Cortical and white matter substrates supporting visuospatial working memory.

OBJECTIVE: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance. METHODS: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts. RESULTS: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76. CONCLUSIONS: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways. SIGNIFICANCE: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Arteries Around the Superior Limiting Sulcus: Motor Complication Avoidance in Insular and Insulo-Opercular Surgery.

BACKGROUND AND OBJECTIVES: Insulo-opercular surgery can cause ischemic motor complications. A source of this is the arteries around the superior limiting sulcus (SLS), which reach the corona radiata, but the detailed anatomy remains unclear. To characterize arteries around the SLS including the long insular arteries (LIAs) and long medullary arteries, we classified them and examined their distribution in relation to the SLS, which helps reduce the risk of ischemia. METHODS: Twenty adult cadaveric hemispheres were studied. Coronal brain slices were created perpendicular to the SLS representing insular gyri (anterior short, middle short, posterior short, anterior long, and posterior long). The arteries within 10-mm proximity of the SLS that reached the corona radiata were excavated and classified by the entry point. RESULTS: A total of 122 arteries were identified. Sixty-three (52%), 20 (16%), and 39 (32%) arteries penetrated the insula (LIAs), peak of the SLS, and operculum (long medullary arteries), respectively. 100 and six (87%) arteries penetrated within 5 mm of the peak of the SLS. The arteries were distributed in the anterior short gyrus (19%), middle short gyrus (17%), posterior short gyrus (20%), anterior long gyrus (19%), and posterior long gyrus (25%). Seven arteries (5.7%) had anastomoses after they penetrated the parenchyma. CONCLUSION: Approximately 90% of the arteries that entered the parenchyma and reached the corona radiata were within a 5-mm radius of the SLS in both the insula and operculum side. This suggests that using the SLS as a landmark during insulo-opercular surgery can decrease the chance of ischemia.

Developmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves.

We investigated the developmental changes in high-frequency oscillation (HFO) and Modulation Index (MI) - the coupling measure between HFO and slow-wave phase. We generated normative brain atlases, using subdural EEG signals from 8251 nonepileptic electrode sites in 114 patients (ages 1.0-41.5 years) who achieved seizure control following resective epilepsy surgery. We observed a higher MI in the occipital lobe across all ages, and occipital MI increased notably during early childhood. The cortical areas exhibiting MI co-growth were connected via the vertical occipital fasciculi and posterior callosal fibers. While occipital HFO rate showed no significant age-association, the temporal, frontal, and parietal lobes exhibited an age-inversed HFO rate. Assessment of 1006 seizure onset sites revealed that z-score normalized MI and HFO rate were higher at seizure onset versus nonepileptic electrode sites. We have publicly shared our intracranial EEG data to enable investigators to validate MI and HFO-centric presurgical evaluations to identify the epileptogenic zone.

Dynamic cortical and tractography atlases of proactive and reactive alpha and high-gamma activities.

Alpha waves-posterior dominant rhythms at 8-12 Hz reactive to eye opening and closure-are among the most fundamental EEG findings in clinical practice and research since Hans Berger first documented them in the early 20th century. Yet, the exact network dynamics of alpha waves in regard to eye movements remains unknown. High-gamma activity at 70-110 Hz is also reactive to eye movements and a summary measure of local cortical activation supporting sensorimotor or cognitive function. We aimed to build the first-ever brain atlases directly visualizing the network dynamics of eye movement-related alpha and high-gamma modulations, at cortical and white matter levels. We studied 28 patients (age: 5-20 years) who underwent intracranial EEG and electro-oculography recordings. We measured alpha and high-gamma modulations at 2167 electrode sites outside the seizure onset zone, interictal spike-generating areas and MRI-visible structural lesions. Dynamic tractography animated white matter streamlines modulated significantly and simultaneously beyond chance, on a millisecond scale. Before eye-closure onset, significant alpha augmentation occurred at the occipital and frontal cortices. After eye-closure onset, alpha-based functional connectivity was strengthened, while high gamma-based connectivity was weakened extensively in both intra-hemispheric and inter-hemispheric pathways involving the central visual areas. The inferior fronto-occipital fasciculus supported the strengthened alpha co-augmentation-based functional connectivity between occipital and frontal lobe regions, whereas the posterior corpus callosum supported the inter-hemispheric functional connectivity between the occipital lobes. After eye-opening offset, significant high-gamma augmentation and alpha attenuation occurred at occipital, fusiform and inferior parietal cortices. High gamma co-augmentation-based functional connectivity was strengthened, whereas alpha-based connectivity was weakened in the posterior inter-hemispheric and intra-hemispheric white matter pathways involving central and peripheral visual areas. Our results do not support the notion that eye closure-related alpha augmentation uniformly reflects feedforward or feedback rhythms propagating from lower to higher order visual cortex, or vice versa. Rather, proactive and reactive alpha waves involve extensive, distinct white matter networks that include the frontal lobe cortices, along with low- and high-order visual areas. High-gamma co-attenuation coupled to alpha co-augmentation in shared brain circuitry after eye closure supports the notion of an idling role for alpha waves during eye closure. These normative dynamic tractography atlases may improve understanding of the significance of EEG alpha waves in assessing the functional integrity of brain networks in clinical practice; they also may help elucidate the effects of eye movements on task-related brain network measures observed in cognitive neuroscience research.

