Standardization of presurgical language fMRI in Greek population: Mapping of six critical regions.

BACKGROUND: Mapping the language system has been crucial in presurgical evaluation especially when the area to be resected is near relevant eloquent cortex. Functional magnetic resonance imaging (fMRI) proved to be a noninvasive alternative of Wada test that can account not only for language lateralization but also for localization when appropriate tasks and MRI sequences are being used. The tasks utilized during the fMRI acquisition are playing a crucial role as to which areas will be activated. Recent studies demonstrated that key language regions exist outside the classical model of "Wernicke-Lichtheim-Geschwind," but sensitive tasks must take place in order to be revealed. On top of that, the tasks should be in mother tongue for appropriate language mapping to be possible. METHODS: For that reason, in this study, we adopted an English protocol that can reveal six language critical regions even in clinical setups and we translated it into Greek to prove its efficacy in Greek population. Twenty healthy right-handed volunteers were recruited and performed the fMRI acquisition in a standardized manner. RESULTS: Results demonstrated that all six language critical regions were activated in all subjects as well as the group mean map. Furthermore, activations were found in the thalamus, the caudate, and the contralateral cerebellum. CONCLUSION: In this study, we standardized an fMRI protocol in Greek and proved that it can reliably activate six language critical regions. We have validated its efficacy for presurgical language mapping in Greek patients capable to be adopted in clinical setup.

Cognitive Biomarkers in the Clinic: Lessons From Presurgical fMRI.

SUMMARY: Cognitive biomarkers are vital and uniquely challenging clinical tools. There has been marked growth in neuroimaging-based cognitive biomarkers across the past 40 years with more in development (e.g., clinical cognitive EEG). The challenges involved in developing cognitive biomarkers and key milestones in their development are reviewed here using clinical functional MRI's evolution as a case study. It is argued that indexing cognition is uniquely challenging because it requires patients to consistently use specific cognitive processes, and it is difficult or impossible to independently verify this occurred. This limitation can be successfully managed through careful analysis of standardized protocols for acquisition and interpretation, and ensuring the clinical application of biomarkers integrates disciplines with complementary expertise. Factors beneficial to the adoption of a novel cognitive biomarker include a clinical need and inadequate alternatives. Key milestones in the development of functional MRI included (1) demonstration that its performance was equivalent to its predecessor; (2) demonstration it predicted a clinically meaningful outcome; and (3) the establishment of infrastructure for both its execution and billing. Review of functional MRI and its predecessors suggest a cycle whereby successful cognitive biomarkers are validated, experience widespread adoption and customization/fragmentation, go through a period of review, and finally are refined and standardized. Those applying future cognitive biomarkers in the clinic can avoid some of the failures of clinical functional MRI by defining the skills and disciplines the method requires and routinely evaluating patient outcomes.

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.

Electrical cortical stimulation can impair production of the alphabet without impairing counting.

Neurosurgery has the potential to cure patients with drug-resistant focal epilepsy, but carries the risk of permanent language impairment when surgery involves the dominant hemisphere of the brain. This risk can be estimated and minimized using electrical stimulation mapping (ESM), which uses cognitive and linguistic tasks during cortical ESM to differentiate "eloquent" and "resectable" areas in the brain. One such task, counting, is often used to screen and characterize language during ESM in patients whose language abilities are limited. Here we report a patient with drug-resistant epilepsy arising from the language-dominant hemisphere using fMRI. Our patient experienced loss of the ability to recite or write the alphabet, but not to count, during ESM of the dominant left posterior superior temporal gyrus. This selective impairment extended to both spoken and written production. We suggest the need for caution when using counting as a sole means to screen language function and as a method of testing low functioning patients using ESM.

Presurgical language fMRI: Technical practices in epilepsy surgical planning.

Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, image acquisition, analysis and interpretation, and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4, or 5 tasks with a modal run duration of 5 min. Variants of over 15 protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols was used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, and brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.

Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning.

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance.

Impairment of consciousness induced by bilateral electrical stimulation of the frontal convexity.

We report a case of impairment of consciousness (IOC) induced by electrical cortical stimulation (ECS) of homologous regions within the lateral frontal convexities in a patient with medically intractable epilepsy. The patient had mixed features of idiopathic generalized and focal epilepsy. On intracranial EEG recording, interictal and ictal discharges showed a high degree of synchrony across widespread bilateral fronto-parietal areas. We identified regions in the lateral frontal lobes that reliably and produced loss of consciousness by ECS. This was accompanied by evoked EEG activity of admixed frequencies over the fronto-parietal, mesial frontal and temporal regions during stimulation and was not associated with after-discharges. Symptoms were immediately reversible upon cessation of stimulation. This finding suggests that focal cortical stimulation can disrupt widespread networks that underlie consciousness. Individuals with high degrees of speculated thalamo-frontal cortical connectivity might be more susceptible to this effect, and the findings highlight the importance of standardizing the testing of level of consciousness during mapping sessions. Although consciousness is commonly impaired in epileptic seizures, limited literature is available on loss of consciousness induced by electrical cortical stimulation (ECS) in humans undergoing intracranial EEG evaluations for localization of epileptic focus. One theory advocates the presence of consciousness 'switch' in subcortical structures. While this model is novel and simplistic, it has its inherent limitations. In this case study, we propose an alternative approach on the entity and discuss the complex circuits underlying it and correlate that with the electrophysiological findings and the pathophysiology of the phenotype of the disease and discuss potential causes for rarity of reports on the subject.

