Patterns and predictors of language representation and the influence of epilepsy surgery on language reorganization in children and young adults with focal lesional epilepsy.

Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery.

Plasticity in language cortex and white matter tracts after resection of dominant inferior parietal lobule arteriovenous malformations: a combined fMRI and DTI study.

OBJECTIVE: The dominant inferior parietal lobe (IPL) contains cortical and subcortical structures that serve language processing. A high incidence of postoperative short-term aphasia and good potential for language reorganization have been observed. The authors' goal was to study the plasticity of the language cortex and language-related fibers in patients with brain arteriovenous malformations (BAVMs) located in the IPL. METHODS: A total of 6 patients who underwent microsurgical treatment of an IPL BAVM were prospectively recruited between September 2016 and May 2018. Blood oxygen level-dependent functional MRI (BOLD-fMRI) and diffusion tensor imaging (DTI) were performed within 1 week before and 6 months after microsurgery. Language-related white matter (WM) eloquent fiber tracts and their contralateral homologous fiber tracts were tracked. The Western Aphasia Battery was administered to assess language function. The authors determined the total number of fibers and mean fractional anisotropy (FA) indices for each individual tract. In addition, they calculated the laterality index (LI) between the activated language cortex voxels in the lesional and contralesional hemispheres and compared these indices between the preoperative and postoperative fMR and DT images. RESULTS: Of the 6 patients with IPL BAVMs, all experienced postoperative short-term language deficits, and 5 (83.3%) recovered completely at 6 months after surgery. Five patients (83.3%) had right homologous reorganization of BOLD signal activations in both Broca's and Wernicke's areas. More fibers were observed in the arcuate fasciculus (AF) in the lesional hemisphere than in the contralesional hemisphere (1905 vs 254 fibers, p = 0.035). Six months after surgery, a significantly increased number of fibers was seen in the right hemispheric AF (249 fibers preoperatively vs 485 postoperatively, p = 0.026). There were significantly more nerve fibers in the postoperative left inferior frontooccipital fasciculus (IFOF) (874 fibers preoperatively vs 1186 postoperatively, p = 0.010). A statistically significant increase in right hemispheric dominance of Wernicke's area was observed. The overall functional LI showed functional lateralization of Wernicke's area in the right hemisphere (LI ≤ -0.20) in all patients. CONCLUSIONS: The authors' findings provide evidence for the functional reorganization by recruiting the right hemispheric homologous region of Broca's and Wernicke's areas, right hemispheric AFs, and left hemispheric IFOFs following resection of IPL BAVMs.Clinical trial registration no.: NCT02868008 (clinicaltrials.gov).

The Artery of Aphasia, A Uniquely Sensitive Posterior Temporal Middle Cerebral Artery Branch that Supplies Language Areas in the Brain: Anatomy and Report of Four Cases.

BACKGROUND: Arterial disruption during brain surgery can cause devastating injuries to wide expanses of white and gray matter beyond the tumor resection cavity. Such damage may occur as a result of disrupting blood flow through en passage arteries. Identification of these arteries is critical to prevent unforeseen neurologic sequelae during brain tumor resection. In this study, we discuss one such artery, termed the artery of aphasia (AoA), which when disrupted can lead to receptive and expressive language deficits. METHODS: We performed a retrospective review of all patients undergoing an awake craniotomy for resection of a glioma by the senior author from 2012 to 2018. Patients were included if they experienced language deficits secondary to postoperative infarction in the left posterior temporal lobe in the distribution of the AoA. The gross anatomy of the AoA was then compared with activation likelihood estimations of the auditory and semantic language networks using coordinate-based meta-analytic techniques. RESULTS: We identified 4 patients with left-sided posterior temporal artery infarctions in the distribution of the AoA on diffusion-weighted magnetic resonance imaging. All 4 patients developed substantial expressive and receptive language deficits after surgery. Functional language improvement occurred in only 2/4 patients. Activation likelihood estimations localized parts of the auditory and semantic language networks in the distribution of the AoA. CONCLUSIONS: The AoA is prone to blood flow disruption despite benign manipulation. Patients seem to have limited capacity for speech recovery after intraoperative ischemia in the distribution of this artery, which supplies parts of the auditory and semantic language networks.

