OBJECTIVE: To validate models incorporating intracranial EEG-derived high-frequency activity (HFA) biomarkers for predicting the seizure onset zone (SOZ) and postsurgical seizure outcomes across independent cohorts and etiologies. METHODS: We quantified interictal HFA occurrence rates together with a comprehensive set of morphological features in people with drug-resistant epilepsy in a derivation cohort (N = 142), a temporal external cohort (N = 35), and two geographical external cohorts (N = 26 and N = 30). We developed models for SOZ localization using data from the 79 derivation cohort individuals who achieved postoperative seizure freedom. Model performance for SOZ localization and postoperative seizure outcome prediction was subsequently evaluated in the derivation, temporal external, and geographical external cohorts. RESULTS: HFA rate, spectral entropy, and power emerged as the most influential features for accurate SOZ classification. The model identified SOZ sites with areas under the curve (AUCs) up to 0.85, 0.86, and 0.75 in the derivation, temporal external, and geographical external cohorts, respectively. The model predicted postoperative seizure freedom in the derivation cohort (AUC up to 0.70) but failed to predict outcomes reliably in external cohorts. Among individuals in the external cohorts with MRI-nonlesional epilepsy, postoperative seizure freedom was predicted with an AUC of up to 0.73, whereas performance declined to 0.46 or lower among individuals with encephalomalacia. CONCLUSIONS: Integration of HFA rates with morphological features yields an SOZ-localization biomarker with cross-center generalizability, whereas postoperative outcome prediction remains dependent on underlying etiology. SIGNIFICANCE: A surgical strategy prioritizing resection of HFA-involved areas may be ineffective in individuals with encephalomalacia, underscoring the need for etiology-specific interpretation of HFA biomarkers.

PURPOSE: Functional/dissociative seizures (FDS) are challenging to diagnose. Video-electroencephalography monitoring, the gold standard for the diagnosis, is impractical for all patients. To improve FDS diagnosis, a scale for suspicion of psychogenic non-epileptic seizures (SS-PNES) was developed in Brazil, consisting of 15 items, on a scale of 0-3 for each item, combining epileptological questions, current and past psychiatric characteristics. A total score of 20 or more is considered as FDS-like. Here, the reliability and validity of SS-PNES were evaluated in a Japanese cohort. METHODS: The subjects were 250 of 326 patients who received a comprehensive epilepsy evaluation at our institution. Factor analyses were applied to the SS-PNES data. RESULTS: A two-factor model with six items was found to be optimal for FDS diagnosis, demonstrating acceptable reliability coefficients and validity to identify FDS. The two factors were named "emotional stress" and "psychiatric characteristics." Most patients with FDS and comorbid epilepsy showed high scores for both factors. However, nearly 40 % of epileptic seizure-only patients were misdiagnosed as FDS-like. CONCLUSION: In our Japanese cohort, the original 15-item scale did not show reproducibility, so a shortened version with a two-factor structure was developed and evaluated. The new SS-PNES-short had high sensitivity but low specificity for identifying FDS. The addition of epilepsy-specific factors may improve the specificity of SS-PNES.

BACKGROUND: Transition from pediatric to adult epilepsy care is increasingly recognized as a determinant of long-term health and social outcomes. This study examined whether transition before school graduation is associated with better adult mental health, social functioning, and employment among individuals with childhood-onset focal epilepsy. METHODS: We retrospectively analyzed 72 adults (35 females, 37 males; age 19-50 years) with childhood-onset focal epilepsy who received comprehensive inpatient evaluation. Participants were categorized into a pre-graduation group (transition during school years; n = 27) and a post-graduation group (transition after completion of education; n = 45). Primary outcomes were depressive symptoms and social functioning. Secondary outcomes included employment status and workplace epilepsy disclosure. Group differences were assessed using independent t tests and χ2 tests. Multivariable linear regression was used to examine independent predictors of psychosocial outcomes after adjusting for demographic, clinical, and psychosocial factors. RESULTS: Baseline demographic and clinical characteristics did not differ significantly between the two groups. Compared with post-graduation transition, pre-graduation transition was associated with significantly lower depressive symptoms (p < 0.01) and higher social functioning (p < 0.05). Employment rate (81.5% vs. 51.1%) was higher in the pre-graduation group (p < 0.05). In adjusted models, pre-graduation transition independently predicted lower depressive symptoms (p < 0.01) and higher social functioning (p < 0.05), even after adjusting for sex, seizure frequency, and other covariates. CONCLUSION: Transitioning to adult care before school graduation was associated with more favorable adult mental health, social participation, and vocational outcomes among individuals with childhood-onset focal epilepsy.

