Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Classification and Lateralization of Temporal Lobe Epilepsies with and without Hippocampal Atrophy Based on Whole-Brain Automatic MRI Segmentation

Brain images contain information suitable for automatically sorting subjects into categories such as healthy controls and patients. We sought to identify morphometric criteria for distinguishing controls (n = 28) from patients with unilateral temporal lobe epilepsy (TLE), 60 with and 20 without hippocampal atrophy (TLE-HA and TLE-N, respectively), and for determining the presumed side of seizure onset. The framework employs multi-atlas segmentation to estimate the volumes of 83 brain structures. A kernel-based separability criterion was then used to identify structures whose volumes discriminate between the groups. Next, we applied support vector machines (SVM) to the selected set for classification on the basis of volumes. We also computed pairwise similarities between all subjects and used spectral analysis to convert these into per-subject features. SVM was again applied to these feature data. After training on a subgroup, all TLE-HA patients were correctly distinguished from controls, achieving an accuracy of 96 ± 2% in both classification schemes. For TLE-N patients, the accuracy was 86 ± 2% based on structural volumes and 91 ± 3% using spectral analysis. Structures discriminating between patients and controls were mainly localized ipsilaterally to the presumed seizure focus. For the TLE-HA group, they were mainly in the temporal lobe; for the TLE-N group they included orbitofrontal regions, as well as the ipsilateral substantia nigra. Correct lateralization of the presumed seizure onset zone was achieved using hippocampi and parahippocampal gyri in all TLE-HA patients using either classification scheme; in the TLE-N patients, lateralization was accurate based on structural volumes in 86 ± 4%, and in 94 ± 4% with the spectral analysis approach. Unilateral TLE has imaging features that can be identified automatically, even when they are invisible to human experts. Such morphometric image features may serve as classification and lateralization criteria. The technique also detects unsuspected distinguishing features like the substantia nigra, warranting further study

Clinical application of neuroimaging in epilepsy

Objective: To evaluate the use of neuroimaging in clinical practice and to assess the prevalence of detected structural abnormalities in epilepsy patients in a clinical set up. Methods: 919 outpatients were identified and the scan results reviewed. A total of 677 patients had chronic active epilepsy (88 had idiopathic generalised epilepsy (IGE), 588 had localisation related epilepsy, one had symptomatic generalised epilepsy), 57 had a single epileptic seizure, 46 were in remission, and 139 had non-epileptic attacks. Results: 391 patients had no scan (53 patients in this group had IGE, 182 had localisation related epilepsy, one had generalised symptomatic epilepsy, 18 had single epileptic attacks, 21 were in remission, 116 had non-epileptic attacks). Altogether 528 patients had a scan, the results were not available in 33, 163 had x ray computed tomography (CT) only, 178 had standard magnetic resonance imaging (MRI) (slice thickness 5 mm), and 154 had high resolution MRI (including a T1 weighted sequence with 1.5 mm thick slices). Some 252 of 495 scans (51%) were abnormal. Abnormalities were hippocampal sclerosis (n=128), atrophy or non-specific white matter lesions (n=35), vascular abnormalities (n=27), tumours (n=25), brain damage (n=24), malformations of cortical development (n=13). Excluding atrophy and non-specific white matter lesions the prevalence of detected abnormalities was 54% in localisation related epilepsy, 18% in single seizure patients, 16% in epilepsy in remission, and 0% in IGE and non-epileptic attacks. Conclusions: Abnormalities were detected in more than half of all patients with localisation related epilepsy, and in about one in five patients with single seizures or epilepsy in remission. Many patients had no scan or only CT or standard MRI. The true prevalence of structural abnormalities may be have been higher. Scanning did not add any information in patients with IGE or non-epileptic attacks

Measurement of Hippocampal Volume Changes in Serial MRI Scans

We present a new method for the detection and measurement of volume changes in human hippocampi in serial Magnetic Resonance Imaging (MRI). The method follows a two-stage approach: (1) precise co-registration and intensity matching of the initial (baseline) and follow-up scan, and (2) refinement and segmentation propagation of the hippocampi outlines drawn in the baseline scan by an expert observer to the matched scan (co-registered and intensity matched follow-up scan of the time series). The first step is performed using MRreg, a rigid registration tool based on cross-correlation and intensity matching, and the second step makes use of the concept of active contour models for tracking the hippocampi outlines in the time series. Keywords: Segmentation, registration, hippocampus, active contour model, volume change, temporal lobe epilepsy, status epilepticus (SE) 1. INTRODUCTION Volume measurements of the hippocampus in MRI images are a highly specific test to reveal hippocampal scle..