fMRI assessment of language lateralization: an objective approach.

Language lateralization based on functional magnetic resonance imaging (fMRI) is often used in clinical neurological settings. Currently, interpretation of the distribution, pattern and extent of language activation can be heavily dependent on the chosen statistical threshold. The aim of the present study was to 1) test the robustness of adaptive thresholding of fMRI data to yield a fixed number of active voxels, and to 2) develop a largely threshold-independent method of assessing when individual patients have statistically atypical language lateralization. Simulated data and real fMRI data in 34 healthy controls and 4 selected epilepsy patients performing a verbal fluency language fMRI task were used. Dependence of laterality on the thresholding method is demonstrated for simulated and real data. Simulated data were used to test the hypothesis that thresholding based upon a fixed number of active voxels would yield a laterality index that was more stable across a range of signal strengths (study power) compared to thresholding at a fixed p value. This stability allowed development of a method comparing an individual to a group of controls across a wide range of thresholds, providing a robust indication of atypical lateralization that is more objective than conventional methods. Thirty healthy controls were used as normative data for the threshold-independent method, and the remaining subjects were used as illustrative examples. The method could also be used more generally to assess relative regional distribution of activity in other neuroimaging paradigms (for example, one could apply it to the assessment of lateralization of activation in a memory task, or to the assessment of anterior-posterior distribution rather than laterality).

A two-compartment gel phantom for optimization and quality assurance in clinical BOLD fMRI.

Clinical applications of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) depend heavily on robust paradigms, imaging methods and analysis procedures. In this work, as a means to optimize and perform quality assurance of the entire imaging and analysis chain, a phantom that provides a well known and reproducible signal change similar to a block type fMRI experiment is presented. It consists of two gel compartments with slightly different T2 that dynamically enter and leave the imaged volume. The homogeneous gel in combination with a cylindrical geometry results in a well-defined T*2 difference causing a signal difference between the two compartments in T*2-weighted MR images. From time series data obtained with the phantom, maps of percent signal change (PSC) and t-values are calculated. As an example of image parameter optimisation, the phantom is demonstrated to be useful for accurate determination of the influence of echo time (TE) on BOLD fMRI results, taking the t-value as a measure of sensitivity. In addition, the phantom is proposed as a tool for quality assurance (QA) since reproducible time series and t-maps are obtained in a series of independent repeat experiments. The phantom is relatively simple to build and can therefore be used by any clinical fMRI center.

Cortical sensory and motor response in a patient whose hand has been replanted: one-year follow up with functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) was used to study how a replanted hand regained its cortical territory parallel to recovery. The cortical response to sensory stimulation shifts from an ipsilateral to a bilateral pattern, and then to a predominantly contralateral activation. The cortical response to motor stimulation was normal from the first investigation.

Flexible statistical modelling detects clinical functional magnetic resonance imaging activation in partially compliant subjects.

Clinical functional magnetic resonance imaging (fMRI) occasionally fails to detect significant activation, often due to variability in task performance. The present study seeks to test whether a more flexible statistical analysis can better detect activation, by accounting for variance associated with variable compliance to the task over time. Experimental results and simulated data both confirm that even at 80% compliance to the task, such a flexible model outperforms standard statistical analysis when assessed using the extent of activation (experimental data), goodness of fit (experimental data), and area under the operator characteristic curve (simulated data). Furthermore, retrospective examination of 14 clinical fMRI examinations reveals that in patients where the standard statistical approach yields activation, there is a measurable gain in model performance in adopting the flexible statistical model, with little or no penalty in lost sensitivity. This indicates that a flexible model should be considered, particularly for clinical patients who may have difficulty complying fully with the study task.

Event-related fMRI of myoclonic jerks arising from dysplastic cortex.

BACKGROUND: Malformations of cortical development can cause epileptiform activity and myoclonic jerks, yet EEG correlates of jerks can be difficult to obtain. METHODS: We studied a woman who had frequent episodes of persistent right-foot jerking since childhood. Ictal and interictal EEG had shown no localizing epileptiform activity. Functional imaging experiments were performed with concurrent video monitoring to document the timing of foot jerks. These studies mapped brain regions controlling voluntary right- and left-foot movements, and spontaneous right-foot jerks. RESULTS: High-resolution structural MR imaging revealed a dysplastic gyrus extending anteriorly off the left central sulcus. Event-related analysis of spontaneous jerks revealed prominent activation of the left precentral gyrus (right-foot motor area), bilateral medial frontal regions (supplementary motor area), and the dysplastic gyrus. Hemodynamic response modeling to foot jerks revealed the hemodynamic response peaked earlier in the dysplastic cortex and SMA regions than in the foot area. DISCUSSION: Event-related fMRI in a patient with spontaneous and induced epileptic foot jerks revealed brain regions active during jerks. The results of this analysis allowed us to tailor subsequent intracerebral recordings. Analysis of the timing of the hemodynamic response showed certain brain regions with an earlier rise in BOLD signal, suggesting a possible initiating role, or different hemodynamic response functions. Hemodynamic response timing should be considered carefully when interpreting event-related studies of epileptiform activity.