Although epilepsy surgery studies have proposed intracranial EEG-derived biomarkers for localizing seizure onset and anticipating postoperative outcomes, evaluation has often been limited to derivation cohorts using internal cross-validation. An influential notion holds that neurons distributed within the seizure onset zone (SOZ) frequently generate high-frequency activity (HFA) and that resection of such sites is associated with favorable postoperative seizure control. However, the extent to which these prediction models generalize to independent patient populations-and across diverse underlying etiologies-has remained largely untested. In this international, multi-center study of drug-resistant focal epilepsy, we retrospectively quantified HFA occurrence rates together with a comprehensive set of morphological features and integrated these metrics into predictive models for SOZ localization and postoperative seizure outcome. We then assessed model performance in fully independent datasets-a temporal external cohort and two geographical external cohorts-each entirely separate from the derivation cohort. In total, 5,142,891 HFA events observed across 22,939 electrodes from 233 patients were analyzed. Among the model inputs, HFA rate, spectral entropy, and power emerged as the most influential features for accurate SOZ classification. The model reliably identified clinician-defined SOZ sites across centers, achieving areas under the curve (AUCs) of up to 0.85 in the derivation cohort using 10-fold cross-validation, up to 0.86 in the temporal external cohort, and up to 0.75 in the geographical external cohorts. Within the derivation cohort, the model predicted postoperative seizure freedom with an AUC of up to 0.70. In contrast, postoperative seizure outcomes could not be predicted reliably across the external cohorts. Specifically, among external-cohort patients with MRI non-lesional epilepsy, postoperative seizure freedom was predicted with an AUC of up to 0.73, whereas performance declined to 0.46 or below among patients with encephalomalacia, an etiology characterized by chronic parenchymal damage and marked neuronal loss. Together, integration of HFA occurrence rates with morphological features yields an SOZ-localization biomarker with cross-center generalizability, whereas postoperative outcome prediction remains highly dependent on underlying etiology. Notably, a surgical strategy that prioritizes resection of HFA-involved areas does not appear to be applicable to patients with encephalomalacia and may be ineffective or even counterproductive in this population. A total of 97.86 GB of iEEG data are publicly available to facilitate external validation by the epilepsy surgery research community and the development of improved biomarkers for epileptogenic zone localization.

OBJECTIVE: The Wada test, an intracarotid amobarbital procedure, is the gold standard for preoperative evaluation of postoperative memory decline in patients with drug-resistant epilepsy. However, it has certain limitations including false negatives due to insufficient hippocampal inhibition and false positives due to extrahippocampal disorders such as aphasia. This study examined the utility of posterior cerebral artery (PCA) selective anesthesia for functional evaluation (SAFE) as an alternative approach to avoid aphasia and assessed its predictive value for postoperative verbal memory decline. METHODS: The authors conducted a single-center retrospective study of patients with drug-resistant epilepsy between May 2018 and December 2023, who subsequently underwent PCA SAFE before anterior temporal lobe resection. The SAFE protocol includes comparable memory tasks before and immediately after anesthetic infusion. Preinfusion assessments established baseline memory function, whereas postinfusion assessments evaluated brain function under selective anesthesia. Patients were required to memorize 8 words, 8 pictures, and 5 figures. After the anesthetic effects subsided, recognition tasks were performed for all presented stimuli. The memory score was calculated by subtracting the number of recognized items encoded under anesthesia from the baseline. Word recognition represented verbal memory, whereas figure recognition represented visual memory. A memory score ≥ 2 points on the side of the epileptic focus or no difference between left and right PCA SAFE was classified as a high risk of postoperative memory decline. A decline of ≥ 15 points in postoperative memory scores on the Wechsler Memory Scale-Revised was defined as significant memory decline. RESULTS: The authors included 11 patients (focus side: left in 8 patients and right in 3 patients). Five patients were classified as having a high risk and 6 as having a low risk for verbal memory decline. All 5 high-risk patients revealed significant postoperative verbal memory decline, whereas 5 of the 6 low-risk patients did not. The sensitivity was 83.3%, and the specificity was 100%. No patients had a significant decline in postoperative visual memory. CONCLUSIONS: PCA SAFE was shown to predict postoperative verbal memory decline with high accuracy. This study highlights the utility of PCA SAFE in reducing aphasic interference in verbal memory, leading to a more accurate evaluation of surgical candidacy in patients with drug-resistant epilepsy.

BACKGROUND: Functional/dissociative seizures (FDS) are often misdiagnosed as epilepsy, leading to delays in appropriate interventions. Although certain factors are associated with diagnostic delays, the overall referral trajectory remains unclear. This study aimed to illustrate the diagnostic journey with a novel visual approach, the "referral odyssey plot," and to depict patient pathways and identify factors associated with referral delays and diagnosis. METHODS: We retrospectively reviewed 50 patients diagnosed with documented FDS at Tohoku University Hospital (2014-2024). All patients underwent comprehensive inpatient evaluation, including long-term video-electroencephalogram monitoring, brain MRI, and psychosocial assessment. Four milestones were defined: seizure onset (T1), first non-epileptologist visit (T2), first epileptologist consultation (T3), and epilepsy monitoring unit admission (T4). Diagnostic pathways were visualized using a referral odyssey plot. Associations between variables and intervals were analyzed using Spearman's correlation, Friedman test, Mann-Whitney U test, and Kruskal-Wallis test. RESULTS: The median total delay (T1-T4) was 51 months (interquartile range: IQR, 83.8). The longest delay occurred between T2 and T3 (median, 41 months; IQR, 74.8) and strongly correlated with total delay (ρ=0.95, p < 0.001). Younger age at onset and a family history of epilepsy were significantly associated with longer T2-T3 intervals. Seizure worry scores were negatively correlated with T1-T2 intervals. CONCLUSION: Referral delay to an epileptologist was the main contributor to prolonged diagnosis of FDS. The referral odyssey plot visualized individual trajectories and bottlenecks, supporting earlier specialist referrals. These findings highlight the need for timely access to epileptologists experienced in the comprehensive evaluation of epilepsy and FDS.

