Thalamotemporal impairment in temporal lobe epilepsy: A combined MRI analysis of structure, integrity and connectivity

Objective Thalamic abnormality in temporal lobe epilepsy (TLE ) is well known from imaging studies, but evidence is lacking regarding connectivity profiles of the thalamus and their involvement in the disease process. We used a novel multisequence magnetic resonance imaging (MRI ) protocol to elucidate the relationship between mesial temporal and thalamic pathology in TLE . Methods For 23 patients with TLE and 23 healthy controls, we performed T 1‐weighted (for analysis of tissue structure), diffusion tensor imaging (tissue connectivity), and T 1 and T 2 relaxation (tissue integrity) MRI across the whole brain. We used connectivity‐based segmentation to determine connectivity patterns of thalamus to ipsilateral cortical regions (occipital, parietal, prefrontal, postcentral, precentral, and temporal). We subsequently determined volumes, mean tractography streamlines, and mean T 1 and T 2 relaxometry values for each thalamic segment preferentially connecting to a given cortical region, and of the hippocampus and entorhinal cortex. Results As expected, patients had significant volume reduction and increased T 2 relaxation time in ipsilateral hippocampus and entorhinal cortex. There was bilateral volume loss, mean streamline reduction, and T 2 increase of the thalamic segment preferentially connected to temporal lobe, corresponding to anterior, dorsomedial, and pulvinar thalamic regions, with no evidence of significant change in any other thalamic segments. Left and right thalamotemporal segment volume and T 2 were significantly correlated with volume and T 2 of ipsilateral (epileptogenic), but not contralateral (nonepileptogenic), mesial temporal structures. Significance These convergent and robust data indicate that thalamic abnormality in TLE is restricted to the area of the thalamus that is preferentially connected to the epileptogenic temporal lobe. The degree of thalamic pathology is related to the extent of mesial temporal lobe damage in TLE

Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study.

We investigated gray and white matter morphology in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE+HS) and first-degree asymptomatic relatives of patients with mTLE+HS. Using T1-weighted magnetic resonance imaging (MRI), we sought to replicate previously reported findings of structural surface abnormalities of the anterior temporal lobe in asymptomatic relatives of patients with mTLE+HS in an independent cohort. We performed whole-brain MRI in 19 patients with mTLE+HS, 14 first-degree asymptomatic relatives of mTLE+HS patients, and 32 healthy control participants. Structural alterations in patients and relatives compared to controls were assessed using automated hippocampal volumetry and cortical surface-based morphometry. We replicated previously reported cortical surface area contractions in the ipsilateral anterior temporal lobe in both patients and relatives compared to healthy controls, with asymptomatic relatives showing similar but less extensive changes than patients. These findings suggest morphologic abnormality in asymptomatic relatives of mTLE+HS patients, suggesting an inherited brain structure endophenotype

Heritability of alpha and sensorimotor network changes in temporal lobe epilepsy.

OBJECTIVE: Electroencephalography (EEG) features in the alpha band have been shown to differ between people with epilepsy and healthy controls. Here, in a group of patients with mesial temporal lobe epilepsy (mTLE), we seek to confirm these EEG features, and using simultaneous functional magnetic resonance imaging, we investigate whether brain networks related to the alpha rhythm differ between patients and healthy controls. Additionally, we investigate whether alpha abnormalities are found as an inherited endophenotype in asymptomatic relatives. METHODS: We acquired scalp EEG and simultaneous EEG and functional magnetic resonance imaging in 24 unrelated patients with unilateral mTLE, 23 asymptomatic first-degree relatives of patients with mTLE, and 32 healthy controls. We compared peak alpha power and frequency from electroencephalographic data in patients and relatives to healthy controls. We identified brain networks associated with alpha oscillations and compared these networks in patients and relatives to healthy controls. RESULTS: Patients had significantly reduced peak alpha frequency (PAF) across all parietal and occipital electrodes. Asymptomatic relatives also had significantly reduced PAF over 14 of 17 parietal and occipital electrodes. Both patients and asymptomatic relatives showed a combination of increased activation and a failure of deactivation in relation to alpha oscillations compared to healthy controls in the sensorimotor network. INTERPRETATION: Genetic factors may contribute to the shift in PAF and alterations in brain networks related to alpha oscillations. These may not entirely be a consequence of anti-epileptic drugs, seizures or hippocampal sclerosis and deserve further investigation as mechanistic contributors to mTLE

You read my mind: fMRI markers of threatening appraisals in people with persistent psychotic experiences

Anomalous perceptual experiences are relatively common in the general population. Evidence indicates that the key to distinguishing individuals with persistent psychotic experiences (PEs) with a need for care from those without is how they appraise their anomalous experiences. Here, we aimed to characterise the neural circuits underlying threatening and non-threatening appraisals in people with and without a need for care for PEs, respectively. A total of 48 participants, consisting of patients with psychosis spectrum disorder (clinical group, n = 16), non-need-for-care participants with PEs (non-clinical group, n = 16), and no-PE healthy control participants (n = 16), underwent functional magnetic resonance imaging while completing the Telepath task, designed to induce an anomalous perceptual experience. Appraisals of the anomalous perceptual experiences were examined, as well as functional brain responses during this window, for significant group differences. We also examined whether activation co-varied with the subjective threat appraisals reported in-task by participants. The clinical group reported elevated subjective threat appraisals compared to both the non-clinical and no-PE control groups, with no differences between the two non-clinical groups. This pattern of results was accompanied by reduced activation in the superior and inferior frontal gyri in the clinical group as compared to the non-clinical and control groups. Precuneus activation scaled with threat appraisals reported in-task. Resilience in the context of persistent anomalous experiences may be explained by intact functioning of fronto-parietal regions, and may correspond to the ability to contextualise and flexibly evaluate psychotic experiences