Incomplete hippocampal inversion in patients with mutations in genes involved in sonic hedgehog signaling.

Sonic hedgehog (Shh) signaling pathways are known to play an important role in the morphological development of the hippocampus in vivo, but their actual roles in humans have not been clarified. Hypothalamic hamartoma (HH) is known to be associated with germline or somatic gene mutations of Shh signaling. We hypothesized that patients with HH and mutations of Shh-related genes also show hippocampal maldevelopment and an abnormal hippocampal infolding angle (HIA). We analyzed 45 patients (age: 1-37 years) with HH who underwent stereotactic radiofrequency thermocoagulation and found Shh-related gene mutations in 20 patients. In addition, 44 pediatric patients without HH (age: 2-25 years) who underwent magnetic resonance imaging (MRI) examinations under the same conditions during the same period were included in this study as a control group. HIA evaluated on MRI was compared between patients with gene mutations and the control group. The median HIA at the cerebral peduncle slice in patients with the gene mutation was 74.36° on the left and 76.11° on the right, and these values were significantly smaller than the corresponding values in the control group (80.46° and 80.56°, respectively, p < 0.01). Thus, mutations of Shh-related genes were correlated to incomplete hippocampal inversion. The HIA, particularly at the cerebral peduncle slice, is a potential indicator of abnormalities of the Shh-signaling pathway.

Sevoflurane-induced high-frequency oscillations, effective connectivity and intraoperative classification of epileptic brain areas.

OBJECTIVE: To determine how sevoflurane anesthesia modulates intraoperative epilepsy biomarkers on electrocorticography, including high-frequency oscillation (HFO) effective connectivity (EC), and to investigate their relation to epileptogenicity and anatomical white matter. METHODS: We studied eight pediatric drug-resistant focal epilepsy patients who achieved seizure control after invasive monitoring and resective surgery. We visualized spatial distributions of the electrocorticography biomarkers at an oxygen baseline, three time-points while sevoflurane was increasing, and at a plateau of 2 minimum alveolar concentration (MAC) sevoflurane. HFO EC was combined with diffusion-weighted imaging, in dynamic tractography. RESULTS: Intraoperative HFO EC diffusely increased as a function of sevoflurane concentration, although most in epileptogenic sites (defined as those included in the resection); their ability to classify epileptogenicity was optimized at sevoflurane 2 MAC. HFO EC could be visualized on major white matter tracts, as a function of sevoflurane level. CONCLUSIONS: The results strengthened the hypothesis that sevoflurane-activated HFO biomarkers may help intraoperatively localize the epileptogenic zone. SIGNIFICANCE: Our results help characterize how HFOs at non-epileptogenic and epileptogenic networks respond to sevoflurane. It may be warranted to establish a normative HFO atlas incorporating the modifying effects of sevoflurane and major white matter pathways, as critical reference in epilepsy presurgical evaluation.

Intra- and inter-hemispheric network dynamics supporting object recognition and speech production.