Differentiating epileptic from non-epileptic seizures is the first step in the diagnosis of epilepsy. We investigated whether the density spectral array (DSA) of ictal EEG could differentiate between these seizures using a deep learning technique. We retrospectively reviewed consecutive patients with mesial temporal lobe epilepsy (mTLE) and functional/dissociative seizures (FDS) and analyzed seizures recorded using long-term video-EEG monitoring. The time of clinical onset was defined as zero, and the EEG recordings were clipped from -3 to + 3 min. Frequency analyses of Cz as well as means of C3 and C4, Fp1 and Fp2, O1 and O2, and all electrodes were performed to generate DSA with a linked-ear reference. ResNet34, which is a convolutional neural network (CNN) model, was trained and tested on these datasets. This study included 48 patients with mTLE and 51 with FDS. The CNN architecture was created using 40 patients with mTLE (91 seizures) and 40 with FDS (82 seizures) as training data, while eight patients with mTLE (15 seizures) and 11 with FDS (18 seizures) were evaluated using the model as test data. Exploratory analyses revealed that the Cz electrode and the Middle 1/3 interval yielded the highest area under the curve among the reduced-electrode settings (0.941), which was statistically confirmed by pre-specified DeLong tests after Bonferroni correction. The DSA of a single-channel EEG (Cz) successfully differentiated between epileptic and non-epileptic seizures using deep learning. These results highlight the potential of this approach as a practical adjunct to early screening and triage, particularly in resource-limited settings.

Epilepsy is a chronic neurological disorder that significantly impairs quality of life. Importantly, interest in seizure forecasting technologies has been growing in recent years. With the widespread adoption of noninvasive wearable devices, research has advanced in analyzing biological, behavioral, and environmental data using artificial intelligence to estimate individualized seizure risk. At Tohoku University, industry-academia collaborations have promoted the development and social implementation of machine-learning-based prediction models. This article provides an overview of the status and challenges of these efforts.

BACKGROUND AND OBJECTIVES: Diseased tissues in the human brain frequently exhibit marked alterations in structural and functional properties compared with adjacent, unaffected regions, whereas healthy tissues display intrinsic, milder topographical variability in these properties. We hypothesized that the epileptogenic zone responsible for drug-resistant focal seizures would be characterized by pronounced alterations in electrographic properties relative to adjacent regions. METHODS: This international, multicenter observational study aimed to test this hypothesis by studying patients with drug-resistant focal epilepsy who underwent curative epilepsy surgery following intracranial EEG (iEEG) recording, with at least 1 year of postoperative follow-up. In this study, "neural spatial volatility" was defined as differences in interictal high-frequency electrographic measures compared with adjacent areas. We tested whether greater neural spatial volatility in resected compared to preserved sites predicts postoperative seizure freedom, independently of clinical, neuroimaging, and ictal iEEG data. In addition, we examined whether incorporating neural spatial volatility into an outcome prediction model, based on the standard-care presurgical evaluation, would improve its performance. RESULTS: In a derivation cohort of 140 patients with 14,933 samples of iEEG electrodes (mean age 13.1 years; female 68 [48.6%]; postoperative seizure freedom 98 [70.0%]), greater neural spatial volatility in resected compared with preserved sites was an independent predictor of postoperative seizure freedom. The outcome prediction model considering the neural spatial volatility improved the classification performance, showing the area under the curve up to 0.825 (95% CI 0.747-0.902; p < 1.0 × 10-15). This result was validated in an independent test dataset of 26 patients with 1,626 samples of iEEG electrodes (mean age 25.7 years; female 14 [53.8%]; postoperative seizure freedom 16 [61.5%]) at a different institution, showing the improvement of prediction performance up to 0.819 (95% CI 0.653-0.985; p < 0.0005). DISCUSSION: Despite the limitations of the retrospective study and the relatively small validation cohort, our findings suggest that increased heterogeneity in the mesoscale distribution of interictal high-frequency activity is a distinguishing feature of the epileptogenic zone in drug-resistant focal epilepsy, potentially offering a novel marker for its localization.

Unawareness of weakness-defined as an explicit failure to recognize one's own limb paresis after brain damage-has long been considered predominantly linked to right-hemisphere dysfunction, yet its laterality remains controversial. We retrospectively analyzed 86 sessions of Selective Anesthesia for Functional Evaluation (SAFE) conducted in 53 patients with surgical epilepsy. SAFE involves delivering a short-acting anesthetic into a single cortical artery branch, resulting in reversible cortical suppression. Contralateral weakness was defined as a positive Barré sign in the upper limb, corresponding to a Manual Muscle Test score of <3. Following the anesthetic effect, patients were asked whether they had experienced any motor impairment. Explicit unawareness was probed using two standardized questions, followed by a limb-specific inquiry. Interviews were conducted in real-time during 28 infusions and repeated within 30 sec of motor recovery in the remaining 58 sessions. Unawareness occurred in 41 of 52 left-hemisphere infusions (78.8%) and in 26 of 34 right-hemisphere infusions (76.5%). Real-time and immediate post hoc ratings were concordant in 26 of 28 paired assessments (93%). Infusions into the M2-superior division were associated with higher rates of unawareness than those into the M2-inferior division (odds ratio = 2.3, 95% confidence interval: 1.1-5.1). Within this reversible perfusion-suppression model, the frequency of unawareness of weakness was hemispherically balanced, promoting a cautious re-evaluation of the presumed right-hemisphere dominance. SAFE provides a practical tool for isolating transient awareness deficits without structural injury and may help bridge pharmacological and lesion-based approaches to brain-behavior mapping.

