Discrepant expressive language lateralization in children and adolescents with epilepsy.

Neuronavigated transcranial magnetic stimulation (nTMS) has emerged as a presurgical language mapping tool distinct from the widely used functional magnetic resonance imaging (fMRI). We report fMRI and nTMS language-mapping results in 19 pediatric-epilepsy patients and compare those to definitive testing by electrical cortical stimulation, Wada test, and/or neuropsychological testing. Most discordant results occurred when fMRI found right-hemispheric language. In those cases, when nTMS showed left-hemispheric or bilateral language representation, left-hemispheric language was confirmed by definitive testing. Therefore, we propose nTMS should be considered for pediatric presurgical language-mapping when fMRI shows right-hemispheric language, with nTMS results superseding fMRI results in those scenarios.

Comparison of seeding methods for visualization of the corticospinal tracts using single tensor tractography.

OBJECTIVES: To compare five different seeding methods to delineate hand, foot, and lip components of the corticospinal tract (CST) using single tensor tractography. METHODS: We studied five healthy subjects and 10 brain tumor patients. For each subject, we used five different seeding methods, from (1) cerebral peduncle (CP), (2) posterior limb of the internal capsule (PLIC), (3) white matter subjacent to functional MRI activations (fMRI), (4) whole brain and then selecting the fibers that pass through both fMRI and CP (WBF-CP), and (5) whole brain and then selecting the fibers that pass through both fMRI and PLIC (WBF-PLIC). Two blinded neuroradiologists rated delineations as anatomically successful or unsuccessful tractography. The proportions of successful trials from different methods were compared by Fisher's exact test. RESULTS: To delineate hand motor tract, seeding through fMRI activation areas was more effective than through CP (p<0.01), but not significantly different from PLIC (p>0.1). WBF-CP delineated hand motor tracts in a larger proportion of trials than CP alone (p<0.05). Similarly, WBF-PLIC depicted hand motor tracts in a larger proportion of trials than PLIC alone (p<0.01). Foot motor tracts were delineated in all trials by either PLIC or whole brain seeding (WBF-CP and WBF-PLIC). Seeding from CP or fMRI activation resulted in foot motor tract visualization in 87% of the trials (95% confidence interval: 60-98%). The lip motor tracts were delineated only by WBF-PLIC and in 36% of trials (95% confidence interval: 11-69%). CONCLUSIONS: Whole brain seeding and then selecting the tracts that pass through two anatomically relevant ROIs can delineate more plausible hand and lip motor tracts than seeding from a single ROI. Foot motor tracts can be successfully delineated regardless of the seeding method used.

Passive fMRI mapping of language function for pediatric epilepsy surgical planning: validation using Wada, ECS, and FMAER.

In this study we validate passive language fMRI protocols designed for clinical application in pediatric epilepsy surgical planning as they do not require overt participation from patients. We introduced a set of quality checks that assess reliability of noninvasive fMRI mappings utilized for clinical purposes. We initially compared two fMRI language mapping paradigms, one active in nature (requiring participation from the patient) and the other passive in nature (requiring no participation from the patient). Group-level analysis in a healthy control cohort demonstrated similar activation of the putative language centers of the brain in the inferior frontal (IFG) and temporoparietal (TPG) regions. Additionally, we showed that passive language fMRI produced more left-lateralized activation in TPG (LI=+0.45) compared to the active task; with similarly robust left-lateralized IFG (LI=+0.24) activations using the passive task. We validated our recommended fMRI mapping protocols in a cohort of 15 pediatric epilepsy patients by direct comparison against the invasive clinical gold-standards. We found that language-specific TPG activation by fMRI agreed to within 9.2mm to subdural localizations by invasive functional mapping in the same patients, and language dominance by fMRI agreed with Wada test results at 80% congruency in TPG and 73% congruency in IFG. Lastly, we tested the recommended passive language fMRI protocols in a cohort of very young patients and confirmed reliable language-specific activation patterns in that challenging cohort. We concluded that language activation maps can be reliably achieved using the passive language fMRI protocols we proposed even in very young (average 7.5 years old) or sedated pediatric epilepsy patients.

Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders.

The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.

Automated delineation of white matter fiber tracts with a multiple region-of-interest approach.