We built normative brain atlases that animate millisecond-scale intra- and inter-hemispheric white matter-level connectivity dynamics supporting object recognition and speech production. We quantified electrocorticographic modulations during three naming tasks using event-related high-gamma activity from 1,114 nonepileptogenic intracranial electrodes (i.e., non-lesional areas unaffected by epileptiform discharges). Using this electrocorticography data, we visualized functional connectivity modulations defined as significant naming-related high-gamma modulations occurring simultaneously at two sites connected by direct white matter streamlines on diffusion-weighted imaging tractography. Immediately after stimulus onset, intra- and inter-hemispheric functional connectivity enhancements were confined mainly across modality-specific perceptual regions. During response preparation, left intra-hemispheric connectivity enhancements propagated in a posterior-to-anterior direction, involving the left precentral and prefrontal areas. After overt response onset, inter- and intra-hemispheric connectivity enhancements mainly encompassed precentral, postcentral, and superior-temporal (STG) gyri. We found task-specific connectivity enhancements during response preparation as follows. Picture naming enhanced activity along the left arcuate fasciculus between the inferior-temporal and precentral/posterior inferior-frontal (pIFG) gyri. Nonspeech environmental sound naming augmented functional connectivity via the left inferior longitudinal and fronto-occipital fasciculi between the medial-occipital and STG/pIFG. Auditory descriptive naming task enhanced usage of the left frontal U-fibers, involving the middle-frontal gyrus. Taken together, the commonly observed network enhancements include inter-hemispheric connectivity optimizing perceptual processing exerted in each hemisphere, left intra-hemispheric connectivity supporting semantic and lexical processing, and inter-hemispheric connectivity for symmetric oral movements during overt speech. Our atlases improve the currently available models of object recognition and speech production by adding neural dynamics via direct intra- and inter-hemispheric white matter tracts.

Developmental organization of neural dynamics supporting auditory perception.

PURPOSE: A prominent view of language acquisition involves learning to ignore irrelevant auditory signals through functional reorganization, enabling more efficient processing of relevant information. Yet, few studies have characterized the neural spatiotemporal dynamics supporting rapid detection and subsequent disregard of irrelevant auditory information, in the developing brain. To address this unknown, the present study modeled the developmental acquisition of cost-efficient neural dynamics for auditory processing, using intracranial electrocorticographic responses measured in individuals receiving standard-of-care treatment for drug-resistant, focal epilepsy. We also provided evidence demonstrating the maturation of an anterior-to-posterior functional division within the superior-temporal gyrus (STG), which is known to exist in the adult STG. METHODS: We studied 32 patients undergoing extraoperative electrocorticography (age range: eight months to 28 years) and analyzed 2,039 intracranial electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI lesions. Patients were given forward (normal) speech sounds, backward-played speech sounds, and signal-correlated noises during a task-free condition. We then quantified sound processing-related neural costs at given time windows using high-gamma amplitude at 70-110 Hz and animated the group-level high-gamma dynamics on a spatially normalized three-dimensional brain surface. Finally, we determined if age independently contributed to high-gamma dynamics across brain regions and time windows. RESULTS: Group-level analysis of noise-related neural costs in the STG revealed developmental enhancement of early high-gamma augmentation and diminution of delayed augmentation. Analysis of speech-related high-gamma activity demonstrated an anterior-to-posterior functional parcellation in the STG. The left anterior STG showed sustained augmentation throughout stimulus presentation, whereas the left posterior STG showed transient augmentation after stimulus onset. We found a double dissociation between the locations and developmental changes in speech sound-related high-gamma dynamics. Early left anterior STG high-gamma augmentation (i.e., within 200 ms post-stimulus onset) showed developmental enhancement, whereas delayed left posterior STG high-gamma augmentation declined with development. CONCLUSIONS: Our observations support the model that, with age, the human STG refines neural dynamics to rapidly detect and subsequently disregard uninformative acoustic noises. Our study also supports the notion that the anterior-to-posterior functional division within the left STG is gradually strengthened for efficient speech-sound perception after birth.

Temporally and functionally distinct large-scale brain network dynamics supporting task switching.