Motor and language deficits correlate with resting state functional magnetic resonance imaging networks in patients with brain tumors.

BACKGROUND AND PURPOSE: Evidence of pre-operative resting state functional magnetic resonance (RS-fMRI) validation by correlating it with clinical pre-operative status in brain tumor patients is scarce. Our aim was to validate the functional relevance of RS-fMRI by investigating the association between RS-fMRI and pre-operative motor and language function performance in patients with brain tumor. MATERIALS AND METHODS: Sixty-nine patients with brain tumors were prospectively recruited. Patients with tumors near precentral gyrus (n = 49) underwent assessment for apparent (paresis) and subtle (finger tapping) deficits. Patients with left frontal tumors in the vicinity of the inferior frontal gyrus (n = 29) underwent assessment for gross (aphasia) and mild language (phonological verbal fluency) deficits. RS-fMRI results were extracted by spatial independent component analysis (ICA). RESULTS: Motor group: paretic patients showed significantly (P = 0.01) decreased BOLD signal in ipsilesional precentral gyrus when compared to contralesional one. Significantly (P < 0.01) lower BOLD signal was also observed in ipsilesional precentral gyrus of paretics when compared with the non-paretics. In asymptomatic patients, a strong positive correlation (r = 0.68, P < 0.01) between ipsilesional motor cortex BOLD signal and contralesional finger tapping performance was observed. Language group: patients with aphasia showed significantly (P = 0.01) decreased RS-fMRI BOLD signal in left BA 44 when compared with non- aphasics. In asymptomatic patients, a strong positive correlation (r = 0.72, P < 0.01) between BA 44 BOLD signal and phonological fluency performance was observed. CONCLUSIONS: Our results showed that RS-fMRI BOLD signal of motor and language networks were significantly affected by the tumors implying the usefulness of the method for assessment of the underlying functions in brain tumors patients.

Focal Cortical Anomalies and Language Impairment in 16p11.2 Deletion and Duplication Syndrome.

Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions.

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.

Does education play a role in language reorganization after surgery in drug refractory temporal lobe epilepsy: An fMRI based study?

OBJECTIVES: Patients with drug refractory epilepsy (DRE) and a high level of education may differ in their language recovery after surgery. Our aim was to determine whether there were differences in the extent of improvement and pattern of reorganization of language functions on functional magnetic resonance imaging (fMRI) after surgery to treat refractory temporal lobe epilepsy (TLE) between patients with more than 12 years of formal education versus those with a shorter period of regular schooling. METHODS: After approval by an institutional ethics committee, 60 right-handed, adult patients of left TLE and 20 right-handed, healthy controls were recruited to the study. Multiple aspects of language (Repetition, Naming, Word fluency, Visual word and Comprehension reading) were tested using the Indian Aphasia Battery (IAB) in the Hindi language; fMRI was performed using a standardized Hindi language paradigm (lexical, semantic, syntactic and comprehension components) in both cases and controls, before and after an anterior temporal lobectomy (in cases) with a 1.5T MR Scanner. An array of performance tests of intelligence and the verbal adult intelligence scale (VAIS) were used to measure the Intelligence Quotient (IQ) in Left TLE (LTLE) patients before and after surgery. Language laterality was estimated using the laterality index (LI-toolbox-spm8). Cohen's d test was performed to determine the effect sizes of the differences in the IAB scores, and Pearson's correlation was applied between regional (IFG and STG) activation in controls and TLE patients with more than 12 years of schooling [higher educational status (HES subgroup)] and those with less than 12 years of schooling [lower educational status (LES subgroup)]. RESULTS: At the baseline, clinical testing with IAB showed better scores in controls than in cases. Better scores were observed in subjects with higher levels of education than in those with lower levels of education. An improvement was observed in IQ scores in both the HES and LES groups after ATLR; significant worsening in the abstract ability subtest was noted in the LES group, whereas in the HES group there was an improvement. Blood-oxygen-level dependent (BOLD) activation during language tasks was observed in both cerebral hemispheres in the TLE cases, while it was observed in the traditional left hemispheric language areas in controls. Postoperatively, greater BOLD activation was observed in the left inferior frontal gyri (IFG, r=0.65*; p<0.05), middle frontal gyrus (MFG, r=0.77**; p<0.01) superior temporal gyri (STG, r=0.88* p<0.02) and angular gyrus (AG, r=0.73*; p<0.04) in HES compared to LES subjects. Similarly, LI showed left lateralization of the frontal (LIw=0.77 & 0.71) and temporal (LIw=0.74 & 0.5) regions in controls and the TLE group (post-surgery) compared to the pre-surgery group during language tasks. CONCLUSIONS: Greater improvement in language skills and BOLD activation in the left hemisphere in TLE-patients (after epilepsy surgery) with a high level of education was similar to that of healthy controls, implying that education has an effect on the functional reorganization/recovery of language areas.