OBJECTIVE: The Wada test, an intracarotid amobarbital procedure, is the gold standard for the preoperative evaluation of postoperative memory decline in patients with drug-resistant epilepsy. However, because the anesthetic perfuses the language areas, infusion into the language-dominant hemisphere also causes aphasia. Although it has been noted that aphasia may affect verbal memory scores in the Wada test, the extent of the effects has not been verified. This study aimed to examine the extent to which verbal memory is affected by aphasia induced by selective anesthetization of the proximal middle cerebral artery (M1) area (which does not affect the hippocampus) in patients with drug-resistant epilepsy. METHODS: This single-center retrospective analysis included patients with drug-resistant epilepsy who underwent the Selective Anesthesia for Functional Evaluation (SAFE) as a preoperative evaluation between May 2018 and December 2023. SAFE includes cognitive tasks of equal difficulty administered before and immediately after anesthetic infusion. The preinfusion assessments confirmed the baseline, whereas the postinfusion assessments evaluated brain function under selective anesthesia. The patients were required to memorize 8 words and 8 pictures. After the anesthetic effects subsided, recognition tasks were performed for both words and pictures. The number of words and pictures successfully recognized were counted as verbal and visual memory scores, respectively. Memory scores were compared between the left and right M1 infusions. RESULTS: Of the 180 SAFE trials conducted during the study period, 38 trials (25 left and 13 right M1 infusions) in 29 patients with confirmed left language dominance and propofol infusion into the M1 were included. All left M1 infusions induced aphasia without causing significant disturbances in consciousness that could have interfered with task completion. The results indicated significantly lower verbal memory scores during left M1 infusions than during right M1 infusions, whereas the visual memory scores were comparable. CONCLUSIONS: The verbal memory score was significantly lower after infusion into the M1 of the language-dominant hemisphere than into the nondominant hemisphere, suggesting that aphasia during stimulus encoding may impair verbal memory. Thus, the Wada test with intracarotid anesthetic infusion may not accurately assess memory function due to aphasia. This study highlights the utility of SAFE in reducing aphasic interference in verbal memory, leading to a more accurate evaluation of surgical candidacy in patients with epilepsy.

Reading engages complex neural networks integrating visual, phonological, and semantic information. The dual-stream model posits ventral and dorsal pathways for lexical and sublexical processing in the left hemisphere and is well-supported in alphabetic languages. However, its applicability to non-alphabetic scripts remains unclear. The Japanese writing system, comprising Kana (syllabograms) and Kanji (morphograms) with distinct orthographic, phonological, and semantic properties, provides a unique framework to investigate neural dissociation between phonological and orthographic-semantic processing. Previous studies suggest that Kanji relies on the ventral route for whole-word recognition and semantic processing, whereas Kana depends mainly on the dorsal route for phonological decoding via grapheme-to-phoneme conversion; however, their spatiotemporal dynamics remain unknown. Using high-gamma power analysis from electrocorticography recordings in 14 patients with epilepsy and subdural implants, we examined the spatiotemporal neural dynamics of Kana and Kanji reading. Participants completed a visual lexical decision task with Kana and Kanji words and pseudowords. Across 912 electrodes, differential high-gamma power analysis showed that Kanji activated bilateral occipitotemporal fusiform regions early (120-550 ms) and the left inferior temporal gyrus (150-240 ms). Conversely, Kana showed prolonged late activation (270-750 ms) in the left-lateralised superior temporal, supramarginal, and inferior frontal gyri, especially during pseudoword processing. These findings indicate that Kanji relies on bilateral ventral stream earlier, while Kana depends on the left dorsal stream, with slower processing reflecting the extra grapheme-to-phoneme conversion. This underscores the value of non-alphabetic languages in elucidating both universal and script-specific neural mechanisms, advancing a cross-linguistic understanding of the reading network.

OBJECTIVE: We visualized functional and effective connectivity within specific white matter networks in response to auditory descriptive questions. METHODS: We investigated 40 Japanese-speaking patients with focal epilepsy and estimated connectivity measures using cortical high-gamma dynamics and MRI tractography. RESULTS: Hearing a wh-interrogative at question onset enhanced inter-hemispheric functional connectivity, with left-to-right callosal facilitatory flows between the superior-temporal gyri, contrasted by functional connectivity diminution with right-to-left callosal suppressive flows between dorsolateral prefrontal regions. Processing verbs associated with concrete objects or adverbs increased left intra-hemispheric connectivity, with bidirectional facilitatory flows through extensive white matter pathways. Questions beginning with what, compared to where, induced greater neural engagement in the left posterior inferior-frontal gyrus at question offset, linked to enhanced functional connectivity and bidirectional facilitatory flows to the temporal lobe neocortex via the arcuate fasciculus. During overt responses, inter-hemispheric functional connectivity was enhanced, with bidirectional callosal flows between Rolandic areas, and individuals with higher IQ scores exhibited less prolonged neural engagement in the left posterior middle frontal gyrus. CONCLUSIONS: Visualization of directional neural interactions within white matter networks during overt naming is feasible. SIGNIFICANCE: Phrase order may influence network dynamics in listeners, even when presented with auditory descriptive questions conveying similar meanings.