OBJECTIVE: Our daily activities require frequent switches among competing responses at the millisecond time scale. We determined the spatiotemporal characteristics and functional significance of rapid, large-scale brain network dynamics during task switching. METHODS: This cross-sectional study investigated patients with drug-resistant focal epilepsy who played a Lumosity cognitive flexibility training game during intracranial electroencephalography (iEEG) recording. According to a given task rule, unpredictably switching across trials, participants had to swipe the screen in the direction the stimulus was pointing or moving. Using this data, we described the spatiotemporal characteristics of iEEG high-gamma augmentation occurring more intensely during switch than repeat trials, unattributable to the effect of task rule (pointing or moving), within-stimulus congruence (the direction of stimulus pointing and moving was same or different in a given trial), or accuracy of an immediately preceding response. Diffusion-weighted imaging (DWI) tractography determined whether distant cortical regions showing enhanced activation during task switch trials were directly connected by white matter tracts. Trial-by-trial iEEG analysis deduced whether the intensity of task switch-related high-gamma augmentation was altered through practice and whether high-gamma amplitude predicted the accuracy of an upcoming response among switch trials. RESULTS: The average number of completed trials during five-minute gameplay was 221.4 per patient (range: 171-285). Task switch trials increased the response times, whereas later trials reduced them. Analysis of iEEG signals sampled from 860 brain sites effectively elucidated the distinct spatiotemporal characteristics of task switch, task rule, and post-error-specific high-gamma modulations. Post-cue, task switch-related high-gamma augmentation was initiated in the right calcarine cortex after 260 ms, right precuneus after 330 ms, right entorhinal after 420 ms, and bilateral anterior middle-frontal gyri after 450 ms. DWI tractography successfully showed the presence of direct white matter tracts connecting the right visual areas to the precuneus and anterior middle-frontal regions but not between the right precuneus and anterior middle-frontal regions. Task-related high-gamma amplitudes in later trials were reduced in the calcarine, entorhinal and anterior middle-frontal regions, but increased in the precuneus. Functionally, enhanced post-cue precuneus high-gamma augmentation improved the accuracy of subsequent responses among switch trials. CONCLUSIONS: Our multimodal analysis uncovered two temporally and functionally distinct network dynamics supporting task switching. High-gamma augmentation in the visual-precuneus pathway may reflect the neural process facilitating an attentional shift to a given updated task rule. High-gamma activity in the visual-dorsolateral prefrontal pathway, rapidly reduced through practice, may reflect the cost of executing appropriate stimulus-response translation.

Naming-related spectral responses predict neuropsychological outcome after epilepsy surgery.

This prospective study determined the use of intracranially recorded spectral responses during naming tasks in predicting neuropsychological performance following epilepsy surgery. We recruited 65 patients with drug-resistant focal epilepsy who underwent preoperative neuropsychological assessment and intracranial EEG recording. The Clinical Evaluation of Language Fundamentals evaluated the baseline and postoperative language function. During extra-operative intracranial EEG recording, we assigned patients to undergo auditory and picture naming tasks. Time-frequency analysis determined the spatiotemporal characteristics of naming-related amplitude modulations, including high gamma augmentation at 70-110 Hz. We surgically removed the presumed epileptogenic zone based on the intracranial EEG and MRI abnormalities while maximally preserving the eloquent areas defined by electrical stimulation mapping. The multivariate regression model incorporating auditory naming-related high gamma augmentation predicted the postoperative changes in Core Language Score with r2 of 0.37 and in Expressive Language Index with r2 of 0.32. Independently of the effects of epilepsy and neuroimaging profiles, higher high gamma augmentation at the resected language-dominant hemispheric area predicted a more severe postoperative decline in Core Language Score and Expressive Language Index. Conversely, the model incorporating picture naming-related high gamma augmentation predicted the change in Receptive Language Index with an r2 of 0.50. Higher high gamma augmentation independently predicted a more severe postoperative decline in Receptive Language Index. Ancillary regression analysis indicated that naming-related low gamma augmentation and alpha/beta attenuation likewise independently predicted a more severe Core Language Score decline. The machine learning-based prediction model suggested that naming-related high gamma augmentation, among all spectral responses used as predictors, most strongly contributed to the improved prediction of patients showing a >5-point Core Language Score decline (reflecting the lower 25th percentile among patients). We generated the model-based atlas visualizing sites, which, if resected, would lead to such a language decline. With a 5-fold cross-validation procedure, the auditory naming-based model predicted patients who had such a postoperative language decline with an accuracy of 0.80. The model indicated that virtual resection of an electrical stimulation mapping-defined language site would have increased the relative risk of the Core Language Score decline by 5.28 (95% confidence interval: 3.47-8.02). Especially, that of an electrical stimulation mapping-defined receptive language site would have maximized it to 15.90 (95% confidence interval: 9.59-26.33). In summary, naming-related spectral responses predict neuropsychological outcomes after epilepsy surgery. We have provided our prediction model as an open-source material, which will indicate the postoperative language function of future patients and facilitate external validation at tertiary epilepsy centres.

