Connectomic Profiling Identifies Responders to Vagus Nerve Stimulation.

OBJECTIVE: Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling. METHODS: Fifty-six children, comprising discovery (n = 38) and validation (n = 18) cohorts, were recruited from 3 separate institutions. Diffusion tensor imaging was used to identify group differences in white matter microstructure, which in turn informed beamforming of resting-state magnetoencephalography recordings. The results were used to generate a support vector machine learning classifier, which was independently validated. This algorithm was compared to a second classifier generated using 31 clinical covariates. RESULTS: Treatment responders demonstrated greater fractional anisotropy in left thalamocortical, limbic, and association fibers, as well as greater connectivity in a functional network encompassing left thalamic, insular, and temporal nodes (p < 0.05). The resulting classifier demonstrated 89.5% accuracy and area under the receiver operating characteristic (ROC) curve of 0.93 on 10-fold cross-validation. In the external validation cohort, this model demonstrated an accuracy of 83.3%, with a sensitivity of 85.7% and specificity of 75.0%. This was significantly superior to predictions using clinical covariates alone, which exhibited an area under the ROC curve of 0.57 (p < 0.008). INTERPRETATION: This study provides the first multi-institutional, multimodal connectomic prediction algorithm for VNS, and provides new insights into its mechanism of action. Reliable identification of VNS responders is critical to mitigate surgical risks for children who may not benefit, and to ensure cost-effective allocation of health care resources. ANN NEUROL 2019;86:743-753.

Functional imaging localization of complex organic hallucinations.

Background: fMRI of mental phenomena is quite difficult to perform because lack of patient's cooperation or because the symptoms are stable. In some exceptional cases, however, fMRI and DTI are capable to provide insights on the anatomy of organic hallucinations. Methods: In this report we describe a 14-year-old boy with a left fronto-dorsal tumor who experienced chronic complex brief, frequent and repetitive complex visual and auditory hallucinations. His clinical picture included multiple and severe social and mood problems. During a presurgical fMRI mapping the patient complained of having the visual and auditory hallucinations. A block-design FMRI paradigm was obtained from the event timecourse. Deterministic DTI of the brain was obtained seeding the lesion as ROI. The patient underwent surgery and electrocorticography of the lesional area. Results: The fMRI of the hallucinations showed activation in the left inferior frontal gyrus (IFG) and the peri-lesional area. The tractography of the tumor revealed structural aberrant connectivity to occipital and temporal areas in addition to the expected connectivity with the IFG via the aslant fasciculus and homotopic contralateral areas. Intraoperative EEG demonstrated epileptic discharges in the tumor and neighboring areas. After resection, the patient's hallucinations stopped completely. He regained his normal social life and recover his normal mood. He remained asymptomatic for 90 days. Afterwards, hallucinations reappeared but with less intensity. Conclusions: To our knowledge, this is the first reported case of combined functional and structural connectivity imaging demonstrating brain regions participating in a network involved in the generation of complex auditory and visual hallucinations.

Fiber pathways supporting early literacy development in 5-8-year-old children.

The development of fluent reading is an extended process that requires the recruitment of a comprehensive system of perisylvian brain regions connected by an extensive network of fiber pathways. In the present cross-sectional study, we focused on fiber pathways-the arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), and vertical occipital fasciculus (VOF)-proposed to support early literacy in typical 5-8-year-old children. We related quantitative metrics of fiber pathway microstructure in these pathways to early literacy measures of phonological awareness and decoding. We found that diffusion properties of the AF, ILF, and VOF not only show age-related differences, but also are predictive of early literacy skills after controlling for the effects of age, general white matter development, sex, IQ, and phonological skill. Perhaps most novel, we provide evidence supporting the involvement of the recently re-identified VOF in early literacy, and further, we provide evidence that a bilateral network of fiber pathways supports early literacy development.

Atypical language representation in children with intractable temporal lobe epilepsy.