Abstract Startle‐induced seizure is a rare type of reflex seizure triggered by unexpected sensory stimuli that often occurs in children with early acquired cerebral lesions or brain malformations. We report a unique case of adult‐onset epilepsy with startle‐induced seizures. A 24‐year‐old woman had suffered high fever and focal to bilateral tonic–clonic seizures. A diagnosis of febrile infection‐related epilepsy syndrome (FIRES) was made based on the febrile infection occurring 7 days to 24 h before the onset of status epilepticus, which met all criteria for cryptogenic new‐onset refractory status epilepticus (NORSE) according to the cryptogenic NORSE score. Immunotherapy and several antiseizure medications resulted in transient resolution of the seizures. Four months later, she experienced startle‐induced seizures triggered by unexpected stimuli, such as auditory, visual, or unexpected events, and manifesting as initial tachycardia followed by right ear deafness, right hemifacial dysesthesia, eye deviation to the right, and tonic–clonic convulsions. Ictal electroencephalography revealed left temporal initial rhythmic delta activity, followed by rhythmic theta activity. The patient was diagnosed with startle epilepsy associated with FIRES and continued to receive anti‐seizure medications. Claustrum‐insular‐operculum lesions may have been the epileptic focus in this case, in contrast to previous cases of epilepsy with startle‐induced seizures originating in a frontoparietal network. This case indicates a new category of adult‐onset post‐FIRES epilepsy with startle‐induced seizures.

OBJECTIVE: Surgery for peri-rolandic epilepsy requires appropriate consideration to balance the functional risk of postoperative motor deficit and seizure outcome. Based on voxel-based morphometric analysis, the authors hypothesized that cortical damage and ischemic subcortical damage related to surgery could affect postoperative motor deterioration. METHODS: Sixteen patients with peri-rolandic epilepsy who underwent resective surgery at a single institution were retrospectively investigated. Their imaging findings, postoperative seizure outcomes, and postoperative neurological deteriorations in motor function, as well as duration, were analyzed. Using the standardized MRI data of each case, the authors examined the surgically resected area on high-resolution 3D MR images and the high-intensity area on diffusion-weighted images, which were converted to voxel data. These voxel data were superimposed on a standard brain image for neuroimaging assessment. Postoperative motor deterioration of the orofacial region, upper limb, or lower limb was noted as no, transient, or permanent deterioration and analyzed in relation to the surgically resected area and subcortical damage. Univariate analysis of the clinical factors was conducted between cases with permanent upper- and/or lower-limb motor deterioration and those with no or transient deterioration. RESULTS: The mean follow-up period was 28 months. Ten patients (62.5%) achieved Engel class I. Fourteen patients (87.5%) experienced postoperative motor deteriorations in the following areas (no/transient/permanent): orofacial (11/5/0), upper limb (9/5/2), and lower limb (9/3/4). All cases with orofacial motor deterioration underwent cortical resection of the inferior third of the peri-rolandic cortex. Cortical resection of the precentral gyrus only, in contrast to both the precentral and postcentral gyri, was not associated with permanent upper- and/or lower-limb motor deterioration. Cortical resection involving the postcentral gyrus was significantly associated with permanent upper- and/or lower-limb motor deterioration in 4 cases (25.0%). Surgically related perforating artery injury caused ischemic subcortical damage, which was significantly associated with postoperative transient or permanent motor deterioration by extending to the corticospinal tract (CST). CONCLUSIONS: Postoperative motor deterioration for peri-rolandic epilepsy was related to both the resected cortex and ischemic subcortical damage. In peri-rolandic epilepsy, cortical resection of the precentral gyrus might not necessarily cause permanent upper- and/or lower-limb motor deterioration because of the functional reserve in other peri-rolandic areas outside the epileptic focus. On the other hand, cortical resection of the postcentral gyrus could cause permanent upper- and/or lower-limb motor deterioration because of injury to the vasculature, which is crucial for the descending motor pathway in the CST.

BACKGROUND AND OBJECTIVES: The influence of the age at which complete corpus callosotomy (CC) surgery is performed on seizure outcomes remains unclear. This study aimed to evaluate the age-dependent aspects of long-term seizure outcomes after complete CC. METHODS: We reviewed 41 patients who underwent one-stage complete CC. Seizure outcomes were analyzed for age at epilepsy onset and at complete CC, focal MRI abnormality, and etiology. RESULTS: The median age was 7 months at epilepsy onset and 93 months at complete CC. The median follow-up duration was 67 months. Sixteen patients had focal MRI lesions and 4 had only general atrophy. Etiology was identified in 20 patients. For overall seizure outcomes (N = 41), complete seizure freedom was achieved in 5 patients, excellent seizure reduction (>80%) in 11, good (50%-80%) in 5, and poor (<50%) in 20. Freedom was correlated with younger age at complete CC and unknown etiology (P ≤ .05). Freedom was only achieved in patients aged younger than 7 years. Worthwhile (≥50%, freedom, excellent, and good) and not worthwhile (<50%, poor) overall seizure reduction showed no statistical difference in age at complete CC. No related factor was found for worthwhile overall seizure reduction. For drop attack outcomes (N = 31), freedom was achieved in 22 cases, excellent in 5, and poor in 4. Freedom was correlated with younger age at complete CC (P < .05) although freedom was achieved in 4 of 7 patients older than 20 years. Age at complete CC showed no statistical difference between worthwhile (≥50%) and not worthwhile (<50%) drop attack reduction. Worthwhile drop attack reduction was correlated with unknown etiology (P < .05). Complications were mild and transient. CONCLUSION: Complete CC is an excellent surgical option based on favorable seizure outcomes and acceptable complications in our present study.