Sevoflurane-based enhancement of phase-amplitude coupling and localization of the epileptogenic zone.

OBJECTIVE: Phase-amplitude coupling between high-frequency (≥150 Hz) and delta (3-4 Hz) oscillations - modulation index (MI) - is a promising, objective biomarker of epileptogenicity. We determined whether sevoflurane anesthesia preferentially enhances this metric within the epileptogenic zone. METHODS: This is an observational study of intraoperative electrocorticography data from 621 electrodes chronically implanted into eight patients with drug-resistant, focal epilepsy. All patients were anesthetized with sevoflurane during resective surgery, which subsequently resulted in seizure control. We classified 'removed' and 'retained' brain sites as epileptogenic and non-epileptogenic, respectively. Mixed model analysis determined which anesthetic stage optimized MI-based classification of epileptogenic sites. RESULTS: MI increased as a function of anesthetic stage, ranging from baseline (i.e., oxygen alone) to 2.0 minimum alveolar concentration (MAC) of sevoflurane, preferentially at sites showing higher initial MI values. This phenomenon was accentuated just prior to sevoflurane reaching 2.0 MAC, at which time, the odds of a site being classified as epileptogenic were enhanced by 86.6 times for every increase of 1.0 MI. CONCLUSIONS: Intraoperative MI best localized the epileptogenic zone immediately before sevoflurane reaching 2.0 MAC in this small cohort of patients. SIGNIFICANCE: Prospective, large cohort studies are warranted to determine whether sevoflurane anesthesia can reduce the need for extraoperative, invasive evaluation.

Six-dimensional dynamic tractography atlas of language connectivity in the developing brain.

During a verbal conversation, our brain moves through a series of complex linguistic processing stages: sound decoding, semantic comprehension, retrieval of semantically coherent words, and overt production of speech outputs. Each process is thought to be supported by a network consisting of local and long-range connections bridging between major cortical areas. Both temporal and extratemporal lobe regions have functional compartments responsible for distinct language domains, including the perception and production of phonological and semantic components. This study provides quantitative evidence of how directly connected inter-lobar neocortical networks support distinct stages of linguistic processing across brain development. Novel six-dimensional tractography was used to intuitively visualize the strength and temporal dynamics of direct inter-lobar effective connectivity between cortical areas activated during each linguistic processing stage. We analysed 3401 non-epileptic intracranial electrode sites from 37 children with focal epilepsy (aged 5-20 years) who underwent extra-operative electrocorticography recording. Principal component analysis of auditory naming-related high-gamma modulations determined the relative involvement of each cortical area during each linguistic processing stage. To quantify direct effective connectivity, we delivered single-pulse electrical stimulation to 488 temporal and 1581 extratemporal lobe sites and measured the early cortico-cortical spectral responses at distant electrodes. Mixed model analyses determined the effects of naming-related high-gamma co-augmentation between connecting regions, age, and cerebral hemisphere on the strength of effective connectivity independent of epilepsy-related factors. Direct effective connectivity was strongest between extratemporal and temporal lobe site pairs, which were simultaneously activated between sentence offset and verbal response onset (i.e. response preparation period); this connectivity was approximately twice more robust than that with temporal lobe sites activated during stimulus listening or overt response. Conversely, extratemporal lobe sites activated during overt response were equally connected with temporal lobe language sites. Older age was associated with increased strength of inter-lobar effective connectivity especially between those activated during response preparation. The arcuate fasciculus supported approximately two-thirds of the direct effective connectivity pathways from temporal to extratemporal auditory language-related areas but only up to half of those in the opposite direction. The uncinate fasciculus consisted of <2% of those in the temporal-to-extratemporal direction and up to 6% of those in the opposite direction. We, for the first time, provided an atlas which quantifies and animates the strength, dynamics, and direction specificity of inter-lobar neural communications between language areas via the white matter pathways. Language-related effective connectivity may be strengthened in an age-dependent manner even after the age of 5.