Functional magnetic resonance imaging shows cortical activation on sensory stimulation of an osseointegrated prosthetic thumb.

Functional magnetic resonance imaging (fMRI) was used to study the cortical integration of an osseointegrated prosthetic thumb that had been attached to the amputee's hand 13 years ago. We found that tactile stimuli applied to the prosthesis activated the primary somatosensory cortex on both sides.

Functional connectivity networks are disrupted in left temporal lobe epilepsy.

OBJECTIVE: Functional connectivity maps the distributed network of brain regions fluctuating synchronously during a continuous brain state. This study sought to investigate whether patients with left temporal lobe epilepsy (TLE) differ from controls in their resting-state functional connectivity between typical language regions. METHODS: We studied 17 patients with left TLE, together with eight healthy controls, using seeded functional connectivity. Seed regions were defined using the regions of maximal activation and deactivation during a language functional magnetic resonance imaging (fMRI) task in a separate cohort of 30 controls. RESULTS: Language fMRI produced the expected activation pattern, which was not different between patients and controls. However, functional connectivity between language areas during rest was markedly different; whereas controls showed connectivity between each of the seed areas and the majority of the language areas, patients showed connectivity only with a few areas, particularly the seed area itself. This difference was significant in the direct comparison of patients and control connectivity maps. INTERPRETATION: We suggest that this reduced connectivity in left temporal lobe epilepsy may reflect a disturbance of the language network during resting state in patients and may be related to subtle language difficulties in this patient population.

Optimized clinical T2 relaxometry with a standard CPMG sequence.

PURPOSE: To optimize the accuracy and precision of T2 measurements using the standard Carr-Purcell-Meiboom-Gill (CPMG) sequence. T2 values obtained with this technique are normally sensitive to imperfect refocusing due to the formation of unwanted stimulated echoes. MATERIALS AND METHODS: Modifications are made to the refocusing slice selection width and the interleaving scheme. A widened refocusing slice improves the uniformity of the refocusing flip angle across the slice. A slow spin echo acquisition provided "gold standard" T2 values. Repeated T2 measurements in phantom and human studies are used to compare the accuracy and precision of the optimized and non-optimized CPMG implementations. RESULTS: The required slice thickness ratio between refocusing and excitation slice widths is found to be 3:1 for typical optimized radiofrequency pulses. T2 values obtained using this optimized implementation more closely correspond to "gold standard" values. Repeated T2 measurements indicate significantly improved correspondence between data and model. A reduction in the fitting error of approximately 70% is demonstrated for phantoms. CONCLUSION: We demonstrate that a relatively simple change to the CPMG relaxometry sequence parameters from the default setup yields significant improvements in the accuracy and precision of T2 measurements.

Effect of prior cognitive state on resting state networks measured with functional connectivity.

To address the extent to which functional connectivity measures an absolute brain state, we observed the effect of prior performance of a language task on resting-state networks in regions associated with language. Six subjects were imaged during rest before and after a block-design language task. Connectivity maps were generated for each of four language regions (identified from analysis of the language activation portion of the study) in each subject for both rest periods. Conjunction analysis demonstrated distinct networks of voxels for each seed region, indicating separate functional subnetworks associated with the different regions. In a comparison of rest before and after the activation task widespread and significant changes were observed in all individuals, suggesting that the measured resting state network reflects a dynamic image of the current brain state. At the group level, an extended network was observed that was largely persistent over time. Even at the group level an increase in connectivity was observed between left and right middle frontal gyri, and between posterior cingulate cortex and medial frontal cortex in the rest after the language task. These results suggest that functional connectivity may be a powerful measure of cognitive state, sensitive to differences between controls and patients together with the particular cognitive processing occurring during the rest state.

How reliable are fMRI-EEG studies of epilepsy? A nonparametric approach to analysis validation and optimization.