This study evaluated language organization in children with intractable epilepsy caused by temporal lobe focal cortical dysplasia (FCD) alone or dual pathology (temporal lobe FCD and hippocampal sclerosis, HS). We analyzed clinical, neurological, fMRI, neuropsychological, and histopathologic data in 46 pediatric patients with temporal lobe lesions who underwent excisional epilepsy surgery. The frequency of atypical language representation was similar in both groups, but children with dual pathology were more likely to be left-handed. Atypical receptive language cortex correlated with lower intellectual capacity, verbal abstract conceptualization, receptive language abilities, verbal working memory, and a history of status epilepticus but did not correlate with higher seizure frequency or early seizure onset. Histopathologic substrate had only a minor influence on neuropsychological status. Greater verbal comprehension deficits were noted in children with atypical receptive language representation, a risk factor for cognitive morbidity.

Pediatric applications of functional magnetic resonance imaging.

Pediatric functional MRI has been used for the last 2 decades but is now gaining wide acceptance in the preoperative workup of children with brain tumors and medically refractory epilepsy. This review covers pediatrics-specific difficulties such as sedation and task paradigm selection according to the child's age and cognitive level. We also illustrate the increasing uses of functional MRI in the depiction of cognitive function, neuropsychiatric disorders and response to pharmacological agents. Finally, we review the uses of resting-state fMRI in the evaluation of children and in the detection of epileptogenic regions.

The spinning dancer illusion and spontaneous brain fluctuations: an fMRI study.

The brain activation associated with the Spinning Dancer Illusion, a cognitive visual illusion, is not entirely known. Inferences from other study modalities point to the involvement of the dorso-parieto-occipital areas in the spontaneous switchings of perception in other bistable non-kinetic illusions. fMRI is a mature technique used to investigate the brain responses associated with mental changes. Resting-state fMRI is a novel technique that may help ascertain the effects of spontaneous brain changes in the top-down regulation of visual perception. The purpose of this report is to describe the brain activation associated with the subjective illusory changes of perception of a kinetic bistable stimulus. We hypothesize that there is a relationship between the perception phases with the very slow cortical spontaneous fluctuations, recently described. A single normal subject who was trained to produce voluntarily perception phase switches underwent a series of fMRI studies whose blocks were either defined post-hoc or accordingly with a predefined timeline to assess spontaneous and voluntarily evoked visual perception switches, respectively. Correlation of findings with resting-state fMRI and independent component analysis of the task series was sought. Phases of the rotation direction were found associated with right parietal activity. Independent component analysis of the task series and their comparison with basal resting-state components suggest that this activity is related to one of the very slow spontaneous brain fluctuations. The spontaneous fluctuations of the cortical activity may explain the subjective changes in perception of direction of the Spinning Dancer Illusion. This observation is a proof-of-principle, suggesting that the spontaneous brain oscillations may influence top-down sensory regulation.

A decisional space for fMRI pattern separation using the principal component analysis--a comparative study of language networks in pediatric epilepsy.

Atypical functional magnetic resonance imaging (fMRI) language patterns may be identified by visual inspection or by region of interest (ROI)-based laterality indices (LI) but are constrained by a priori assumptions. We compared a data-driven novel application of principal component analysis (PCA) to conventional methods. We studied 122 fMRI data sets from control and localization-related epilepsy patients provided by five children's hospitals. Each subject performed an auditory description decision task. The data sets, acquired with different scanners but similar acquisition parameters, were processed through fMRIB software library to obtain 3D activation maps in standard space. A PCA analysis was applied to generate the decisional space and the data cluster into three distinct activation patterns. The classified activation maps were interpreted by (1) blinded reader rating based on predefined language patterns and (2) by language area ROI-based LI (i.e., fixed threshold vs. bootstrap approaches). The different classification results were compared through κ inter-rater agreement statistics. The unique decisional space classified activation maps into three clusters (a) lower intensity typical language representation, (b) higher intensity typical, as well as (c) higher intensity atypical representation. Inter-rater agreements among the three raters were excellent (Fleiss κ = 0.85, P = 0.05). There was substantial to excellent agreement between the conventional visual rating and LI methods (κ = 0.69-0.82, P = 0.05). The PCA-based method yielded excellent agreement with conventional methods (κ = 0.82, P = 0.05). The automated and data-driven PCA decisional space segregates language-related activation patterns in excellent agreement with current clinical rating and ROI-based methods.

Sub-patterns of language network reorganization in pediatric localization related epilepsy: a multisite study.