White matter fiber bundles of the brain can be delineated by tractography utilizing multiple regions-of-interest (MROI) defined by anatomical landmarks. These MROI can be used to specify regions in which to seed, select, or reject tractography fibers. Manual identification of anatomical MROI enables the delineation of white matter fiber bundles, but requires considerable training to develop expertise, considerable time to carry out and suffers from unwanted inter- and intra-rater variability. In a study of 20 healthy volunteers, we compared three methodologies for automated delineation of the white matter fiber bundles. Using these methodologies, fiber bundle MROI for each volunteer were automatically generated. We assessed three strategies for inferring the automatic MROI utilizing nonrigid alignment of reference images and projection of template MROI. We assessed the bundle delineation error associated with alignment utilizing T1-weighted MRI, fractional anisotropy images, and full tensor images. We confirmed the smallest delineation error was achieved using the full tensor images. We then assessed three projection strategies for automatic determination of MROI in each volunteer. Quantitative comparisons were made using the root-mean-squared error observed between streamline density images constructed from fiber bundles identified automatically and by manually drawn MROI in the same subjects. We demonstrate that a multiple template consensus label fusion algorithm generated fiber bundles most consistent with the manual reference standard.

A combined fMRI and DTI examination of functional language lateralization and arcuate fasciculus structure: Effects of degree versus direction of hand preference.

The present study examined the relationship between hand preference degree and direction, functional language lateralization in Broca's and Wernicke's areas, and structural measures of the arcuate fasciculus. Results revealed an effect of degree of hand preference on arcuate fasciculus structure, such that consistently-handed individuals, regardless of the direction of hand preference, demonstrated the most asymmetric arcuate fasciculus, with larger left versus right arcuate, as measured by DTI. Functional language lateralization in Wernicke's area, measured via fMRI, was related to arcuate fasciculus volume in consistent-left-handers only, and only in people who were not right hemisphere lateralized for language; given the small sample size for this finding, future investigation is warranted. Results suggest handedness degree may be an important variable to investigate in the context of neuroanatomical asymmetries.

Contributions to singing ability by the posterior portion of the superior temporal gyrus of the non-language-dominant hemisphere: first evidence from subdural cortical stimulation, Wada testing, and fMRI.

INTRODUCTION: Although the substrates that mediate singing abilities in the human brain are not well understood, invasive brain mapping techniques used for clinical decision making such as intracranial electro-cortical testing and Wada testing offer a rare opportunity to examine music-related function in a select group of subjects, affording exceptional spatial and temporal specificity. METHODS: We studied eight patients with medically refractory epilepsy undergoing indwelling subdural electrode seizure focus localization. All patients underwent Wada testing for language lateralization. Functional assessment of language and music tasks was done by electrode grid cortical stimulation. One patient was also tested non-invasively with functional magnetic resonance imaging (fMRI). Functional organization of singing ability compared to language ability was determined based on four regions-of-interest (ROIs): left and right inferior frontal gyrus (IFG), and left and right posterior superior temporal gyrus (pSTG). RESULTS: In some subjects, electrical stimulation of dominant pSTG can interfere with speech and not singing, whereas stimulation of non-dominant pSTG area can interfere with singing and not speech. Stimulation of the dominant IFG tends to interfere with both musical and language expression, while non-dominant IFG stimulation was often observed to cause no interference with either task; and finally, that stimulation of areas adjacent to but not within non-dominant pSTG typically does not affect either ability. Functional fMRI mappings of one subject revealed similar music/language dissociation with respect to activation asymmetry within the ROIs. CONCLUSION: Despite inherent limitations with respect to strictly research objectives, invasive clinical techniques offer a rare opportunity to probe musical and language cognitive processes of the brain in a select group of patients.

Threshold-independent functional MRI determination of language dominance: a validation study against clinical gold standards.

Functional MRI (fMRI) is often used for presurgical language lateralization. In the most common approach, a laterality index (LI) is calculated on the basis of suprathreshold voxels. However, strong dependencies between LI and threshold can diminish the effectiveness of this technique; in this study we investigated an original methodology that is independent of threshold. We compared this threshold-independent method against the common threshold-dependent method in 14 patients with epilepsy who underwent Wada testing. In addition, clinical results from electrocortical language mapping and postoperative language findings were used to assess the validity of the fMRI lateralization method. The threshold-dependent methodology yielded ambiguous or incongruent lateralization outcomes in 4 of 14 patients in the inferior frontal gyrus (IFG) and in 6 of 14 patients in the supramarginal gyrus (SMG). Conversely, the threshold-independent method yielded unambiguous lateralization in all the patients tested, and demonstrated lateralization outcomes incongruent with clinical standards in 2 of 14 patients in IFG and in 1 of 14 patients in SMG. This validation study demonstrates that the threshold-dependent LI calculation is prone to significant within-patient variability that could render results unreliable; the threshold-independent method can generate distinct LIs that are more concordant with gold standard clinical findings.