Simultaneously acquired functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data hold great promise for localizing the spatial source of epileptiform events detected in the EEG trace. Despite a number of studies applying this method, there has been no independent and systematic validation of the approach. The present study uses a nonparametric method to show that interictal discharges lead to a blood oxygen level dependent (BOLD) response that is significantly different to that obtained by examining random 'events'. We also use this approach to examine the optimization of analysis strategy for detecting these BOLD responses. Two patients with frequent epileptiform events and a healthy control were studied. The fMRI data for each patient were analyzed using a model derived from the timings of the epileptiform events detected on EEG during fMRI scanning. Twenty sets of random pseudoevents were used to generate a null distribution representing the level of chance correlation between the EEG events and fMRI data. The same pseudoevents were applied to control data. We demonstrate that it is possible to detect blood oxygen level-dependent (BOLD) changes related to interictal discharges with specific and independent knowledge about the reliability of this activation. Biologically generated events complicate the fMRI-EEG experiment. Our proposed validation examines whether identified events have an associated BOLD response beyond chance and allows optimization of analysis strategies. This is an important step beyond standard analysis. It informs clinical interpretation because it permits assessment of the reliability of the connection between interictal EEG events and the BOLD response to those events.

A high-field functional MRI study of quadri-lingual subjects.

We assessed six multilingual subjects by functional MRI using a Noun Verb Generation task in four different languages. We hypothesised that the degree of proficiency in each language would be related to the extent of functional activity measured in a region of interest analysis. Proficiency in each language was quantified using two neuropsychological tests. All four languages activated overlapping brain areas, corresponding to the major language regions. The number of activated voxels correlated with proficiency, so that the activated volume increased for languages in which a subject had poorer proficiency. Activation did not appear to be dependent on the age at which the language was learnt.

Changes in effective connectivity models in the presence of task-correlated motion: an fMRI study.

We investigated the effects of motion-correction strategy and time course selection method when structural equation modeling is applied to fMRI data in the presence of task-correlated motion. Three motion-correction methods were employed for a group of 12 subjects performing an orthographic lexical retrieval task: (1) a rigid body realignment as implemented in SPM99, (2) a rigid body realignment combined with the inclusion of motion parameters in the statistical model, and (3) the FLIRT motion correction followed by an ICA analysis aiming to identify and remove the motion-related components and the ghosting artifacts. For each motion correction, the time courses of the activated regions were selected in three ways: (1) using the voxels with the highest Z scores, (2) using the average across all the statistically significant voxels in the region of interest, and (3) using a within-region, across-subjects, singular value decomposition. The resulting models of effective connectivity were markedly different, although the activation pattern was not substantially altered by the motion-correction method. Higher values for the path coefficients were obtained for the models fitted to the covariance matrices based on the average time courses than for the covariance matrices based on a single voxel time course. Our results suggest caution with the interpretation of task-induced changes in effective connectivity since, for higher-order cognitive brain functions, multiple models can be fitted to a given data set and these models cannot be rejected on an anatomical or cognitive basis. Hum. Brain Mapping 21:49-63, 2004.

Voxel-based relaxometry: a new approach for analysis of T2 relaxometry changes in epilepsy.

The measurement of the T2 relaxation time (T2 relaxometry) had been established as a reliable tool for the assessment of certain conditions such as temporal lobe epilepsy. The standard procedure for analysis of T2 data uses manually drawn regions of interest (ROIs). This approach is limited by its subjective nature and its restricted scope of investigation within selected regions of the brain. In this study, we introduce a voxel-based analysis approach termed voxel-based relaxometry (VBR). Tissue signal changes were assessed in 19 patients with hippocampal sclerosis (HS) and in 38 healthy controls using (i) conventional ROI-based analysis with several bilateral ROIs and also (ii) the VBR method in which the T2 maps are warped to a stereotactic space, smoothed and statistically compared. Conventional ROI analysis identified the expected T2 increase in the sclerotic hippocampus in all HS patients. Furthermore, 13 of the 19 patients displayed a T2 increase in at least one of the other ROIs. The VBR analysis showed a similar pattern of statistically significant areas of increased T2 within the sclerotic hippocampus. In addition, extrahippocampal areas of increased T2 were apparent including the anterior temporal lobe white matter and the parahippocampal gyrus. The results of the VBR analysis are in agreement with the conventional ROI analysis. The VBR analysis has the advantage of providing an even-handed assessment of T2 differences through the brain. We recommend VBR as an alternative means of relaxometry data analysis that provides an objective assessment of differences between subjects.

fMRI "deactivation" of the posterior cingulate during generalized spike and wave.