To study the neural networks reorganization in pediatric epilepsy, a consortium of imaging centers was established to collect functional imaging data. Common paradigms and similar acquisition parameters were used. We studied 122 children (64 control and 58 LRE patients) across five sites using EPI BOLD fMRI and an auditory description decision task. After normalization to the MNI atlas, activation maps generated by FSL were separated into three sub-groups using a distance method in the principal component analysis (PCA)-based decisional space. Three activation patterns were identified: (1) the typical distributed network expected for task in left inferior frontal gyrus (Broca's) and along left superior temporal gyrus (Wernicke's) (60 controls, 35 patients); (2) a variant left dominant pattern with greater activation in IFG, mesial left frontal lobe, and right cerebellum (three controls, 15 patients); and (3) activation in the right counterparts of the first pattern in Broca's area (one control, eight patients). Patients were over represented in Groups 2 and 3 (P < 0.0004). There were no scanner (P = 0.4) or site effects (P = 0.6). Our data-driven method for fMRI activation pattern separation is independent of a priori notions and bias inherent in region of interest and visual analyses. In addition to the anticipated atypical right dominant activation pattern, a sub-pattern was identified that involved intensity and extent differences of activation within the distributed left hemisphere language processing network. These findings suggest a different, perhaps less efficient, cognitive strategy for LRE group to perform the task.

Identification of Negative BOLD Responses in Epilepsy Using Windkessel Models.

Alongside positive blood oxygenation level-dependent (BOLD) responses associated with interictal epileptic discharges, a variety of negative BOLD responses (NBRs) are typically found in epileptic patients. Previous studies suggest that, in general, up to four mechanisms might underlie the genesis of NBRs in the brain: (i) neuronal disruption of network activity, (ii) altered balance of neurometabolic/vascular couplings, (iii) arterial blood stealing, and (iv) enhanced cortical inhibition. Detecting and classifying these mechanisms from BOLD signals are pivotal for the improvement of the specificity of the electroencephalography-functional magnetic resonance imaging (EEG-fMRI) image modality to identify the seizure-onset zones in refractory local epilepsy. This requires models with physiological interpretation that furnish the understanding of how these mechanisms are fingerprinted by their BOLD responses. Here, we used a Windkessel model with viscoelastic compliance/inductance in combination with dynamic models of both neuronal population activity and tissue/blood O2 to classify the hemodynamic response functions (HRFs) linked to the above mechanisms in the irritative zones of epileptic patients. First, we evaluated the most relevant imprints on the BOLD response caused by variations of key model parameters. Second, we demonstrated that a general linear model is enough to accurately represent the four different types of NBRs. Third, we tested the ability of a machine learning classifier, built from a simulated ensemble of HRFs, to predict the mechanism underlying the BOLD signal from irritative zones. Cross-validation indicates that these four mechanisms can be classified from realistic fMRI BOLD signals. To demonstrate proof of concept, we applied our methodology to EEG-fMRI data from five epileptic patients undergoing neurosurgery, suggesting the presence of some of these mechanisms. We concluded that a proper identification and interpretation of NBR mechanisms in epilepsy can be performed by combining general linear models and biophysically inspired models.

The role of the arcuate fasciculus in conduction aphasia.

In aphasia literature, it has been considered that a speech repetition defect represents the main constituent of conduction aphasia. Conduction aphasia has frequently been interpreted as a language impairment due to lesions of the arcuate fasciculus (AF) that disconnect receptive language areas from expressive ones. Modern neuroradiological studies suggest that the AF connects posterior receptive areas with premotor/motor areas, and not with Broca's area. Some clinical and neurophysiological findings challenge the role of the AF in language transferring. Unusual cases of inter-hemispheric dissociation of language lateralization (e.g. Broca's area in the left, and Wernicke's area in the right hemisphere) have been reported without evident repetition defects; electrocortical studies have found that the AF not only transmits information from temporal to frontal areas, but also in the opposite direction; transferring of speech information from the temporal to the frontal lobe utilizes two different streams and conduction aphasia can be found in cases of cortical damage without subcortical extension. Taken altogether, these findings may suggest that the AF is not required for repetition although could have a subsidiary role in it. A new language network model is proposed, emphasizing that the AF connects posterior brain areas with Broca's area via a relay station in the premotor/motor areas.

Neural networks of motor and cognitive inhibition are dissociated between brain hemispheres: an fMRI study.