Hippocampectomy is effective for drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis. However, multiple studies have reported high risks associated with hippocampectomy in patients with mesial temporal lobe epilepsy without hippocampal sclerosis on magnetic resonance imaging and in those with preserved memory function. Verbal memory and language functions are believed to coexist in the same hemisphere. We present a case of left mesial temporal lobe epilepsy with atypical memory function lateralization revealed by super-selective infusion of propofol to the intracranial artery (super-selective Wada test). A 24-year-old right-handed man with drug-resistant focal impaired awareness seizures was diagnosed with left mesial temporal lobe epilepsy without hippocampal sclerosis, but he showed preserved verbal intelligence quotient and memory, suggesting a high risk of severe memory decline after hippocampectomy. We performed super-selective Wada test to the posterior cerebral artery to assess the lateralization of verbal and visual memory separately, and to the middle cerebral artery to assess language function. The results revealed right-sided dominance for both verbal and visual memory, although the language was left-dominant. Hippocampectomy was performed and resulted in freedom from seizures. Memory assessments 1 year postoperatively showed no decline in all subtests. In patients with drug-resistant epilepsy exhibiting atypical neuropsychological profiles, the memory-dominant, and language-dominant hemispheres may not align; detailed evaluations of function lateralization are necessary for tailored treatment.

Recurring utterances (RUs) are a distinct language symptom observed in severe aphasia, known to be associated with global or Broca's aphasia, though their neural basis remains unclear. We present a case of RU induced by selective left frontal suppression using a novel technique named the super-selective Wada test (ssWada), which involves temporary anesthetization of specific brain regions through super-selective catheterization of cerebral arteries. This method allows for precise simulation of localized brain dysfunction. We applied this technique on a 49-year-old right-handed man with drug-resistant epilepsy as a preoperative examination. Propofol administration to the superior branch of the left middle cerebral artery (MCA), supplying the pars triangularis, pars opercularis, middle frontal gyrus, and part of the precentral gyrus, induced Broca's aphasia with RUs. The RU content was the phrase uttered at anesthesia administration. Notably, the anesthetic did not affect the temporal language area or basal ganglia. The patient showed minimal awareness of his abnormal speech despite preserved receptive language function and memory, aligning with previous observations of anosognosia in patients with RU. Contrastingly, anesthetic infusion into the inferior branch of the left MCA resulted in mixed aphasia, while right MCA infusion induced no language impairments. This case demonstrates that RUs can arise without deficits in the posterior language area or basal ganglia. It illustrates the potential of ssWada in investigating neural substrates of neuropsychological symptoms through temporary, localized brain disruption. This approach offers novel insights into brain-behavior relationships in language processing and cognition.

INTRODUCTION: It is hard to realize the extent of the expected postoperative neurological deficit for patients themselves. The provision of appropriate information can contribute not only to examining surgical indications but also to filling the gap between patient and expert expectations. We hypothesized that propofol infusion into the intracranial arteries (ssWada) could induce focal neurological symptoms with preserved wakefulness, enabling the patients to evaluate the postsurgical risk subjectively. METHODS: Presurgical evaluation using ssWada was performed in 28 patients with drug-resistant epilepsy. Based on anatomical knowledge, propofol was super-selectively infused into the intracranial arteries including the M1, M2, and M3 segments of the middle cerebral artery (MCA), A2 segment of the anterior cerebral artery, and P2 segment of the posterior cerebral artery to evaluate the neurological and cognitive symptoms. We retrospectively analyzed a total of 107 infusion trials, including their target vessels, and elicited symptoms of motor weakness, sensory disturbance, language, unilateral hemispatial neglect (UHN), and hemianopsia. We evaluated preserved wakefulness which enabled subjective evaluations of the symptoms and comparison of the subjective experience to the objective findings, besides adverse effects during the procedure. RESULTS: Preserved wakefulness was found in 97.2% of all trials. Changes in neurological symptoms were positively evaluated for motor weakness in 51.4%, sensory disturbance in 5.6%, language in 48.6%, UHN in 22.4%, and hemianopsia in 32.7%. Six trials elicited seizures. Multivariate analysis showed significant correlations between symptom and infusion site of language and left side, language and MCA branches, motor weakness and A2 or M2 superior division, and hemianopsia and P2. Transient adverse effect was observed in 8 cases with 12 infusion trials (11.2 %). CONCLUSION: The ssWada could elicit focal neurological symptoms with preserved wakefulness. The methodology enables specific evaluation of risk for cortical resection and subjective evaluation of the expected outcome by the patients.

Herein, we present the case of a 21-year-old man with a history of generalized tonic seizures since the age of 4 years. These seizures occurred either spontaneously or could be provoked by auditory stimuli such as the sounds of a vacuum cleaner or an electric shaver. Despite trials with 10 different anti-seizure medications, his seizures remained refractory. Interictal electroencephalography (EEG) revealed generalized epileptiform activity, whereas ictal EEG showed a generalized attenuation pattern. Magnetic resonance imaging revealed extensive chronic infarctions, predominantly in the bilateral cerebral watershed areas. At the age of 17, the patient underwent a one-stage complete callosotomy, which only achieved remission of auditory-provoked seizures. Based on this experience and published reports, we propose that the posterior corpus callosum, particularly the isthmus and anterior splenium, may be involved in seizures caused by unexpected sound stimuli.