Long-term satisfaction after extraoperative invasive EEG recording.

This retrospective cohort study investigated 53 patients with drug-resistant focal epilepsy and identified factors predictive of long-term satisfaction of patients and families following extraoperative intracranial EEG (iEEG) recording. The mixed model analysis assessed the utility of intracranial EEG (iEEG) predictor variables, including the seizure-onset zone (SOZ), modulation index (MI), and naming-related high-gamma activity. Modulation index, quantifying the coupling between high-frequency activity at >80 Hz and local slow wave at 3-4 Hz, effectively functions as a surrogate marker of the burden of interictal spike-and-slow-wave discharges. The mixed model specifically incorporated 'subtraction-MI', defined as the subtraction of mean z-score normalized MI across all preserved sites from that across all resected sites. Auditory naming-related high-gamma activity at 70-110 Hz is a biomarker to characterize the underlying language and speech function. The model incorporated 'maximum resected high-gamma', defined as the high-gamma percent change largest among sites included in the resected language-dominant hemispheric region. The model also incorporated the clinical and imaging profiles of given patients. The analysis revealed that complete removal of SOZ (p = 0.003) and younger patient age (p = 0.040) were independently associated with greater satisfaction. Neither 'subtraction-MI' nor 'maximum naming-related high-gamma' showed a significant and independent association with long-term satisfaction in our patient cohort. The observed impact of complete resection of SOZ and early surgery can be considered when counseling candidates for epilepsy surgery.

Spontaneous modulations of high-frequency cortical activity.

OBJECTIVE: We clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state. METHODS: We studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation. RESULTS: The dynamic atlas demonstrated transient high-gamma suppression in the striatal cortex before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%. CONCLUSIONS: We successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades. SIGNIFICANCE: Measuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.

Dynamic tractography-based localization of spike sources and animation of spike propagations.

OBJECTIVE: This study was undertaken to build and validate a novel dynamic tractography-based model for localizing interictal spike sources and visualizing monosynaptic spike propagations through the white matter. METHODS: This cross-sectional study investigated 1900 spike events recorded in 19 patients with drug-resistant temporal lobe epilepsy (TLE) who underwent extraoperative intracranial electroencephalography (iEEG) and resective surgery. Twelve patients had mesial TLE (mTLE) without a magnetic resonance imaging-visible mass lesion. The remaining seven had a mass lesion in the temporal lobe neocortex. We identified the leading and lagging sites, defined as those initially and subsequently (but within ≤50 ms) showing spike-related augmentation of broadband iEEG activity. In each patient, we estimated the sources of 100 spike discharges using the latencies at given electrode sites and diffusion-weighted imaging-based streamline length measures. We determined whether the spatial relationship between the estimated spike sources and resection was associated with postoperative seizure outcomes. We generated videos presenting the spatiotemporal change of spike-related fiber activation sites by estimating the propagation velocity using the streamline length and spike latency measures. RESULTS: The spike propagation velocity from the source was 1.03 mm/ms on average (95% confidence interval = .91-1.15) across 133 tracts noted in the 19 patients. The estimated spike sources in mTLE patients with International League Against Epilepsy Class 1 outcome were more likely to be in the resected area (83.9% vs. 72.3%, φ = .137, p < .001) and in the medial temporal lobe region (80.5% vs. 72.5%, φ = .090, p = .002) than those associated with the Class ≥2 outcomes. The resulting video successfully animated spike propagations, which were confined within the temporal lobe in mTLE but involved extratemporal lobe areas in lesional TLE. SIGNIFICANCE: We have, for the first time, provided dynamic tractography visualizing the spatiotemporal profiles of rapid propagations of interictal spikes through the white matter. Dynamic tractography has the potential to serve as a unique epilepsy biomarker.