Paradigms exploring cognitive inhibition involve motor responses, which may confound the results. We compare cognitive inhibition activation obtained without motor involvement, to motor inhibition alone, in a group of young right-handed volunteers, utilizing a classical color Stroop task (CST), and a Stop Task. Comparison of fMRI activation was performed contrasting lateralization indexes of different Regions of Interest (ROI). Cognitive inhibition showed left brain lateralization, while motor inhibition showed right brain lateralization. Homologue brain areas involved the inferior frontal gyrus, inferior parietal lobule, middle temporal gyrus, and anterior cingulate gyrus. These circuitries appear to support that inhibition is a complicated function involving working memory, attention, semantic decision, and motivation modules.

Lesion Network Localization of Seizure Freedom following MR-guided Laser Interstitial Thermal Ablation.

Treatment-resistant epilepsy is a common and debilitating neurological condition, for which neurosurgical cure is possible. Despite undergoing nearly identical ablation procedures however, individuals with treatment-resistant epilepsy frequently exhibit heterogeneous outcomes. We hypothesized that treatment response may be related to the brain regions to which MR-guided laser ablation volumes are functionally connected. To test this, we mapped the resting-state functional connectivity of surgical ablations that either resulted in seizure freedom (N = 11) or did not result in seizure freedom (N = 16) in over 1,000 normative connectomes. There was no difference seizure outcome with respect to the anatomical location of the ablations, and very little overlap between ablation areas was identified using the Dice Index. Ablations that did not result in seizure-freedom were preferentially connected to a number of cortical and subcortical regions, as well as multiple canonical resting-state networks. In contrast, ablations that led to seizure-freedom were more functionally connected to prefrontal cortices. Here, we demonstrate that underlying normative neural circuitry may in part explain heterogenous outcomes following ablation procedures in different brain regions. These findings may ultimately inform target selection for ablative epilepsy surgery based on normative intrinsic connectivity of the targeted volume.

Executive Functions Brain System: An Activation Likelihood Estimation Meta-analytic Study.

BACKGROUND AND OBJECTIVE: To characterize commonalities and differences between two executive functions: reasoning and inhibitory control. METHODS: A total of 5,974 participants in 346 fMRI experiments of inhibition or reasoning were selected. First level analysis consisted of Analysis of Likelihood Estimation (ALE) studies performed in two pooled data groups: (a) brain areas involved in reasoning and (b) brain areas involved in inhibition. Second level analysis consisted of two contrasts: (i) brain areas involved in reasoning but not in inhibition and (ii) brain areas involved in inhibition but not in reasoning. Lateralization Indexes were calculated. RESULTS: Four brain areas appear as the most critical: the dorsolateral aspect of the frontal lobes, the superior parietal lobules, the mesial aspect of the premotor area (supplementary motor area), and some subcortical areas, particularly the putamen and the thalamus. ALE contrasts showed significant differentiation of the networks, with the reasoning > inhibition-contrast showing a predominantly leftward participation, and the inhibition > reasoning-contrast, a clear right advantage. CONCLUSION: Executive functions are mediated by sizable brain areas including not only cortical, but also involving subcortical areas in both hemispheres. The strength of activation shows dissociation between the hemispheres for inhibition (rightward) and reasoning (leftward) functions.

Nontask-Related Brain Lateralization Biomarkers in Children: The Asymmetry of Language Areas on Functional Connectivity Functional Magnetic Resonance Imaging.

In this work, we will test the hypothesis that the connectivity of language areas in normal children is asymmetric between the hemispheres. Intrahemispheric region of interest (ROI)-to-ROI connectivity was assessed in 40 normal right-handed children. Asymmetries were assessed (1) between the hemispheres (global language connectivity); (2) between Brodmann areas (BAs) pairs (pairwise connectivity); and (3) between two homotopic BA (Global BA connectivity). Sixteen BAs were selected: 6, 7, 9, 19, 21, 22, 37, 38, 39, 40, 41, 42, 44, 45, 46, and 47. T scores for connectivity of each BA pair were ascertained using the MATLAB toolbox CONN. Lateralization index (LI) scores based on T-values were obtained. Only LIs with 2SD above the mean were considered as significant. Comparisons between T-value groups (per side and per BA) were performed utilizing double-sided T-tests. Null hypothesis was rejected for p < 0.05. There was not a statistical difference between global left and right connectivity strength (p = 0.40). There was significant pairwise connectivity asymmetry for the following pairs: BA7-BA44 (LI = 0.662); BA21-BA42 (LI = -0.616); BA21-BA40 (LI = -0.595); BA38-BA44 (LI = 0.470); BA39-BA44 (LI = -0.903); and BA42-BA47 (LI = -0.445). Language-related brain connectivity asymmetries have been demonstrated in a group of children and young adolescents. Two pairs related to Broca's area were left dominant (BA44-BA38 and BA44-BA7) and four pairs right dominant (BA42-BA47, BA39-BA44, BA21-BA40, and BA21-BA42).

