The claustrum is a highly connected structure hypothesized to orchestrate conscious experience, yet its role in humans remains enigmatic. To address this question, we prospectively investigated patients with drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG) implantation driven by clinical indications, with electrode trajectories optimized to target the claustrum. Across the eight participants, the stimulated claustrum was left-sided in six and right-sided in two. Focal stimulation of the left claustrum reproducibly induced a transient arrest of ongoing thought and a reduced behavioral responsiveness in one of eight patients, consistent with mind blanking (MB). Simultaneous intracranial recordings revealed site-specific suppression of neural activity within the anterior cingulate cortex (ACC). Machine learning-based analysis further confirmed that spectral attenuation across frequency bands in the ACC served as reliable electrophysiological fingerprints of this stimulation-induced mind blanking. Finally, 1 Hz claustrum-cortical evoked potentials identified a robust claustrum-ACC pathway. Together, these findings suggest that the claustrum-ACC pathway is critically involved in ongoing conscious thought, and its disruption offers a circuit-level mechanism for MB. (ClinicalTrials.gov identifier: NCT06575413).

Focal motor seizures (FMS) are often unresectable because of motor risk. We aimed to evaluate the long-term effectiveness and safety of subthalamic nucleus deep brain stimulation (STN-DBS) in patients with FMS and to identify suitable candidate patients. We analyzed long-term outcomes in 22 patients with FMS treated with STN-DBS, classifying patients as responders (≥50% seizure reduction) or non-responders and relating outcomes to seizure-focus topography using focus-frequency maps and region-of-interest–based volumetrics. In a SEEG cohort of 13 patients with electrodes in the sensorimotor cortex and the STN, including 1 from the DBS cohort, we quantified changes in interictal spike (IIS) rates and broadband (0.5–90 Hz) power spectral density (PSD) across distinct sensorimotor subregions during 100-Hz STN stimulation. At final follow-up (mean 45 months), median seizure reduction was 55%, with 14/22 responders and six patients achieved >90% reduction, including one seizure-free. STN-DBS was well tolerated, with no surgical complications and one explant for infection. Responders’ seizure foci clustered in a medial sensorimotor strip comprising the paracentral lobule (PCL), supplementary motor area (SMA) and trunk representations of the precentral and postcentral gyri, and greater involvement of the PCL and trunk areas correlated with better outcome. SEEG analyses showed a global reduction in broadband power but regionally selective suppression of epileptiform activity, confined to the PCL and SMA. Together, STN-DBS appears to be a safe, effective option for FMS, and patients whose seizure foci involve the medial sensorimotor strip may be potential candidates.

OBJECTIVE:CDKL5 deficiency disorder (CDD) is a rare, severe developmental and epileptic encephalopathy. There is a pressing need to develop effective and sustainable therapeutic strategies. We aimed to investigate the causal association between febrile episodes and epileptic seizures for therapeutic implications in CDD patients. METHODS:The study was a nationwide, cross-sectional survey on CDD patients in China (ClinicalTrials.gov, NCT06663163). Detailed phenotypic and genotypic data were collected through an online questionnaire with uploaded original medical records, genetic testing results, and peri-fever seizure diaries. The primary outcome was changes in epileptic seizure frequency during and post-fever phases compared to a 1-month pre-fever phase based on seizure diaries. RESULTS:Between October 2024 and December 2024, we received 131 questionnaires. Forty-seven questionnaires were removed after excluding duplicates and missing data. Ultimately, 84 eligible participants with complete uploads were included, from 26 of 34 (76.5%) province-level regions in China. Among these, 47 (56.0%) patients had significant decreased seizure frequency only during febrile episodes, and 27 (32.1%) patients with daily seizures achieved at least a seizure-free day. Notably, 20 patients (23.8%) exhibited post-fever seizure reduction: 12 (25.5%) for 3 days to 1 week, and 6 (12.8%) for more than 2 weeks (maximum > 40 days). The effect was independent of patients' clinical and genetic characteristics. INTERPRETATION:Our findings, for the first time, revealed that fever-related seizure reduction is a distinctive and prevalent genotype-phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.