BACKGROUND: The classical Wada test (cWada), performed by injecting a short-acting anesthetic through the intracarotid route, helps determine language dominance. In the cWada, adverse effects are observed in 10-30% of trials, hindering accurate assessments. In this study, we assessed the effectiveness of the super-selective Wada test (ssWada), a more selective approach for anesthetic infusion into the middle cerebral artery (MCA). METHODS: We retrospectively examined the data of 17 patients with epilepsy who underwent ssWada via anesthetic injection into one M1 segment of the MCA and at least one contralateral trial. RESULTS: The ssWada identified 12 patients with left language dominance, 3 with right language dominance, and 2 with bilateral language distribution. Nine trials on the language dominant side resulted in global aphasia for patients with left- or right language dominance. Of the 13 trials conducted on the non-dominant language side, 12 revealed intact language function and one resulted in confusion. Among these, the outcomes of global aphasia or no language impairment were confirmed in the contralateral trials. Among the 22 trials of unilateral M1 injections in patients with unilateral language dominance, 21 (95.5%) showed either global aphasia or no language impairment, indicating language dominance. CONCLUSIONS: The ssWada yields clear results, with a high rate of over 90% in determining the language dominant hemisphere with few side effects.

BACKGROUND: Atypical localization of language function can result in unexpected postsurgical deficits after cortical resection, but it is difficult to predict the risk in the presurgical evaluation. The authors experienced a rare case of the bilateral and independent existence of different components of language function identified by segmented evaluation of anatomical anterior and posterior language areas using the superselective infusion of propofol. OBSERVATIONS: A 32-year-old right-handed female presented with drug-resistant epilepsy. Comprehensive epilepsy evaluation suggested that the epileptic foci involved the whole left frontal lobe but provided less evidence of structural abnormality. To estimate the extent of functional deterioration likely to be caused by an extended left frontal lobectomy, the authors evaluated segmented cortical function in the ipsi- and contralateral hemispheres by the superselective infusion of propofol into the branches of the intracranial artery. The results revealed bilateral and asymmetrical localization of language function because the patient presented with different components of aphasia in each hemisphere. Based on the authors' assessment of her functional tolerance, an extended left frontal lobectomy was performed and resulted in neurological deficits within the anticipated range. LESSONS: An accurate understanding of the correlations between vascular and functional anatomy and the highly specific evaluation of language function provides more advanced presurgical assessment, allowing more tailored planning of cortical resection.

The "odyssey plot" was used to visualize referral delays in epilepsy surgery. Participants were 36 patients (19 males; 13-67 years, median 27 years) with mesial temporal lobe epilepsy with hippocampal sclerosis (HS) who underwent resection surgery. The "referral odyssey plot" included five clinical episodes: seizure onset (T1), first visits to a non-epileptologist (T2) and to an epileptologist (T3), first admission to our epilepsy monitoring unit (EMU) (T4), and resection surgery (T5). For each patient, we identified the first seizure type: the physician who first diagnosed focal aware seizure (FAS), focal impaired awareness seizure (FIAS), focal to bilateral tonic-clonic seizure (FBTCS), and radiologically suspected HS. Within the overall delay (T1-T5, median 18 years; interquartile range [IQR] 14), non-epileptologist's delay (T2-T3, 11.5 years; IQR 12.25) was far (p < 0.0001) longer than patient's (T1-T2, 0 year; IQR 2.25), epileptologist's (T3-T4, 1 year; IQR 4), or after-EMU delay (T4-T5, 1 year; IQR 1). FAS onset cases had significantly longer T1-T2 (N = 5, median 7 years; IQR 6) than FIAS (N = 22, 0 year; IQR 1, p < 0.005) or FBTCS onset cases (N = 9, 0 year; IQR 0, p < 0.001). FAS was correctly diagnosed first by non-epileptologists in 17.9%, by out-patient epileptologists in 35.7%, and at the EMU in 46.4%. FIAS was correctly diagnosed first by non-epileptologists in 94.4% and by out-patient epileptologists in 5.6%. Non-epileptologists diagnosed FBTCS in all cases. HS was diagnosed by non-epileptologists in 13.9%, by out-patient epileptologists in 47.2%, and at the EMU in 38.9%. Early referral to epileptologists is most critical for early surgery. Early utilization of the EMU is highly recommended because FAS is often overlooked by outpatient epileptologists. The odyssey plot will be useful to improve the healthcare system for other types of epilepsy.

The medial side of the operculum is invisible from the lateral surface of cerebral cortex, and its functions remain largely unexplored using direct evidence. Non-invasive and invasive studies have proved functions on peri-sylvian area including the inferior frontal gyrus (IFG) and superior temporal gyrus within the language-dominant hemisphere for semantic processing during verbal communication. However, within the non-dominant hemisphere, there was less evidence of its functions except for pitch or prosody processing. Here we add direct evidence for the functions of the non-dominant hemisphere, the causal involvement of the medial IFG for subjective auditory perception, which is affected by the context of the condition, regarded as a contribution in higher order auditory perception. The phenomenon was clearly distinguished from absolute and invariant pitch perception which is regarded as lower order auditory perception. Electrical stimulation of the medial surface of pars triangularis of IFG in non-dominant hemisphere via depth electrode in an epilepsy patient rapidly and reproducibly elicited perception of pitch changes of auditory input. Pitches were perceived as either higher or lower than those given without stimulation and there was no selectivity for sound type. The patient perceived sounds as higher when she had greater control over the situation when her eyes were open and there were self-cues, and as lower when her eyes were closed and there were investigator-cues. Time-frequency analysis of electrocorticography signals during auditory naming demonstrated medial IFG activation, characterized by low-gamma band augmentation during her own vocal response. The overall evidence provides a neural substrate for altered perception of other vocal tones according to the condition context.

