailed analysis of individual structures. Hum. Brain Mapping 19:224–247,2003. ©2003 Wiley‐Liss,Inc.

Voxel-by-Voxel Comparison of Automatically Segmented Cerebral Gray Matter—A Rater-Independent Comparison of Structural MRI in Patients with Epilepsy

Quantitative evaluation of MRI in patients with epilepsy can give more information than qualitative assessment. Previously developed volume-of-interest-based methods identified subtle widespread structural changes in the neocortex beyond the visualized lesions in patients with malformations of cortical development (MCD) and hippocampal sclerosis (HS) and also in MRI-negative patients with juvenile myoclonic epilepsy (JME). This study evaluates a voxel-based automated analysis of structural MRI in epilepsy. After fully automated segmentation of cerebral gray matter from structural T1-weighted, high-resolution MRI scans, we applied the automated and objective technique of statistical parametric mapping (SPM) to the analysis of gray matter of 35 control subjects, 10 patients with partial seizures and MCD, 10 patients with left temporal lobe epilepsy (TLE) and HS, 10 patients with left TLE and normal MR quantitation of the hippocampus, and 20 patients with JME. At a corrected threshold of P < 0.05, significant abnormalities were found in 3/35 controls; in all 10 patients with MCD, 6 of whom had additional lesions beyond the margins of the visualized abnormalities; in 2/10 TLE patients with HS; in 2/10 MRI-negative TLE; and in 4/20 JME patients. Group comparisons between control subjects and HS patients identified the affected left temporal lobe with an increase in gray matter in the posterior temporal lobe, but did not identify hippocampal atrophy. The group of MRI-negative TLE patients showed no abnormalities compared with control subjects. Group comparison between control subjects and JME patients identified a mesial frontal increase in gray matter. The SPM-based voxel-by-voxel comparison of gray matter distribution identified MCD and abnormalities beyond the visualized lesion in individual MCD patients. The method did not reliably identify HS in individual patients or identify abnormalities in individual MRI-negative patients with TLE or JME in a proportion larger than the chance findings in the control group. Using group comparisons, structural abnormalities in the neocortical gray matter of patients with TLE and HS were lateralized to the affected temporal lobe. In patients with JME as a group, an increase in gray matter was localized to the mesial frontal area, corroborating earlier quantitative MRI findings.

Volumes, spatial extents and a probabilistic atlas of the human basal ganglia and thalamus.

The basal ganglia and thalamus are involved in processing all physiological behaviors and affected by many diseases. Accurate localization is a crucial issue in neuroimaging, particularly when working with groups of normalized images in a standard stereotaxic space. Here, manual delineation of the central structures (thalamus; nucleus caudatus and accumbens; putamen, pallidum, substantia nigra) was performed on 30 high resolution MRIs of healthy young adults (15 female, median age 31 years) in native space. Protocol inter-rater reliabilities were quantified as structure overlap (similarity indices, SIs). Structural volumes were calculated in native space, and after spatial normalization to stereotaxic space (MNI/ICBM152) and in relation to hemispheric volumes. Spatial extents relative to the anterior commissure (AC) were extracted. The 30 resulting atlases were then used to create probabilistic maps in stereotaxic space. Inter-rater SIs were high at 0.85-0.92 except for the nucleus accumbens. In native space, caudate, nucleus accumbens and putamen were significantly larger on the left, and the globus pallidus larger in males. After normalizing for brain volume, the nucleus accumbens, putamen and thalamus were larger on the left, with the gender difference in the globus pallidus still detectable. Some of these volume differences translated into significantly different distances from the AC. The probabilistic maps showed that overall the central structures boundaries are relatively unchanged after spatial normalization. We present a comprehensive assessment of thalamic and basal ganglia volumetric and geometric data in both native and stereotaxic spaces. Probabilistic maps in MNI/ICBM152 space will allow accurate localization in group analyses.

