The changing landscape of electrical stimulation language mapping with subdural electrodes and stereoelectroencephalography for pediatric epilepsy: A literature review and commentary.

Electrical stimulation mapping (ESM) is used to locate the brain areas supporting language directly within the human cortex to minimize the risk of functional decline following epilepsy surgery. ESM is completed by utilizing subdural grid or depth electrodes (stereo-electroencephalography [sEEG]) in combination with behavioral evaluation of language. Despite technological advances, there is no standardized method of assessing language during pediatric ESM. To identify current clinical practices for pediatric ESM of language, we surveyed neuropsychologists in the Pediatric Epilepsy Research Consortium. Results indicated that sEEG is used for functional mapping at >80% of participating epilepsy surgery centers (n = 13/16) in the United States. However, >65% of sites did not report a standardized protocol to map language. Survey results indicated a clear need for practice recommendations regarding ESM of language. We then utilized PubMed/Medline and PsychInfo to identify 42 articles that reported on ESM of language, of which 18 met inclusion criteria, which included use of ESM/signal recording to localize language regions in children (<21 years) and a detailed account of the procedure and language measures used, and region-specific language localization outcomes. Articles were grouped based on the language domain assessed, language measures used, and the brain regions involved. Our review revealed the need for evidence-based clinical guidelines for pediatric language paradigms during ESM and a standardized language mapping protocol as well as standardized reporting of brain regions in research. Relevant limitations and future directions are discussed with a focus on considerations for pediatric language mapping.

Comparison of fMRI language laterality with and without sedation in pediatric epilepsy.

Functional MRI is an essential component of presurgical language mapping. In clinical settings, young children may be sedated for the MRI with the functional stimuli presented passively. Research has found that sedation changes language activation in healthy adults and children. However, there is limited research comparing sedated and unsedated functional MRI in pediatric epilepsy patients. We compared language activation patterns in children with epilepsy who received sedation for functional MRI to the ones who did not. We retrospectively identified the patients with focal epilepsy who underwent presurgical functional MRI including Auditory Descriptive Decision Task at Boston Children's Hospital from 2014 to 2022. Patients were divided into sedated and awake groups, based on their sedation status during functional MRI. Auditory Descriptive Decision Task stimuli were presented passively to the sedated group per clinical protocol. We extracted language activation maps contrasted against a control task (reverse speech) in the Frontal and Temporal language regions and calculated separate language laterality indexes for each region. We considered positive laterality indexes as left dominant, negative laterality indexes as right dominant, and absolute laterality indexes <0.2 as bilateral. We defined 2 language patterns: typical (i.e., primarily left-sided) and atypical. Typical pattern required at least one left dominant region (either frontal or temporal) and no right dominant region. We then compared the language patterns between the sedated and awake groups. Seventy patients met the inclusion criteria, 25 sedated, and 45 awake. Using the Auditory Descriptive Decision Task paradigm, when adjusted for age, handedness, gender, and laterality of lesion in a weighted logistic regression model, the odds of the atypical pattern were 13.2 times higher in the sedated group compared to the awake group (Confidence Interval: 2.55-68.41, p-value < 0.01). Sedation may alter language activation patterns in pediatric epilepsy patients. Language patterns on sedated functional MRI with passive tasks may not represent language networks during wakefulness, sedation may differentially suppress some networks, or require a different task or method of analysis to capture the awake language network. Given the critical surgical implication of these findings, additional studies are needed to better understand how sedation impacts the functional MRI blood oxygenation level-dependent signal. Consistent with current practice, sedated functional MRI should be interpreted with greater caution and requires additional validation as well as research on post-surgical language outcomes.

Functional Connectivity as a Potential Mechanism for Language Plasticity.