The Wada test is the gold standard for determining language-dominant hemisphere. However, the precise determination of language areas in each patient requires more invasive methods, such as electrocortical stimulation. Some studies have reported the use of anesthetic injection into selective cerebral arteries to predict postoperative function. To assess the function of the anterior and posterior language areas separately, we developed an advanced test named the "super-selective Wada test" (ssWada). The ssWada procedure is as follows: an endovascular neurosurgeon identifies the arterial branches of the middle cerebral artery (MCA) perfusing the anterior language area of the inferior frontal gyrus and the posterior language area of the posterior part of the superior temporal gyrus using angiography. Behavioral neurologists assess language symptoms before and after propofol administration using a microcatheter tip in the selected arterial branch. From 30 serial patients with epilepsy who underwent ssWada test at Tohoku University Hospital, we retrospectively reviewed patients in whom multiple areas in the bilateral MCA region was examined. Eight cases were identified in this study. All eight cases had been considered for resection of the area overlapping the classical language area. Three of the eight cases were left-dominant, and the within-hemisphere distribution was also considered typical. One case was determined to be left-dominant but atypical in the intra-hemispheric functional distribution. Two cases were right-dominant, and the intra-hemispheric functional distribution was considered a mirror image of the typical pattern. The remaining two cases were considered atypical, not only in terms of bilateral language function, but also in terms of anterior-posterior functional distribution. This case series demonstrates the potential utility of ssWada in revealing separate function of the anterior and posterior language areas. The ssWada allows simulation of local surgical brain resection and detailed investigation of language function, which potentially contributes to planning the resection area. Although indications for ssWada are quite limited, it could play a complementary role to noninvasive testing because it provides information related to resection using a different approach.

In cases of malignant gliomas located at language eloquent area, it is often difficult to preoperatively detect those area with functional MRI. Awake surgery is often used to spare the language eloquent area during surgery for such tumors; it is not available for a patient whose intracranial pressure is elevated due to the malignant tumor. The Wada test involves infusing anesthetic agents into the internal carotid artery to determine language dominancy before surgery for epilepsy or brain tumor. The super-selective Wada test is a technique to detect more detailed functional localization by infusing anesthetics into far distal middle cerebral artery branches. We present a 37-year-old man suffering from a left frontal lobe glioblastoma, in whom detection of an artery supplying Broca's area was attempted by a super-selective Wada test. The super-selective Wada test successfully detected the branch of middle cerebral artery supplying Broca's area. Total resection of the contrast-enhancing area was achieved without damaging the artery supplying Broca's area without any neurological sequelae. This is the first report describing the usefulness of the super-selective Wada test in glioblastoma treatment. Our findings suggest that the super-selective Wada test is a powerful and useful means to distinguish the artery that supplies the language area from the tumor feeding artery in cases of tumors in the language eloquent area.

The left prefrontal cortex is essential for verbal communication. It remains uncertain at what timing, to what extent, and what type of phrase initiates left-hemispheric dominant prefrontal activation during comprehension of spoken sentences. We clarified this issue by measuring event-related high-gamma activity during a task to respond to three-phrase questions configured in different orders. Questions beginning with a wh-interrogative deactivated the left posterior prefrontal cortex right after the 1st phrase offset and the anterior prefrontal cortex after the 2nd phrase offset. Left prefrontal high-gamma activity augmented subsequently and maximized around the 3rd phrase offset. Conversely, questions starting with a concrete phrase deactivated the right orbitofrontal region and then activated the left posterior prefrontal cortex after the 1st phrase offset. Regardless of sentence types, high-gamma activity emerged earlier, by one phrase, in the left posterior prefrontal than anterior prefrontal region. Sentences beginning with a wh-interrogative may initially deactivate the left prefrontal cortex to prioritize the bottom-up processing of upcoming auditory information. A concrete phrase may obliterate the inhibitory function of the right orbitofrontal region and facilitate top-down lexical prediction by the left prefrontal cortex. The left anterior prefrontal regions may be recruited for semantic integration of multiple concrete phrases.

Cognitive decline is a well-known chronic side effect of multidisciplinary treatment of pineal region tumors, whereas epilepsy is an under-reported chronic consequence caused by multiple potential factors including radiotherapy, surgery, or chemotherapy. Some long-term survivors have suffered drug-resistant epilepsy after treatment, which impaired the quality of life. We report five consecutive patients with drug-resistant epilepsy after combined treatment of pineal region tumor (5 men, aged 21-42 years) among 1201 epilepsy patients who underwent comprehensive evaluation in our tertiary epilepsy center from 2011 to 2018. The comprehensive epilepsy evaluation included medical interview, long-term video electroencephalography (EEG) monitoring (VEM), and magnetic resonance (MR) imaging. The patients started to have seizures at 2-22 years after initial treatment for the tumor. Four of the five patients had focal impaired awareness seizures, whereas one patient had only visual aura. All patients had EEG seizures during VEM, which confirmed the diagnosis of focal epilepsy, but three patients had no interictal epileptiform discharges (IEDs). Two patients had diagnoses of focal epilepsy arising from the left occipital region based on ictal EEG findings. Both patients had MR imaging lesion in the left occipital lobe, radiation-induced cavernoma, or surgical injury. The remaining three patients showed poor localization of epileptogenic foci based on VEM and MR imaging. Drug-resistant epilepsy after multidisciplinary treatment of pineal region tumor is characterized by focal impaired awareness seizures with poorly localized EEG onset or rare interictal spikes.