Language plasticity after hemispherotomy of the dominant hemisphere in 3 patients: Implication of non-linguistic networks.

The neural networks involved in language recovery following hemispherotomy of the dominant hemisphere after language acquisition in children remain poorly known. Twelve hemispherotomized children (mean age at surgery: 11.3years) with comparable post-operative neuropsychological patterns underwent multi-task language functional MRI. Three of them had recovered from an initial postoperative aphasia i.e., hemispherotomy was performed on the language-dominant hemisphere. Our main results revealed (1) perisylvian activations in all patients after either left or right hemispherotomy; (2) no differences in activations between groups regarding the side of hemispherotomy; (3) additional activations in pre-frontal (3/3) and hippocampal/parahippocampal and occipito-parietal (2/3) areas, when comparing language activation in each of the three subjects with hemispherotomy of the language-dominant hemisphere to the group of 9 non-dominant hemispherotomized patients. These neural networks support the stronger engagement of learning and memory during language recovery in a hemisphere that was not initially actively subserving language.

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.

Partly segregated cortico-subcortical pathways support phonologic and semantic verbal fluency: A lesion study.

Verbal fluency refers to the ability to generate as many words as possible in a limited time interval, without repetition and according to either a phonologic (each word begins with a given letter) or a semantic rule (each word belongs to a given semantic category). While current literature suggests the involvement of left fronto-temporal structures in fluency tasks, whether the same or distinct brain areas are necessary for each type of fluency remains unclear. We tested the hypothesis for an involvement of partly segregated cortico-subcortical structures between phonologic and semantic fluency by examining with a voxel-based lesion symptom mapping approach the effects of brain lesions on fluency scores corrected for age and education level in a group of 191 unselected brain-damaged patients with a first left or right hemispheric lesion. There was a positive correlation between the scores to the two types of fluency, suggesting that common mechanisms underlie the word generation independent of the production rule. The lesion-symptom mapping revealed that lesions to left basal ganglia impaired both types of fluency and that left superior temporal, supramarginal and rolandic operculum lesions selectively impaired phonologic fluency and left middle temporal lesions impaired semantic fluency. Our results corroborate current neurocognitive models of word retrieval and production, and refine the role of cortical-subcortical interaction in lexical search by highlighting the common executive role of basal ganglia in both types of verbal fluency and the preferential involvement of the ventral and dorsal language pathway in semantic and phonologic fluency, respectively.

A potential protective effect in multilingual patients with semantic dementia: two case reports of patients speaking Taiwanese and Japanese.

