Tumor location and reduction in functional MRI estimates of language laterality

OBJECTIVE Brain tumors located close to the language cortex may distort functional MRI (fMRI)–based estimates of language dominance. The nature of this distortion, and whether this is an artifact of numerous confounders, remains unknown. The authors hypothesized tumor bias based on laterality estimates independent of confounders and that the effects are the greatest for tumors proximal to Broca's area. METHODS To answer this question, the authors reviewed more than 1113 patients who underwent preoperative fMRI to match samples on 11 known confounders (tumor location, size, type, and grade; seizure history; prior neurosurgery; aphasia presence and severity; and patient age, sex, and handedness). The samples included 30 patients with left hemisphere tumors (15 anterior and 15 posterior) and 30 with right hemisphere tumors (15 anterior and 15 posterior), thus totaling 60 patients (25 women; 18 left-handed and 4 ambidextrous; mean age 47 [SD 14.1] years). Importantly, the authors matched not only patients with left and right hemisphere tumors but also those with anterior and posterior tumors. Standard fMRI laterality indices (LIs) were calculated using whole-brain and region of interest (ROI) approaches (Broca's and Wernicke's areas). RESULTS Tumors close to Broca's area in the left hemisphere decreased LIs independently of known confounders. At the whole-brain level, this appeared to reflect a decrease in LI values in patients with left anterior tumors compared with patients with right anterior tumors. ROI analysis replicated these findings. Broca's area LIs were significantly lower (p = 0.02) in patients with left anterior tumors (mean LI 0.28) when compared with patients with right anterior tumors (mean LI 0.70). Changes in Wernicke's area–based LIs did not differ as a function of the tumor hemisphere. Therefore, in patients with left anterior tumors, it is essential to assess language laterality using left posterior ROIs. In all remaining tumor groups (left posterior tumors and right hemisphere tumors), language laterality derived from the anterior language ROI was the most robust measure of language dominance. CONCLUSIONS Patients with tumors close to Broca's area showed more bilateral fMRI language maps independent of known confounders. The authors caution against the assumption that this reduced language laterality suggests no or little risk to language function following tumor resection in the left inferior frontal gyrus. Their results address how to interpret fMRI data for neurosurgical purposes, along with theoretical questions of contralesional functional compensation and disinhibition.

A quantitative approach for measuring laterality in clinical fMRI for preoperative language mapping

Purpose fMRI is increasingly used for presurgical language mapping, but lack of standard methodology has made it difficult to combine/compare data across institutions or determine the relative efficacy of different approaches. Here, we describe a quantitative analytic framework for determining language laterality in clinical fMRI that addresses these concerns. Methods We retrospectively analyzed fMRI data from 59 patients who underwent presurgical language mapping at our institution with identical imaging and behavioral protocols. First, we compared the efficacy of different regional masks in capturing language activations. Then, we systematically explored how laterality indices (LIs) computed from these masks vary as a function of task and activation threshold. Finally, we determined the percentile threshold that maximized the correlation between the results of our LI approach and the laterality assessments from the original clinical radiology reports. Results First, we found that a regional mask derived from a meta-analysis of the fMRI literature better captured language task activations than masks based on anatomically defined language areas. Then, we showed that an LI approach based on this functional mask and percentile thresholding of subject activation can quantify the relative ability of different language tasks to lateralize language function at the population level. Finally, we determined that the 92nd percentile of subject-level activation provides the optimal LI threshold with which to reproduce the original clinical reports. Conclusion A quantitative framework for determining language laterality that uses a functionally-derived language mask and percentile thresholding of subject activation can combine/compare results across tasks and patients and reproduce clinical assessments of language laterality.

Presurgical Language Mapping in Patients With Intractable Epilepsy: A Review Study

Introduction: about 20% to 30% of patients with epilepsy are diagnosed with drug-resistant epilepsy and one third of these are candidates for epilepsy surgery. Surgical resection of the epileptogenic tissue is a well-established method for treating patients with intractable focal epilepsy. Determining language laterality and locality is an important part of a comprehensive epilepsy program before surgery. Functional Magnetic Resonance Imaging (fMRI) has been increasingly employed as a non-invasive alternative method for the Wada test and cortical stimulation. Sensitive and accurate language tasks are essential for any reliable fMRI mapping. Methods: The present study reviews the methods of presurgical fMRI language mapping and their dedicated fMRI tasks, specifically for patients with epilepsy. Results: Different language tasks including verbal fluency are used in fMRI to determine language laterality and locality in different languages such as Persian. there are some considerations including the language materials and technical protocols for task design that all presurgical teams should take into consideration. Conclusion: Accurate presurgical language mapping is very important to preserve patients language after surgery. This review was the first part of a project for designing standard tasks in Persian to help precise presurgical evaluation and in Iranian PWFIE.

The Topology of Pediatric Structural Asymmetries in Language-Related Cortex

Structural asymmetries in language-related brain regions have long been hypothesized to underlie hemispheric language laterality and variability in language functions. These structural asymmetries have been examined using voxel-level, gross volumetric, and surface area measures of gray matter and white matter. Here we used deformation-based and persistent homology approaches to characterize the three-dimensional topology of brain structure asymmetries within language-related areas that were defined in functional neuroimaging experiments. Persistence diagrams representing the range of values for each spatially unique structural asymmetry were collected within language-related regions of interest across 212 children (mean age (years) = 10.56, range 6.39–16.92; 39% female). These topological data exhibited both leftward and rightward asymmetries within the same language-related regions. Permutation testing demonstrated that age and sex effects were most consistent and pronounced in the superior temporal sulcus, where older children and males had more rightward asymmetries. While, consistent with previous findings, these associations exhibited small effect sizes that were observable because of the relatively large sample. In addition, the density of rightward asymmetry structures in nearly all language-related regions was consistently higher than the density of leftward asymmetric structures. These findings guide the prediction that the topological pattern of structural asymmetries in language-related regions underlies the organization of language.