Objective interictal electrophysiology biomarkers optimize prediction of epilepsy surgery outcome.

Researchers have looked for rapidly- and objectively-measurable electrophysiology biomarkers that accurately localize the epileptogenic zone. Promising candidates include interictal high-frequency oscillation and phase-amplitude coupling. Investigators have independently created the toolboxes that compute the high-frequency oscillation rate and the severity of phase-amplitude coupling. This study of 135 patients determined what toolboxes and analytic approaches would optimally classify patients achieving post-operative seizure control. Four different detector toolboxes computed the rate of high-frequency oscillation at ≥80 Hz at intracranial EEG channels. Another toolbox calculated the modulation index reflecting the strength of phase-amplitude coupling between high-frequency oscillation and slow-wave at 3-4 Hz. We defined the completeness of resection of interictally-abnormal regions as the subtraction of high-frequency oscillation rate (or modulation index) averaged across all preserved sites from that averaged across all resected sites. We computed the outcome classification accuracy of the logistic regression-based standard model considering clinical, ictal intracranial EEG and neuroimaging variables alone. We then determined how well the incorporation of high-frequency oscillation/modulation index would improve the standard model mentioned above. To assess the anatomical variability across non-epileptic sites, we generated the normative atlas of detector-specific high-frequency oscillation and modulation index. Each atlas allowed us to compute the statistical deviation of high-frequency oscillation/modulation index from the non-epileptic mean. We determined whether the model accuracy would be improved by incorporating absolute or normalized high-frequency oscillation/modulation index as a biomarker assessing interictally-abnormal regions. We finally determined whether the model accuracy would be improved by selectively incorporating high-frequency oscillation verified to have high-frequency oscillatory components unattributable to a high-pass filtering effect. Ninety-five patients achieved successful seizure control, defined as International League against Epilepsy class 1 outcome. Multivariate logistic regression analysis demonstrated that complete resection of interictally-abnormal regions additively increased the chance of success. The model accuracy was further improved by incorporating z-score normalized high-frequency oscillation/modulation index or selective incorporation of verified high-frequency oscillation. The standard model had a classification accuracy of 0.75. Incorporation of normalized high-frequency oscillation/modulation index or verified high-frequency oscillation improved the classification accuracy up to 0.82. These outcome prediction models survived the cross-validation process and demonstrated an agreement between the model-based likelihood of success and the observed success on an individual basis. Interictal high-frequency oscillation and modulation index had a comparably additive utility in epilepsy presurgical evaluation. Our empirical data support the theoretical notion that the prediction of post-operative seizure outcomes can be optimized with the consideration of both interictal and ictal abnormalities.

Four-dimensional tractography animates propagations of neural activation via distinct interhemispheric pathways.

OBJECTIVE: To visualize and validate the dynamics of interhemispheric neural propagations induced by single-pulse electrical stimulation (SPES). METHODS: This methodological study included three patients with drug-resistant focal epilepsy who underwent measurement of cortico-cortical spectral responses (CCSRs) during bilateral stereo-electroencephalography recording. We delivered SPES to 83 electrode pairs and analyzed CCSRs recorded at 268 nonepileptic electrode sites. Diffusion-weighted imaging (DWI) tractography localized the interhemispheric white matter pathways as streamlines directly connecting two electrode sites. We localized and visualized the putative SPES-related fiber activation, at each 1-ms time window, based on the propagation velocity defined as the DWI-based streamline length divided by the early CCSR peak latency. RESULTS: The resulting movie, herein referred to as four-dimensional tractography, delineated the spatiotemporal dynamics of fiber activation via the corpus callosum and anterior commissure. Longer streamline length was associated with delayed peak latency and smaller amplitude of CCSRs. The cortical regions adjacent to each fiber activation site indeed exhibited CCSRs at the same time window. CONCLUSIONS: Our four-dimensional tractography successfully animated neural propagations via distinct interhemispheric pathways. SIGNIFICANCE: Our novel animation method has the potential to help investigators in addressing the mechanistic significance of the interhemispheric network dynamics supporting physiological function.