PURPOSE: Several reports have suggested that multilingualism has a protective effect against semantic dementia. Here, we provide further evidence for this effect. CASE REPORTS FIRST: The patient was a 75-year-old right-handed Taiwanese woman who had retired after working as a tailor. She was able to speak Taiwanese, Japanese and Mandarin Chinese fluently until 5 years ago. She gradually developed symptoms of profound anomia and difficulty with word-finding. Her mother tongue was Taiwanese and she had learned Japanese as her first symbolized language. She had used Mandarin Chinese for most of her life, but depended on Japanese to read and write (such as reading a newspaper and keeping accounts). However, she could now speak only very simple Taiwanese and Japanese, and could recognize only simple Japanese characters. SECOND: The patient was a 62-year-old right-handed man who had worked as an ironworker. He could speak Taiwanese and Mandarin Chinese fluently until 5 years ago. His mother tongue was Taiwanese. After 5 years of language deterioration, he was unable to communicate with his family members or recognize any characters, including numbers. SPECT RESULTS: Brain perfusion ECD SPECT (Tc-99m-ethyl cysteinate dimer single-photon emission computed tomography) showed less perfusion in the multilingual patient (Case #1) than in the bilingual patient (Case #2). Neuropsychological tests also demonstrated a slower rate of degeneration in the multilingual patient. CONCLUSION: We speculate that reading and writing in Japanese had a greater impact on the semantic system in Case #1. Thus, this patient showed relatively less degeneration or functional inactivity, as shown by perfusion in the frontal lobe, and this might be due to the persistent activation involved in multilingualism.

Evidence of bilateral temporal lobe involvement in primary progressive aphasia: a SPECT study.

UNLABELLED: Primary progressive aphasia (PPA) is rare. Only limited series have been reported with SPECT or PET. Moreover, in the majority of studies, the left-to-right asymmetry ratio was used, leading to difficulties in right hemisphere analyzes. METHODS: Twenty-nine patients with clinical criteria of PPA (Mesulam and Weintraub) were included and compared with 12 control subjects. Complete language examination was performed in all patients. SPECT was performed on a double-head gamma camera after intravenous injection of hexamethylpropyleneamine oxime (22 patients and 12 control subjects) or ethylcysteinate dimer (7 patients). Nineteen regions of interest (ROIs) were drawn on each hemisphere in all patients using the Talairach atlas. The perfusion index (PI = cortex-to-cerebellum ratio) was calculated for each ROI. Atrophy was quantified on MRI by consensus of 3 observers in 16 cortical ROIs. ANOVAs were used to compare the PI between (a). patients and control subjects, (b). patients with (n = 15) or without (n = 14) lexicosemantic abnormalities (LS+ vs. LS-) and patients with (n = 19) or without (n = 10) arthric disorders (A+ vs. A-), and (c). patients with or without atrophy. RESULTS: In the 29 patients, the PI was significantly lower in the left temporopolar, left lateral temporal, left Wernicke, left parietal, and right lateral temporal cortex when compared with control subjects (P < 0.001). In LS+ patients versus control subjects, the PI significantly decreased in the left temporal cortex (lateral temporal; medial temporal; temporopolar; Wernicke), left Broca, left parietal, and right lateral temporal cortex (P < 0.001). In addition, LS+ versus LS- comparison showed a significant decrease in the left lateral, left medial temporal, and left Broca cortex (P < 0.001). In comparison with control subjects, the PI was not significantly different in A+ patients, whereas in A- patients the PI was significantly decreased in the left and right lateral temporal cortex, left Wernicke, and left parietal cortex. Moreover, the PI significantly decreased in the left lateral temporal region in A+ patients compared with A- patients. Finally, in patients without atrophy, the PI significantly decreased in the right and left lateral temporal cortex and the left parietal cortex (P < 0.01). CONCLUSION: Our study demonstrates that right-handed patients with PPA present a decreased perfusion in the bilateral temporal cortex. Moreover, in these regions, morphologic abnormalities are preceded by perfusion abnormalities. Finally, our results show that large left temporal dysfunction occurs in patients with LS disorders.