Decoupling of functional and structural language networks in temporal lobe epilepsy

OBJECTIVE: To identify functional and structural alterations in language networks of people with temporal lobe epilepsy (TLE), who frequently present with naming and word-finding difficulties. METHODS: Fifty-five patients with unilateral TLE (29 left) and 16 controls were studied with auditory and picture naming functional magnetic resonance imaging (fMRI) tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain functional connectivity analyses (psychophysiological interaction). White matter language pathways were investigated using diffusion tensor imaging and neurite orientation dispersion and density imaging metrics extracted along fiber bundles starting from fMRI-guided seeds. Regression analyses were performed to investigate the correlation of functional connectivity with diffusion MRI metrics. RESULTS: In the whole group of patients and controls, weaker functional connectivity from the left posterobasal temporal lobe (1) to the bilateral anterior temporal lobe, precentral gyrus, and lingual gyrus during auditory naming and (2) to the bilateral occipital cortex and right fusiform gyrus during picture naming was associated with decreased neurite orientation dispersion and higher free water fraction of white matter tracts. Compared to controls, TLE patients exhibited fewer structural connections and an impaired coupling of functional and structural metrics. SIGNIFICANCE: TLE is associated with an impairment and decoupling of functional and structural language networks. White matter damage, as evidenced by diffusion abnormalities, may contribute to impaired functional connectivity and language dysfunction in TLE

ICN_Atlas: Automated description and quantification of functional MRI activation patterns in the framework of intrinsic connectivity networks.

Generally, the interpretation of functional MRI (fMRI) activation maps continues to rely on assessing their relationship to anatomical structures, mostly in a qualitative and often subjective way. Recently, the existence of persistent and stable brain networks of functional nature has been revealed; in particular these so-called intrinsic connectivity networks (ICNs) appear to link patterns of resting state and task-related state connectivity. These networks provide an opportunity of functionally-derived description and interpretation of fMRI maps, that may be especially important in cases where the maps are predominantly task-unrelated, such as studies of spontaneous brain activity e.g. in the case of seizure-related fMRI maps in epilepsy patients or sleep states. Here we present a new toolbox (ICN_Atlas) aimed at facilitating the interpretation of fMRI data in the context of ICN. More specifically, the new methodology was designed to describe fMRI maps in function-oriented, objective and quantitative way using a set of 15 metrics conceived to quantify the degree of 'engagement' of ICNs for any given fMRI-derived statistical map of interest. We demonstrate that the proposed framework provides a highly reliable quantification of fMRI activation maps using a publicly available longitudinal (test-retest) resting-state fMRI dataset. The utility of the ICN_Atlas is also illustrated on a parametric task-modulation fMRI dataset, and on a dataset of a patient who had repeated seizures during resting-state fMRI, confirmed on simultaneously recorded EEG. The proposed ICN_Atlas toolbox is freely available for download at http://icnatlas.com and at http://www.nitrc.org for researchers to use in their fMRI investigations

Naming fMRI predicts the effect of temporal lobe resection on language decline

Objective: To develop language functional MRI (fMRI) methods that accurately predict postsurgical naming decline in temporal lobe epilepsy (TLE). Methods: Forty‐six patients with TLE (25 left) and 19 controls underwent two overt fMRI paradigms (auditory naming and picture naming, both with active baseline conditions) and one covert task (verbal fluency). Clinical naming performance was assessed preoperatively and 4 months following anterior temporal lobe resection. Preoperative fMRI activations were correlated with postoperative naming decline. Individual laterality indices (LI) were calculated for temporal (auditory and picture naming) and frontal regions (verbal fluency) and were considered as predictors of naming decline in multiple regression models, along with other clinical variables (age at onset of seizures, preoperative naming scores, hippocampal volume, age). Results: In left TLE patients, activation of the left posterior inferior temporal gyrus during auditory naming and activation of left fusiform gyrus during picture naming were related to greater postoperative naming decline. Activation LI were the best individual predictors of naming decline in a multivariate regression model. For picture naming, an LI of higher than 0.34 gave 100% sensitivity and 92% specificity (positive predictive value (PPV) 91.6%). For auditory naming, a temporal lobe LI higher than 0.18 identified all patients with a clinically significant naming decline with 100% sensitivity and 58% specificity (PPV: 58.3%). No effect was seen for verbal fluency. Interpretation: Auditory and picture naming fMRI are clinically applicable to predict postoperative naming decline after left temporal lobe resection in individual patients, with picture naming being more specific

Impaired naming performance in temporal lobe epilepsy: language fMRI responses are modulated by disease characteristics.

OBJECTIVE: To investigate alterations of language networks and their relation to impaired naming performance in temporal lobe epilepsy (TLE) using functional MRI. METHODS: Seventy-two adult TLE patients (41 left) and 36 controls were studied with overt auditory and picture naming fMRI tasks to assess temporal lobe language areas, and a covert verbal fluency task to probe frontal lobe language regions. Correlation of fMRI activation with clinical naming scores, and alteration of language network patterns in relation to epilepsy duration, age at onset and seizure frequency, were investigated with whole-brain multiple regression analyses. RESULTS: Auditory and picture naming fMRI activated the left posterior temporal lobe, and stronger activation correlated with better clinical naming scores. Verbal fluency MRI mainly activated frontal lobe regions. In left and right TLE, a later age of epilepsy onset related to stronger temporal lobe activations, while earlier age of onset was associated with impaired deactivation of extratemporal regions. In left TLE patients, longer disease duration and higher seizure frequency were associated with reduced deactivation. Frontal lobe language networks were unaffected by disease characteristics. CONCLUSIONS: While frontal lobe language regions appear spared, temporal lobe language areas are susceptible to dysfunction and reorganisation, particularly in left TLE. Early onset and long duration of epilepsy, and high seizure frequency, were associated with compromised activation and deactivation patterns of task-associated regions, which might account for impaired naming performance in individuals with TLE

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

BACKGROUND: Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined. METHODS: We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n = 102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment. RESULTS: OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR = 2.09; P = 0.034; 95% CI: 1.06-4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR = 3.55; P = 0.002; 95% CI: 1.59-7.96) and TTP (HR = 2.97; P = 0.008; 95% CI: 1.33-6.67) compared with patients without CYP2D6 inhibitors. CONCLUSION: CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care. British Journal of Cancer (2010) 103, 765-771. doi:10.1038/sj.bjc.6605800 www.bjcancer.com Published online 10 August 2010 (C) 2010 Cancer Research U