Effects of depth electrode montage and single-pulse electrical stimulation sites on neuronal responses and effective connectivity.

OBJECTIVE: To determine the optimal depth electrode montages for the assessment of effective connectivity based on single-pulse electrical stimulation (SPES). To determine the effect of SPES locations on the extent of resulting neuronal propagations. METHODS: We studied 14 epilepsy patients who underwent invasive monitoring with depth electrodes and measurement of cortico-cortical evoked potentials (CCEPs) and cortico-cortical spectral responses (CCSRs). We determined the effects of electrode montage and stimulus sites on the CCEP/CCSR amplitudes. RESULTS: Bipolar and Laplacian montages effectively reduced the degree of SPES-related signal deflections at extra-cortical levels, including outside the brain, while maintaining those at the cortical level. SPES of structures more proximal to the deep white matter, compared to the cortical surface, elicited greater CCEPs and CCSRs. CONCLUSIONS: On depth electrode recording, bipolar and Laplacian montages are suitable for measurement of near-field CCEPs and CCSRs. SPES of the white matter axons may induce neuronal propagations to extensive regions of the cerebral cortex. SIGNIFICANCE: This study helps to establish the practical guidelines on the diagnostic use of CCEPs/CCSRs.

Dynamic tractography: Integrating cortico-cortical evoked potentials and diffusion imaging.

INTRODUCTION: Cortico-cortical evoked potentials (CCEPs) are utilized to identify effective networks in the human brain. Following single-pulse electrical stimulation of cortical electrodes, evoked responses are recorded from distant cortical areas. A negative deflection (N1) which occurs 10-50 â€‹ms post-stimulus is considered to be a marker for direct cortico-cortical connectivity. However, with CCEPs alone it is not possible to observe the white matter pathways that conduct the signal or accurately predict N1 amplitude and latency at downstream recoding sites. Here, we develop a new approach, termed "dynamic tractography," which integrates CCEP data with diffusion-weighted imaging (DWI) data collected from the same patients. This innovative method allows greater insights into cortico-cortical networks than provided by each method alone and may improve the understanding of large-scale networks that support cognitive functions. The dynamic tractography model produces several fundamental hypotheses which we investigate: 1) DWI-based pathlength predicts N1 latency; 2) DWI-based pathlength negatively predicts N1 voltage; and 3) fractional anisotropy (FA) along the white matter path predicts N1 propagation velocity. METHODS: Twenty-three neurosurgical patients with drug-resistant epilepsy underwent both extraoperative CCEP recordings and preoperative DWI scans. Subdural grids of 3 â€‹mm diameter electrodes were used for stimulation and recording, with 98-128 eligible electrodes per patient. CCEPs were elicited by trains of 1 â€‹Hz stimuli with an intensity of 5 â€‹mA and recorded at a sample rate of 1 â€‹kHz. N1 peak and latency were defined as the maximum of a negative deflection within 10-50 â€‹ms post-stimulus with a z-score > 5 relative to baseline. Electrodes and DWI were coregistered to construct electrode connectomes for white matter quantification. RESULTS: Clinical variables (age, sex, number of anti-epileptic drugs, handedness, and stimulated hemisphere) did not correlate with the key outcome measures (N1 peak amplitude, latency, velocity, or DWI pathlength). All subjects and electrodes were therefore pooled into a group-level analysis to determine overall patterns. As hypothesized, DWI path length positively predicted N1 latency (R2 â€‹= â€‹0.81, ߠ​= â€‹1.51, p â€‹= â€‹4.76e-16) and negatively predicted N1 voltage (R2 â€‹= â€‹0.79, ߠ​= â€‹-0.094, p â€‹= â€‹9.30e-15), while FA predicted N1 propagation velocity (R2 â€‹= â€‹0.35, ߠ​= â€‹48.0, p â€‹= â€‹0.001). CONCLUSION: We have demonstrated that the strength and timing of the CCEP N1 is dependent on the properties of the underlying white matter network. Integrated CCEP and DWI visualization allows robust localization of intact axonal pathways which effectively interconnect eloquent cortex.