Heritability of language laterality assessed by functional transcranial Doppler ultrasound: a twin study

Background: Prior studies have estimated heritability of around 0.25 for the trait of handedness, with studies of structural brain asymmetry giving estimates in a similar or lower range. Little is known about heritability of functional language lateralization. This report describes heritability estimates using functional language laterality and handedness phenotypes in a twin sample previously reported by Wilson and Bishop (2018). Methods: The total sample consisted of 194 twin pairs (49% monozygotic) aged from 6 to 11 years. A language laterality index was obtained for 141 twin pairs, who completed a protocol where relative blood flow through left and right middle cerebral arteries was measured using functional transcranial Doppler ultrasound (fTCD) while the child described animation sequences. Handedness data was available from the Edinburgh Handedness Inventory (EHI) and Quantification of Hand Preference (QHP) for all 194 pairs. Heritability was assessed using conventional structural equation modeling, assuming no effect of shared environment (AE model). Results: For the two handedness measures, heritability estimates (95% CI) were consistent with prior research: .25 (.03 - .34) and .18 (0 – .31) respectively for the EHI and QHP. For the language laterality index, however, the twin-cotwin correlations were close to zero for both MZ and DZ twins, and the heritability estimate was zero (0 - .15). Conclusions: A single study cannot rule out a genetic effect on language lateralisation. It is possible that the low twin-cotwin correlations were affected by noisy data: although the split-half reliability of the fTCD-based laterality index was high (0.85), we did not have information on test-retest reliability in children, which is likely to be lower. We cannot reject the hypothesis that there is low but nonzero heritability for this trait, but our data suggest that individual variation in language lateralisation is predominantly due to stochastic variation in neurodevelopment.

Heritability of language laterality assessed by functional transcranial Doppler ultrasound: a twin study

Background: Prior studies have estimated heritability of around 0.25 for the trait of handedness, with studies of structural brain asymmetry giving estimates in a similar or lower range. Little is known about heritability of functional language lateralization. This report describes heritability estimates using functional language laterality and handedness phenotypes in a twin sample previously reported by Wilson and Bishop (2018). Methods: The total sample consisted of 194 twin pairs (49% monozygotic) aged from 6 to 11 years. A language laterality index was obtained for 141 twin pairs, who completed a protocol where relative blood flow through left and right middle cerebral arteries was measured using functional transcranial Doppler ultrasound (fTCD) while the child described animation sequences. Handedness data was available from the Edinburgh Handedness Inventory (EHI) and Quantification of Hand Preference (QHP) for all 194 pairs. Heritability was assessed using conventional structural equation modeling, assuming no effect of shared environment (AE model). Results: For the two handedness measures, heritability estimates were consistent with prior research: 0.23 and 0.22 respectively for the EHI and QHP. For the language laterality index, however, the twin-cotwin correlations were close to zero for both MZ and DZ twins, and the heritability estimate was zero. Conclusions: A single study cannot rule out a genetic effect on language lateralisation. It is possible that the low twin-cotwin correlations were affected by noisy data: although the split-half reliability of the fTCD-based laterality index was high (0.85), we did not have information on test-retest reliability in children, which is likely to be lower. We cannot reject the hypothesis that there is low but nonzero heritability for this trait, but our data suggest that individual variation in language lateralisation is predominantly due to stochastic variation in neurodevelopment.

Measurement of language laterality using functional transcranial Doppler ultrasound: a comparison of different tasks

Background: Relative blood flow in the two middle cerebral arteries can be measured using functional transcranial Doppler sonography (fTCD) to give an index of lateralisation as participants perform a specific task. Language laterality has mostly been studied with fTCD using a word generation task, but it is not clear whether this is optimal. Methods: Using fTCD, we evaluated a sentence generation task that has shown good reliability and strong left lateralisation in fMRI. We interleaved trials of word generation, sentence generation and list generation and assessed agreement of these tasks in 31 participants (29 right-handers). Results: Although word generation and sentence generation both gave robust left-lateralisation, lateralisation was significantly stronger for sentence generation. Bland-Altman analysis showed that these two methods were not equivalent. The comparison list generation task was not systematically lateralised, but nevertheless laterality indices (LIs) from this task were significantly correlated with the other two tasks. Subtracting list generation LI from sentence generation LI did not affect the strength of the laterality index. Conclusions: This was a pre-registered methodological study designed to explore novel approaches to optimising measurement of language lateralisation using fTCD. It confirmed that sentence generation gives robust left lateralisation in most people, but is not equivalent to the classic word generation task. Although list generation does not show left-lateralisation at the group level, the LI on this task was correlated with left-lateralised tasks. This suggests that word and sentence generation involve adding a constant directional bias to an underlying continuum of laterality that is reliable in individuals but not biased in either direction. In future research we suggest that consistency of laterality across tasks might have more functional significance than strength or direction of laterality on any one task.