Comparison of blocked and event-related fMRI designs for pre-surgical language mapping.

Language functional magnetic resonance imaging (fMRI) is a promising non-invasive technique for pre-surgical planning in patients whose lesions are adjacent to or within critical language areas. Most language fMRI studies in patients use blocked experimental design. In this study, we compared a blocked design and a rapid event-related design with a jittered inter-stimulus-interval (ISI) (or stochastic design) for language fMRI in six healthy controls, and eight brain tumor patients, using a vocalized antonym generation task. Comparisons were based on visual inspection of fMRI activation maps and degree of language lateralization, both of which were assessed at a constant statistical threshold for each design. The results indicated a relatively high degree of discordance between the two task designs. In general, the event-related design provided maps with more robust activations in the putative language areas than the blocked design, especially for brain tumor patients. Our results suggest that the rapid event-related design has potential for providing comparable or even higher detection power over the blocked design for localizing language function in brain tumor patients, and therefore may be able to generate more sensitive language maps. More patient studies, and further investigation and optimization of language fMRI paradigms will be needed to determine the utility and validity of this approach for pre-surgical planning.

Group independent component analysis of language fMRI from word generation tasks.

Language fMRI has been used to study brain regions involved in language processing and has been applied to pre-surgical language mapping. However, in order to provide clinicians with optimal information, the sensitivity and specificity of language fMRI needs to be improved. Type II error of failing to reach statistical significance when the language activations are genuinely present may be particularly relevant to pre-surgical planning, by falsely indicating low surgical risk in areas where no activations are shown. Furthermore, since the execution of language paradigms involves cognitive processes other than language function per se, the conventional general linear model (GLM) method may identify non-language-specific activations. In this study, we assessed an exploratory approach, independent component analysis (ICA), as a potential complementary method to the inferential GLM method in language mapping applications. We specifically investigated whether this approach might reduce type II error as well as generate more language-specific maps. Fourteen right-handed healthy subjects were studied with fMRI during two word generation tasks. A similarity analysis across tasks was proposed to select components of interest. Union analysis was performed on the language-specific components to increase sensitivity, and conjunction analysis was performed to identify language areas more likely to be essential. Compared with GLM, ICA identified more activated voxels in the putative language areas, and signals from other sources were isolated into different components. Encouraging results from one brain tumor patient are also presented. ICA may be used as a complementary tool to GLM in improving pre-surgical language mapping.

Functional MRI of memory in the hippocampus: Laterality indices may be more meaningful if calculated from whole voxel distributions.

Lateralization of memory by functional MRI (fMRI) may be helpful for surgical planning related to the medial temporal lobe (MTL). Most fMRI memory studies have calculated lateralization indices (LI) in the MTL from suprathreshold voxels only, but the selection of threshold remains highly arbitrary. We hypothesized that LIs could be reliably extracted from the distribution of voxels encompassing all positive T statistical values, each weighted by their own statistical significance. We also hypothesized that patient LIs that are two or more standard deviations (SD) away from the control group mean LI may be more clinically relevant than LIs that are not compared to control group. Thirteen healthy subjects had memory fMRI, and five epilepsy patients had both fMRI and the intracarotid amobarbital procedure (IAP). The fMRI task consisted of encoding patterns, scenes, and words. We found that normal subjects' LIs extracted from whole weighted statistical distributions tended to lateralize to the left for words, to the right for patterns, and intermediately for scenes, consistent with previous research. Weighted LIs were less variable than those calculated from suprathreshold voxels only. Using this approach, all patients had fMRI memory lateralizations consistent with IAP results. The weighted LIs provided a more clear-cut distinction of patients from the normal group (in terms of SDs from the group mean) than the suprathreshold voxel count approach. Our results suggest that using weighted distributions can be a useful strategy for assessing memory lateralization by fMRI in the MTL.