BACKGROUND AND OBJECTIVES: Task fMRI is a clinical tool for language lateralization, but has limitations, and cannot provide information about network-level plasticity. Additional methods are needed to improve the precision of presurgical language mapping. We investigate language resting-state functional connectivity (RS fMRI; FC) in typically developing children (TD) and children with epilepsy. Our objectives were to (1) understand how FC components differ between TD children and those with epilepsy; (2) elucidate how the location of disease (frontal/temporal epilepsy foci) affects FC; and (3) investigate the relationship between age and FC. METHODS: Our sample included 55 TD children (mean age 12 years, range 7-18) and 31 patients with focal epilepsy (mean age 13 years, range 7-18). All participants underwent RS fMRI. Using a bilateral canonical language map as target, vertex-wise intrahemispheric FC map and interhemispheric FC map for each participant were computed and thresholded at top 10% to compute an FC laterality index (FCLI; [(L - R)/(L + R)]) of the frontal and temporal regions for both integration (intrahemispheric FC; FCLIi) and segregation (interhemispheric FC; FCLIs) maps. RESULTS: We found FC differences in the developing language network based on disease, seizure foci location, and age. Frontal and temporal FCLIi was different between groups (t[84] = 2.82, p < 0.01; t[84] = 4.68, p < 0.01, respectively). Frontal epilepsy foci had the largest differences from TD (Cohen d frontal FCLIi = 0.84, FCLIs = 0.51; temporal FCLIi = 1.29). Development and disease have opposing influences on the laterality of FC based on groups. In the frontal foci group, FCLIi decreased with age (r = -0.42), whereas in the temporal foci group, FCLIi increased with age (r = 0.40). Within the epilepsy group, increases in right frontal integration FCLI relates to increased right frontal task activation in our mostly left language dominant group (r = 0.52, p < 0.01). Language network connectivity is associated with higher verbal intelligence in children with epilepsy (r = 0.45, p < 0.05). DISCUSSION: These findings lend preliminary evidence that FC reflects network plasticity in the form of adaptation and compensation, or the ability to recruit support and reallocate resources within and outside of the traditional network to compensate for disease. FC expands on task-based fMRI and provides complementary and potentially useful information about the language network that is not captured using task-based fMRI alone.

Double Dissociation of Auditory Attention Span and Visual Attention in Long-Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways.

OBJECTIVE: Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation. METHODS: Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment. RESULTS: A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62). CONCLUSIONS: The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

Neuroimaging of the component white matter connections and structures within the cerebellar-frontal pathway in posterior fossa tumor survivors.

INTRODUCTION: In posterior fossa tumor survivors, lower white matter integrity (WMI) in the right cerebellar-left frontal pathway has been well documented and appears to be related to proximity to the cerebellum, radiation treatment, as well as time since treatment in both cranial radiation and surgery-only treatment groups. The current study investigated theories of transneural degeneration following cerebellar tumor resection that may underlie or relate to reductions in WMI and regional brain volumes using correlations. We hypothesized a positive relationship between the volume of the right cerebellum and known white matter output pathways, as well as with the volume of structures that receive cerebellar projections along the pathway. METHODS: Adult survivors of childhood brain tumors were recruited (n = 29; age, M = 22 years, SD = 5; 45% female). Age- and gender-matched controls were also included (n = 29). Participants completed 3 T diffusion-weighted and T1 MPRAGE MRI scans. Brain structure volume relative to intracranial vault served as regional volumetric measures. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. In the survivor group, partial correlations between WMI and regional volume included controlling for disease severity. RESULTS: In posterior fossa tumor survivors, the volumes of the cerebellum, thalamus, and frontal lobe were correlated with WMI of the thalamic-frontal segment of the cerebellar-frontal pathway (r = 0.41-0.49, p < .05). Cerebellar atrophy was correlated with reduced WMI in the cerebellar-rubral segment (FA, r = -0.32 p > .05; RD, r = 0.53, p < .01). In the no-radiation survivor group, the regional volume of each structure along the pathway was associated with WMI in the cerebellar-rubral segment. In the radiation survivor group, significant correlations were found between the regional brain volume of each structure and the thalamic-frontal segment of the pathway. DISCUSSION: The results of this multimodal neuroimaging study provide correlational evidence that the mechanism of injury subsequent to brain tumor treatment may be different depending on type of treatment(s). Without radiation, the primary mechanism of injury is cerebellar tumor growth, resection, and hydrocephalus. Therefore, the most proximal connection to that injury (cerebellar-rubral pathway) was correlated with reductions in volume along the pathway. In contrast, the survivor group treated with radiation may have had possible radiation-induced demyelination of the thalamic-frontal portion of the pathway, based on a strong correlation with volume loss in the cerebellum, red nucleus, thalamus, and frontal lobe.