Using spike-triggered fMRI, we sought to document regional changes in blood oxygen level-dependent (BOLD) activity associated with spontaneous generalised spike and slow-wave discharges (S&W). Five adult patients were studied who had idiopathic generalised epilepsy (IGE) and frequent S&W. EEG was recorded inside a 3T MRI, allowing acquisition of single, whole-brain fMRI images following S&W, as well as baseline images. Between 4 and 25 spike and wave complexes were captured in individuals. Four of the five individuals showed significant S&W-related BOLD signal reductions ("deactivation") in the posterior cingulate (P<0.001 uncorrected). Significant changes were absent only in the individual with fewest spikes. Group analysis including all five subjects confirmed fMRI deactivation in the posterior cingulate. Some S&W-related BOLD signal increases were seen in the depths of the precentral sulci in individuals and on group analysis. No significant S&W-related changes in thalamic BOLD activity were observed. The posterior cingulate may have a role in the electroclinical phenomenon of S&W and "absence." Possibilities include a causative role, with reduced activity in the cingulate facilitating the onset of S&W, a secondary role, explaining the cognitive changes observed during prolonged S&W, or an epiphenomenon.

Correlation between language organization and diffusion tensor abnormalities in refractory partial epilepsy.

PURPOSE: Atypical language organization is more frequently found in patients with refractory partial epilepsy than in healthy controls; however, the reasons for this are not well known. Here we assess the relation between language laterality index (LI) and white-matter tract changes. METHODS: Nine patients with refractory partial epilepsy were assessed with a 3-T GE scanner. Functional magnetic resonance imaging (fMRI) of language and diffusion tensor imaging (DTI) were acquired. For the fMRI, a noun-verb generation task was performed, all images were motion corrected, and activated pixels in classic language areas were counted. The DTI images were acquired in six standard directions with an initial non-diffusion-weighted scan. The "average anisotropy" was determined in a region of interest in the frontal lobe, temporal lobe, and parietal lobe white matter. An asymmetry index (AI) was calculated for language and DTI. Atypical language lateralization was diagnosed if the lateralization index (LI)-language was smaller than 0.4. RESULTS: Two of the nine patients had atypical language localization (LI-language, -0.6, and 0.3); both had left temporal DTI asymmetry (LI-DTI, -0.3 and -0.2). The remaining seven patients had typical language localization, and no marked DTI abnormalities. Asymmetry in temporal lobe DTI correlated with LI-language (r= 0.8; p = 0.006). CONCLUSIONS: Atypical language lateralization in patients with partial epilepsy may be associated with white-matter tract abnormalities.

Evaluating subject specific preprocessing choices in multisubject fMRI data sets using data-driven performance metrics.

This study investigated the possible benefit of subject specific optimization of preprocessing strategies in functional magnetic resonance imaging (fMRI) experiments. The optimization was performed using the data-driven performance metrics developed recently [Neuroimage 15 (2002), 747]. We applied numerous preprocessing strategies and a multivariate statistical analysis to each of the 20 subjects in our two example fMRI data sets. We found that the optimal preprocessing strategy varied, in general, from subject to subject. For example, in one data set, optimum smoothing levels varied from 16 mm (4 subjects), 10 mm (5 subjects), to no smoothing at all (1 subject). This strongly suggests that group-specific preprocessing schemes may not give optimum results. For both studies, optimizing the preprocessing for each subject resulted in an increased number of suprathresholded voxels in within-subject analyses. Furthermore, we demonstrated that we were able to aggregate the optimized data with a random effects group analysis, resulting in improved sensitivity in one study and the detection of interesting, previously undetected results in the other.

Theoretical simulation of oxygen tension measurement in the tissue using a microelectrode: II. Simulated measurements in tissues.

BACKGROUND AND PURPOSE: The objectives of this study were to make a computer simulation of tissues with different vascular structures and to simulate measurements of oxygen tension using an Eppendorf-like electrode in these tissues and to compare the response to radiation of the tissues with the real oxygen distributions (called input distribution) with the response to radiation of the tissues in which the oxygen distribution is given by the results of the simulated measurements (called output distribution). MATERIALS AND METHODS: The structure of various tissues and the measurements of oxygen tension using a microelectrode were simulated using a computer program. The mathematical model used combines the description of a gradient of tissue oxygenation and the electrode absorption process. RESULTS: We have compared the oxygen distributions resulting from diffusion (input) with those obtained from a simulation of measurements (output) for various tissues in the same points. Because the electrode measurement is an averaging process, the calculated oxygen distributions are different from the expected ones and the extreme high and low values are not detected. We have then calculated the survival curves describing the response to radiation if there is a small fraction of truly hypoxic cells (expected values) or a large fraction of cells at intermediate values (observed results) in order to determine the differences between them. CONCLUSIONS: The results of our study show that oxygen electrode measurements do not give the true distribution of pO(2) values in the tissue. However, our results do not contradict the numerous empirical correlations between the Eppendorf measurements of tumour oxygenation and the outcome of treatments. Measurement results will be misleading for modelling purposes since they do not reflect the actual distributions of oxygen tensions in the measured tissue. Decisions based on such modelling could be very dangerous, especially with respect to the clinical response of tumours to new treatments.