Presurgical hyperconnectivity of the ablation volume is associated with seizure-freedom after magnetic resonance-guided laser interstitial thermal therapy.

PURPOSE: Magnetic Resonance-guided Laser Interstitial Thermal Therapy (MRgLITT) is an emerging minimally-invasive alternative to resective surgery for medically-intractable epilepsy. The precise lesioning effect produced by MRgLITT supplies opportunities to glean insights into epileptogenic regions and their interactions with functional brain networks. In this exploratory analysis, we sought to characterize associations between MRgLITT ablation zones and large-scale brain networks that portended seizure outcome using resting-state fMRI. METHODS: Presurgical fMRI and intraoperatively volumetric structural imaging were obtained, from which the ablation volume was segmented. The network properties of the ablation volume within the brain's large-scale brain networks were characterized using graph theory and compared between children who were and were not rendered seizure-free. RESULTS: Of the seventeen included children, five achieved seizure freedom following MRgLITT. Greater functional connectivity of the ablation volume to canonical resting-state networks was associated with seizure-freedom (p < 0.05, FDR-corrected). The ablated volume in children who subsequently became seizure-free following MRgLITT had significantly greater strength, and eigenvector centrality within the large-scale brain network. CONCLUSIONS: These findings provide novel insights into the interaction between epileptogenic cortex and large-scale brain networks. The association between ablation volume and resting-state networks may supply novel avenues for presurgical planning and patient stratification.

Should Broca's area include Brodmann area 47?

BACKGROUND: Understanding brain organization of speech production has been a principal goal of neuroscience. Historically, brain speech production has been associated with so-called Broca's area (Brodmann area ­BA- 44 and 45), however, modern neuroimaging developments suggest speech production is associated with networks rather than with areas. The purpose of this paper was to analyze the connectivity of BA47 ( pars orbitalis) in relation to language . METHOD: A meta-analysis was conducted to assess the language network in which BA47 is involved. The Brainmap database was used. Twenty papers corresponding to 29 experimental conditions with a total of 373 subjects were included. RESULTS: Our results suggest that BA47 participates in a "frontal language production system" (or extended Broca's system). The BA47  connectivity found is also concordant with a minor role in language semantics. CONCLUSIONS: BA47 plays a central role in the language production system.

Presurgical thalamocortical connectivity is associated with response to vagus nerve stimulation in children with intractable epilepsy.

Although chronic vagus nerve stimulation (VNS) is an established treatment for medically-intractable childhood epilepsy, there is considerable heterogeneity in seizure response and little data are available to pre-operatively identify patients who may benefit from treatment. Since the therapeutic effect of VNS may be mediated by afferent projections to the thalamus, we tested the hypothesis that intrinsic thalamocortical connectivity is associated with seizure response following chronic VNS in children with epilepsy. Twenty-one children (ages 5-21 years) with medically-intractable epilepsy underwent resting-state fMRI prior to implantation of VNS. Ten received sedation, while 11 did not. Whole brain connectivity to thalamic regions of interest was performed. Multivariate generalized linear models were used to correlate resting-state data with seizure outcomes, while adjusting for age and sedation status. A supervised support vector machine (SVM) algorithm was used to classify response to chronic VNS on the basis of intrinsic connectivity. Of the 21 subjects, 11 (52%) had 50% or greater improvement in seizure control after VNS. Enhanced connectivity of the thalami to the anterior cingulate cortex (ACC) and left insula was associated with greater VNS efficacy. Within our test cohort, SVM correctly classified response to chronic VNS with 86% accuracy. In an external cohort of 8 children, the predictive model correctly classified the seizure response with 88% accuracy. We find that enhanced intrinsic connectivity within thalamocortical circuitry is associated with seizure response following VNS. These results encourage the study of intrinsic connectivity to inform neural network-based, personalized treatment decisions for children with intractable epilepsy.