Neurodevelopmental model of long-term outcomes of adult survivors of childhood brain tumors.

Childhood brain tumors and related treatments disrupt the developing brain and have a cascading impact on core cognitive skills and intellectual (intelligence quotient [IQ]) and academic achievement outcomes. Theoretical models for this cascade have been developed based on the literature, but no studies thus far have empirically evaluated the models. The current study aimed to empirically test the two extant models and generate a new data-driven model of the relationships among neurodevelopmental risk factors, core cognitive skills (i.e., processing speed, attention span, working memory), and IQ and achievement outcomes. Fifty-seven adult survivors of childhood brain tumors and fifty-seven demographically matched neurotypical individuals were included in the current study. The average age at brain tumor diagnosis was 8 years, and the average time since diagnosis was 17 years. Three a priori path models tested the hypothesized relationships among variables. Results of the path analyses revealed that the hybrid model best fit the data for both survivors and controls based on all statistical criteria. For survivors, processing speed was the core cognitive skill most widely associated with neurodevelopmental risk factors and outcomes. However, working memory and attention span also had unique contributions to IQ and academic achievement. Processing speed appears to be the central cognitive skill that disrupts the other core cognitive skills of attention span and working memory, and all three make a unique contribution to IQ and academic achievement. This is best demonstrated by a novel neurodevelopmental model that combines components of two earlier untested theoretical models.

Childhood Brain Tumors: a Systematic Review of the Structural Neuroimaging Literature.

Due to medical advances, a large portion of children survive brain tumor diagnosis and treatment. Therefore, it is important to identify the neuroanatomical and neurocognitive outcomes associated with survivorship. This review summarizes the specific regional structural neuroimaging findings, the broad structural findings, as well as the corresponding neurocognitive domains affected in brain tumor populations. Across studies, damage is commonly reported near the cerebellum, brain stem, and subcortical regions, as well as the frontal lobes. These results are consistent with the expected neuroanatomical damage following posterior fossa brain tumors, which was the most common tumor location of the studies in this review. Damage to these regions impacts a broad range of neurocognitive outcomes, as well as a number of specific neurocognitive domains. Damage to more ventral and subcortical brain regions correlated with lower motor speed, processing speed, attention, and memory. Relevant limitations and future directions are discussed with a focus on disentangling the complex and multifaceted factors associated with the consequences of brain tumor survivorship.

Cerebellar Atrophy in Adult Survivors of Childhood Cerebellar Tumor.

OBJECTIVES: The cerebellum (CB) is known for its role in supporting processing speed (PS) and cognitive efficiencies. The CB often sustains damage from treatment and resection in pediatric patients with posterior fossa tumors. Limited research suggests that CB atrophy may be associated with the radiation treatment experienced during childhood. The purpose of the study was to measure cerebellar atrophy to determine its neurobehavioral correlates. METHODS: Brain magnetic resonance images were collected from 25 adult survivors of CB tumors and age- and gender-matched controls (M age= 24 years (SD=5), 52% female). Average age at diagnosis was 9 years (SD=5) and average time since diagnosis was 15 years (SD=5). PS was measured by the Symbol Digit Modality Test. To quantify atrophy, an objective formula was developed based on prior literature, in which Atrophy=[(CB White+CB Gray Volume)/Intracranial Vault (ICV)]controls-[(CB White+CB Gray+Lesion Size Volume)/ICV]survivors. RESULTS: Regression analyses found that the interaction term (age at diagnosis*radiation) predicts CB atrophy; regression equations included the Neurological Predictor Scale, lesion size, atrophy, and the interaction term and accounted for 33% of the variance in oral PS and 48% of the variance in written PS. Both interactions suggest that individuals with smaller CB lesion size but a greater degree of CB atrophy had slower PS, whereas individuals with a larger CB lesion size and less CB atrophy were less affected. CONCLUSION: The results of the current study suggest that young age at diagnosis and radiation is associated with CB atrophy, which interacts with lesion size to impact both written and oral PS.