Focal cortical release of endogenous opioids during reading induced seizures

BACKGROUNDnStudies in animals implicate endogenous release of opioid peptides as a mechanism for terminating partial and generalised seizures. To localise dynamic changes in opioid neurotransmission associated with partial seizures and higher cognitive function, we investigated the release of endogenous opioids in patients with reading-induced seizures compared with healthy controls.nnnMETHODSnFive patients who had reading epilepsy and six controls had 11C-diprenorphine (DPN) positron-emission-tomography (PET) scans while reading a string of symbols (baseline) or a scientific paper (activation). Statistical parametric mapping was used to find areas with differences in opioid-receptor binding.nnnFINDINGSnOn activation scans mean 11C-DPN binding to opioid receptors was significantly lower (p<0.05 corrected for multiple non-independent comparisons) in the left parieto-temporo-occipital cortex (Brodmann area 37) in reading-epilepsy patients compared with controls.nnnINTERPRETATIONnThese findings suggest that opioid-like substances are involved in the termination of reading-induced seizures.

Automatic detection and quantification of hippocampal atrophy on MRI in temporal lobe epilepsy: A proof-of-principle study

In temporal lobe epilepsy (TLE), hippocampal atrophy (HA) is a marker of poor prognosis regarding seizure remission, but predicts success of anterior temporal lobe resection. Manual quantification of HA on MRI is time-consuming and limited by investigator availability. Normal ranges of hippocampal volumes, both in absolute terms and relative to intracranial volume, and of hippocampal asymmetry were defined using an automatic label propagation and decision fusion technique based on thirty manually derived atlases of healthy controls. Manual test-retest reliability and overlaps of automatically and manually determined hippocampal volumes were quantified with similarity indices (SIs). Correct clinical identification of ipsilateral HA, and contralaterally normal hippocampal volumes, was determined in nine patients with histologically confirmed hippocampal sclerosis in terms of volumes and asymmetry indices (AIs) for standard statistical thresholds and with receiver operating characteristic (ROC) analysis. Manual test-retest reliability was very high, with SIs between 0.87 and 0.90. Manual and automatic hippocampus labels overlapped with a SI of 0.83 on the unaffected but with 0.76 on the atrophic side. Accuracy was higher for less atrophic hippocampi. The automatic method correctly identified 6/9 HAs in terms of absolute volume, 7/9 in terms of relative volume at a standard 2 SD threshold, and 9/9 for AIs. ROC-determined thresholds allowed clinically desirable correct identification of all HAs (100% sensitivity) with 85-100% specificity for volumes, and 100% specificity for AIs. The method has the potential to automatically detect unilateral HA, but further work is needed to determine its performance in detecting clinically important bilateral disease.

Central Benzodiazepine/γ‐Aminobutyric AcidA Receptors in Idiopathic Generalized Epilepsy: An [11C]Flumazenil Positron Emission Tomography Study

Summary: Purpose: Previous [11C]flumazenil (FMZ) positron emission tomography (PET) investigations in patients with idiopathic generalized epilepsy (IGE) have demonstrated nonsignificant global cortical decreases in central benzodiazepine γ‐aminobutyric acid, (GABAA) receptor (cBZR) binding or focal decreases in the thalamus and increases in the cerebellar nuclei with no changes in cerebral cortex. We previously reported lower [11C]FMZ binding in cerebral cortex of IGE patients treated with valproate (VPA) than in cerebral cortex of controls. We now report high‐resolution three‐dimensional [11C]FMZ PET studies in a larger number of subjects using an improved method to detect differences in cBZR between IGE patients and controls and a more powerful longitudinal design to determine the functional effect of VPA.

Statistical neuroanatomy of the human inferior frontal gyrus and probabilistic atlas in a standard stereotaxic space

We manually defined the inferior frontal gyrus (IFG) on high‐resolution MRIs in native space in 30 healthy subjects (15 female, median age 31 years; 15 male, median age 30 years), resulting in 30 individual atlases. Using standard software (SPM99), these were spatially transformed to a widely used stereotaxic space (MNI/ICBM 152) to create probabilistic maps. In native space, the total IFG volume was on average 5%, and the gray matter (GM) portion 12% larger in women (not significant). Expressed as a percentage of ipsilateral frontal lobe volume (i.e., correcting for brain size), the IFG was an average of 20%, and the GM portion of the IFG 27%, larger in women (P < 0.005). Correcting for total lobar volume yielded the same result. No asymmetry was found in IFG volumes. There were significant positional differences between the right and left IFGs, with the right IFG being further lateral in both native and stereotaxic space. Variability was similar on the left and right, but more pronounced anteriorly and superiorly. We show differences in IFG volume, composition, and position between sexes and between hemispheres. Applications include probabilistic determination of location in group studies, automatic labeling of new scans, and detection of anatomical abnormalities in patients. Hum Brain Mapp, 2007.