Interrater reliability in assessing quality of diagnostic accuracy studies using the QUADAS tool. A preliminary assessment.

RATIONALE AND OBJECTIVES: Quality Assessment of Diagnostic Accuracy Studies (QUADAS) is a new tool to measure the methodological quality of diagnostic accuracy studies in systematic reviews. We used data from a systematic review of magnetic resonance spectroscopy (MRS) in the characterization of suspected brain tumors to provide a preliminary evaluation of the inter-rater reliability of QUADAS. MATERIALS AND METHODS: A structured literature search identified 19 diagnostic accuracy studies. These publications were distributed randomly to primary and secondary reviewers for dual independent assessment. Reviewers recorded methodological quality by using QUADAS on a custom-designed spreadsheet. We calculated correlation, percentage of agreement, and kappa statistic to assess inter-rater reliability. RESULTS: Most studies in our review were judged to have used an accurate reference standard. Conversely, the MRS literature frequently failed to specify the length of time between index and reference tests or that the clinicians were unaware of the index test findings when reporting the reference standard. There was good correlation (rho = 0.78) between reviewers in assessment of the overall number of quality criteria met. However, mean agreement for individual QUADAS questions was only fair (kappa = 0.22) and ranged from no agreement beyond chance (kappa < 0) to moderate agreement (kappa = 0.58). CONCLUSION: Inter-rater reliability in our study was relatively low. Nevertheless, we believe that QUADAS potentially is a useful tool for highlighting the strengths and weaknesses of existing diagnostic accuracy studies. Low reliability suggests that different reviewers will reach different conclusions if QUADAS is used to exclude "low-quality" articles from meta-analyses. We discuss methods for improving the validity and reliability of QUADAS.

How Extended Is Wernicke's Area? Meta-Analytic Connectivity Study of BA20 and Integrative Proposal.

Understanding the functions of different brain areas has represented a major endeavor of contemporary neurosciences. The purpose of this paper was to pinpoint the connectivity of Brodmann area 20 (BA20) (inferior temporal gyrus, fusiform gyrus) in language tasks. A meta-analysis was conducted to assess the language network in which BA20 is involved. The DataBase of Brainmap was used; 11 papers corresponding to 12 experimental conditions with a total of 207 subjects were included in this analysis. Our results demonstrated seven clusters of activation including other temporal lobe areas (BA3, BA21), the insula, and the prefrontal cortex; minor clusters in the cingulate gyrus and the occipital lobe were observed; however, the volumes of all the activation clusters were small. Our results suggest that regardless of BA20 having certain participation in language processes it cannot be considered as a core language processing area (Wernicke's area); nonetheless, it could be regarded as kind of language processing marginal area, participating in "extended Wernicke's area" or simply "Wernicke's system." It is suggested that "core Wernicke's area" roughly corresponds to BA21, BA22, BA41, and BA42, while a "language associations area" roughly corresponds to BA20, BA37, BA38, BA39, and BA40 ("extended Wernicke's area" or "Wernicke's system").

Connectivity of BA46 involvement in the executive control of language.

BACKGROUND: Understanding the functions of different brain areas has represented a major endeavor of contemporary neurosciences. Modern neuroimaging developments suggest cognitive functions are associated with networks rather than with specific areas. OBJECTIVES: The purpose of this paper was to analyze the connectivity of Brodmann area (BA) 46 (anterior middle frontal gyrus) in relation to language. METHODS: A meta-analysis was conducted to assess the language network in which BA46 is involved. The DataBase of Brainmap was used; 19 papers corresponding to 60 experimental conditions with a total of 245 subjects were included. RESULTS: Our results suggest the core network of BA46. The localization and modules involved suggest BA46 participation in a "frontal language production system" (or extended Broca's system). The depicted BA46 connectivity is also concordant with a minor role in language semantics and language understanding. CONCLUSION: It was concluded that BA46 plays a central role in the language production system, most likely related to its executive control.