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent‐driven equilibrium single‐pulse observation of T(1) and T(2) protocol to produce apparent proton density, T(1), T(2), myelin water, intracellular water, and free‐water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high‐resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High‐resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

Purpose: Validation of quantitative MR measuresfor myelin imaging in the postmortem multiple sclerosis spinal cord. Methods: Four fixed spinal cord samples were imaged first with a 3T clinical MR scannerto identify areas of interest forscanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1, T2, myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. Results: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. Conclusion: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFN beta -1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T-1-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFN beta -1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFN<beta>-1b (placebo 2.6%, IFN beta -1b, 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFN beta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFN beta -treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease

Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe epilepsy

Approximately one in every two patients with pharmacoresistant temporal lobe epilepsy will not be rendered completely seizure-free after temporal lobe surgery. The reasons for this are unknown and are likely to be multifactorial. Quantitative volumetric magnetic resonance imaging techniques have provided limited insight into the causes of persistent postoperative seizures in patients with temporal lobe epilepsy. The relationship between postoperative outcome and preoperative pathology of white matter tracts, which constitute crucial components of epileptogenic networks, is unknown. We investigated regional tissue characteristics of preoperative temporal lobe white matter tracts known to be important in the generation and propagation of temporal lobe seizures in temporal lobe epilepsy, using diffusion tensor imaging and automated fibre quantification. We studied 43 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis and 44 healthy controls. Patients underwent preoperative imaging, amygdalohippocampectomy and postoperative assessment using the International League Against Epilepsy seizure outcome scale. From preoperative imaging, the fimbria-fornix, parahippocampal white matter bundle and uncinate fasciculus were reconstructed, and scalar diffusion metrics were calculated along the length of each tract. Altogether, 51.2% of patients were rendered completely seizure-free and 48.8% continued to experience postoperative seizure symptoms. Relative to controls, both patient groups exhibited strong and significant diffusion abnormalities along the length of the uncinate bilaterally, the ipsilateral parahippocampal white matter bundle, and the ipsilateral fimbria-fornix in regions located within the medial temporal lobe. However, only patients with persistent postoperative seizures showed evidence of significant pathology of tract sections located in the ipsilateral dorsal fornix and in the contralateral parahippocampal white matter bundle. Using receiver operating characteristic curves, diffusion characteristics of these regions could classify individual patients according to outcome with 84% sensitivity and 89% specificity. Pathological changes in the dorsal fornix were beyond the margins of resection, and contralateral parahippocampal changes may suggest a bitemporal disorder in some patients. Furthermore, diffusion characteristics of the ipsilateral uncinate could classify patients from controls with a sensitivity of 98%; importantly, by co-registering the preoperative fibre maps to postoperative surgical lacuna maps, we observed that the extent of uncinate resection was significantly greater in patients who were rendered seizure-free, suggesting that a smaller resection of the uncinate may represent insufficient disconnection of an anterior temporal epileptogenic network. These results may have the potential to be developed into imaging prognostic markers of postoperative outcome and provide new insights for why some patients with temporal lobe epilepsy continue to experience postoperative seizures

PocketMatch: A new algorithm to compare binding sites in protein structures

Background: Recognizing similarities and deriving relationships among protein molecules is a fundamental&#xd;&#xa;requirement in present-day biology. Similarities can be present at various levels which can be detected through comparison of protein sequences or their structural folds. In some cases similarities obscure at these levels could be present merely in the substructures at their binding sites. Inferring functional similarities between protein molecules by comparing their binding sites is still largely exploratory and not as yet a routine protocol. One of&#xd;&#xa;the main reasons for this is the limitation in the choice of appropriate analytical tools that can compare binding sites with high sensitivity. To benefit from the enormous amount of structural data that is being rapidly accumulated, it is essential to have high throughput tools that enable large scale binding site comparison.&#xd;&#xa;&#xd;&#xa;Results: Here we present a new algorithm PocketMatch for comparison of binding sites in a frame invariant&#xd;&#xa;manner. Each binding site is represented by 90 lists of sorted distances capturing shape and chemical nature of the site. The sorted arrays are then aligned using an incremental alignment method and scored to obtain PMScores for pairs of sites. A comprehensive sensitivity analysis and an extensive validation of the algorithm have been carried out. Perturbation studies where the geometry of a given site was retained but the residue types were changed randomly, indicated that chance similarities were virtually non-existent. Our analysis also demonstrates that shape information alone is insufficient to discriminate between diverse binding sites, unless&#xd;&#xa;combined with chemical nature of amino acids.&#xd;&#xa;&#xd;&#xa;Conclusions: A new algorithm has been developed to compare binding sites in accurate, efficient and&#xd;&#xa;high-throughput manner. Though the representation used is conceptually simplistic, we demonstrate that along&#xd;&#xa;with the new alignment strategy used, it is sufficient to enable binding comparison with high sensitivity. Novel methodology has also been presented for validating the algorithm for accuracy and sensitivity with respect to geometry and chemical nature of the site. The method is also fast and takes about 1/250th second for one comparison on a single processor. A parallel version on BlueGene has also been implemented