Presurgical language fMRI: Mapping of six critical regions.

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Broca's and Wernicke's areas, although multiple other language-critical areas are now well-known. We evaluated whether clinicians could use a novel approach, including clinician-driven individualized thresholding, to reliably identify six language regions, including Broca's Area, Wernicke's Area (inferior, superior), Exner's Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly thresholded and combined these to identify the six regions. The resulting maps were compared to fixed threshold maps. Clinicians generated maps that overlapped significantly, and were highly consistent, when at least one task came from the same set. Cases diverged when clinicians prioritized different language regions or addressed noise differently. Language laterality closely mirrored Wada data (85% accuracy). Activation consistent with all six language regions was consistently identified. In blind review, three external, independent clinicians rated the individualized fMRI language maps as superior to fixed threshold maps; identified the majority of regions significantly more frequently; and judged language laterality to mirror Wada lateralization more often. These data provide initial validation of a novel, clinician-based approach to localizing language cortex. They also demonstrate clinical fMRI is superior when analyzed by an experienced clinician and that when fMRI data is of low quality judgments of laterality are unreliable and should be withheld. Hum Brain Mapp 38:4239-4255, 2017. © 2017 Wiley Periodicals, Inc.

Language system organization in a quadrilingual with a brain tumor: Implications for understanding of the language network.

In pre-neurosurgery language mapping it is critical to identify language-specific regions in multilingual speakers. We conducted pre-operative functional magnetic resonance imaging, and intraoperative language mapping in the unique case of a highly proficient quadrilingual with a left frontal brain tumor who acquired her second language at age 5, and her third and fourth languages at 15. We found a predominantly different organization in each language with only a few areas shared by all 4 languages. Contrary to existing evidence, impairment across languages was not related to age of acquisition, amount of exposure, or language similarity. This case suggests that the functional structure of the language system may be highly idiosyncratic in multilingual individuals and supports detailed study in this group to inform neurocognitive models of language.

Role of the Wada test and functional magnetic resonance imaging in preoperative mapping of language and memory: two atypical cases.

The Wada test is an invasive procedure used to determine cerebral memory and language dominance as well as risk of cognitive deficits following neurosurgery. However, the potential risks of Wada testing have led some to consider foregoing Wada testing in candidates for resective epilepsy surgery with right hemispheric seizure onset. We present two atypical cases in which the Wada test showed unexpected memory and language lateralization. These cases underscore the importance of functional magnetic resonance in which imaging and Wada examination in right-handed individuals even when the lesion would not suggest atypical language representation.

Elemental spatial and temporal association formation in left temporal lobe epilepsy.

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as "self-projection" or "association formation". We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed.

Optimization of tractography of the optic radiations.

Imaging and delineation of the optic radiations (OpRs) remains challenging, despite repeated attempts to achieve reliable validated tractography of this complex structure. Previous studies have used varying methods to generate representations of the OpR which differ markedly from one another and, frequently, from the OpR's known structure. We systematically examined the influence of a key variable that has differed across previous studies, the tractography seed region, in 13 adult participants (nine male; mean age 31 years; SD 8.7 years; range 16-47). First, we compared six seed regions at the lateral geniculate nucleus (LGN) and sagittal stratum based on the literature and known OpR anatomy. Three of the LGN regions seeded streamlines consistent with the OpR's three "bundles," whereas a fourth seeded streamlines consistent with each of the three bundles. The remaining two generated OpR streamlines unreliably and inconsistently. Two stratum regions seeded the radiations. This analysis identified a set of optimal regions of interest (ROI) for seeding OpR tractography and important inclusion and exclusion ROI. An optimized approach was then used to seed LGN regions to the stratum. The radiations, including streamlines consistent with Meyer's Loop, were streamlined in all cases. Streamlines extended 0.2 ± 2.4 mm anterior to the tip of the anterior horn of the lateral ventricle. These data suggest some existing approaches likely seed representations of the OpR that are visually plausible but do not capture all OpR components, and that using an optimized combination of regions seeded previously allows optimal mapping of this complex structure.

What's the story? The tale of reading fluency told at speed.

Fluent readers process written text rapidly and accurately, and comprehend what they read. Historically, reading fluency has been modeled as the product of discrete skills such as single word decoding. More recent conceptualizations emphasize that fluent reading is the product of competency in, and the coordination of, multiple cognitive sub-skills (a multi-componential view). In this study, we examined how the pattern of activation in core reading regions changes as the ability to read fluently is manipulated through reading speed. We evaluated 13 right-handed adults with a novel fMRI task assessing fluent sentence reading and lower-order letter reading at each participant's normal fluent reading speed, as well as constrained (slowed) and accelerated reading speeds. Comparing fluent reading conditions with rest revealed regions including bilateral occipito-fusiform, left middle temporal, and inferior frontal gyral clusters across reading speeds. The selectivity of these regions' responses to fluent sentence reading was shown by comparison with the letter reading task. Region of interest analyses showed that at constrained and accelerated speeds these regions responded significantly more to fluent sentence reading. Critically, as reading speed increased, activation increased in a single reading-related region: occipital/fusiform cortex (left > right). These results demonstrate that while brain regions engaged in reading respond selectively during fluent reading, these regions respond differently as the ability to read fluently is manipulated. Implications for our understanding of reading fluency, reading development, and reading disorders are discussed.