Balancing bias, reliability, noise properties and the need for parametric maps in quantitative ligand PET: [11C]diprenorphine test–retest data

[(11)C]diprenorphine (DPN) is a non-subtype selective opioid receptor PET ligand with slow kinetics and no region devoid of specific binding. Parametric maps are desirable but have to overcome high noise at the voxel level. We obtained parameter values, parametric map image quality, test-retest reproducibility and reliability (using intraclass correlation coefficients (ICCs)) for conventional spectral analysis and a derived method (rank shaping), compared them with values obtained through sampling of volumes of interest (VOIs) on the dynamic data sets and tested whether smaller amounts of radioactivity injected maintained reliability. Ten subjects were injected twice with either approximately 185 MBq or approximately 135 MBq of [(11)C]DPN, followed by dynamic PET for 90 min. Data were movement corrected with a frame-to-frame co-registration method. Arterial plasma input functions corrected for radiolabelled metabolites were created. There was no overall effect of movement correction except for one subject with substantial movement whose test-retest differences decreased by approximately 50%. Actual parametric values depended heavily on the cutoff for slow frequencies (between 0.0008 s(-1) and 0.00063 s(-1)). Image quality was satisfactory for restricted base ranges when using conventional spectral analysis. The rank shaping method allowed maximising of this range but had similar bias. VOI-based methods had the widest dynamic range between regions. Average percentage test-retest differences were smallest for the parametric maps with restricted base ranges; similarly ICCs were highest for these (up to 0.86) but unacceptably low for VOI-derived VD estimates at the low doses of injected radioactivity (0.24/0.04). Our data can inform the choice of methodology for a given biological problem.

Absolute PET Quantification with Correction for Partial Volume Effects within Cerebral Structures

The accurate quantification of positron emission tomography (PET) data is limited by partial volume effects (PVE), which depend on the size of the structure studied in relation to the spatial resolution and which may lead to over- or underestimation of the true tissue tracer concentration. This study describes a new approach to measure accurately the true tracer activity within multiple volumes of interest (VOI) of any size and shape. This approach to PVE correction is based on (1) segmenting magnetic resonance (MR) images into anatomical probabilistic maps of cerebrospinal fluid and white and gray matter, with further subdivision into multiple VOIs; (2) convolving each segmented probabilistic MR map with a PET point spread function; and (3) solving the resultant linear set of equations, Ax = b, where b is the PET image, A contains all the convolved MR VOI images, and x contains the unknown tracer concentrations to be estimated. The solution is obtained using a linear least-squares (LLS) approach giving simultaneous estimates of all parameters corrected for PVE, without restriction on the number of VOIs. The method and the algorithm were validated with computer simulations and an anthropomorphic phantom model. The LLS method was applied to human [11C]flumazenil (FMZ) PET studies of two patients with temporal lobe epilepsy and histologically verified unilateral hippocampal sclerosis. After PVE correction, the in vivo measurement of reduced FMZ volume of distribution within the hippocampus corresponded to the ex vivo, autoradiographically determined reduction of FMZ receptor availability. This PVE correction method allows accurate PET quantification in multiple small cerebral structures and has been directly validated with independent autoradiographic data.

Periventricular white matter flumazenil binding and postoperative outcome in hippocampal sclerosis

Summary:u2002 Purpose: In patients with hippocampal sclerosis (HS), anterior temporal lobe resection offers the possibility of a long‐lasting suppression of seizures in two thirds of patients. White matter (WM) [11C]flumazenil volume of distribution (FMZ‐Vd) reflects the number of neuronal cell bodies in WM. Our objective was to correlate WM FMZ‐Vd in patients with unilateral HS and postsurgical outcome.