Accurate non-invasive characterization of complex brain dynamics, especially aberrant network activity in epilepsy, is crucial yet challenging due to the invasiveness of iEEG and limitations of non-invasive MEG. We introduce DiffLSTM-MTE, a novel deep learning framework that reconstructs virtual iEEG (ViEEG) from MEG recordings. This framework synergistically integrates an LSTM for temporal modeling of MEG with a conditional Denoising Diffusion Probabilistic Model (DDPM) for synthesizing realistic iEEG. Our physiologically-informed training objective incorporates losses for noise prediction, spectral fidelity, and Interictal Epileptiform Discharges (IEDs) preservation. Evaluated on data from five epilepsy patients, DiffLSTM-MTE demonstrates high temporal fidelity (mean Pearson R = 0.71 +/- 0.08 ), preserves spectral characteristics (The mean PSD RMSE is < 0.071), reconstructs spatial coherence (mean correlation 0.92 +/- 0.04 ), and accurately characterizes IEDs (76% +/- 7 % alignment). These results highlight DiffLSTM-MTE's potential as a non-invasive tool to enhance epilepsy diagnostics and pre-surgical assessment by providing richer, patient-specific neurophysiological insights.

The m.10158T > C mutation in the mitochondrial gene (MT-ND3) is a rare cause of adult-onset mitochondrial encephalopathy, typically presenting as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) with predominant cortical involvement. Early cerebellar onset and progressive atrophy are atypical. To investigate the underlying pathophysiology, we innovatively applied TSPO-PET to visualize neuroinflammation and mitochondrial pathology linked to mitochondrial encephalopathies. A 32-year-old woman had a 20-year progressive disorder starting with migraines at age 12. Left cerebellar atrophy was found incidentally at 15, followed by episodic ataxia, dysarthria, and generalized seizures at 24. She later developed refractory status epilepticus, right side sensory ataxic symptoms, and neurocognitive decline. MRI showed progressive bilateral cerebellar atrophy and multifocal cortical lesions. Genetic testing identified the m.10158T > C mutation. TSPO-PET revealed increased uptake, indicating neuroinflammation, in the left thalamus, temporoparietal-occipital lobe, bilateral cerebellum, corresponding FDG-PET showed hypometabolism. Of note, the MRI-normal regions, including the right thalamus, hippocampus and brainstem, exhibited elevated TSPO uptake with or without subtle FDG changes. Our study defined an atypical MELAS phenotype associated with m.10158T > C mutation, characterized by cerebellar early involvement, subsequent progressive atrophy, and repeated stroke-like episodes. In addition, TSPO-PET uptake extends well beyond the boundaries of detectable structural damage, demonstrating that molecular pathology exceeds visible damage. To our knowledge, our study represents the first preliminary exploration of in vivo histopathological changes using a second-generation TSPO radioligand (¹⁸F-DPA-714) in a patient with MELAS, advancing our understanding of the relationship between neuroinflammation and primary mitochondrial diseases.

Pathological subtypes are key determinants of surgical strategy and prognosis in refractory mesial temporal lobe epilepsy (MTLE), with hippocampal sclerosis (HS) associated with better outcomes than gliosis only. Subtype-specific patterns of cerebral metabolism and neuroinflammation, which may inform lesion localization and subtype differentiation, remain poorly defined. This study aimed to delineate these patterns using ¹⁸F-FDG PET and translocator protein (TSPO) PET with ¹⁸F-DPA-714 for precise localization, with emphasis on the added value of quantitative analysis. Patients with unilateral refractory MTLE undergoing surgery were retrospectively included, and pathological subtypes were classified according to histological profiles (HS, n = 43; gliosis only, n = 41). Patients underwent sequential integrated dual-tracer PET/MR imaging within one week. Age- and sex-matched healthy controls (HC) were recruited. Whole-brain voxel-wise and temporal lobe subregional analyses were performed. Localization performance was assessed by visual inspection and quantitative analysis employing an asymmetry index (AI) derived from standardized uptake value ratios. Sensitivity and accuracy were calculated, with false discovery rate correction applied for multiple comparisons. In total, 43 MTLE-HS and 41 MTLE-gliosis only were included. Compared with HC, both HS and gliosis exhibited significant 18F-FDG hypometabolism alongside increased 18F-DPA-714 uptake, more pronounced in HS. Whole-brain 18F-DPA-714 abnormalities were more confined to temporal regions, affording clearer lateralization and localization than 18F-FDG. In temporal-lobe subregional analysis, 18F-FDG outperformed 18F-DPA-714 for subtype discrimination, and hippocampal AI value achieved the best performance (35/43 [81.4

As a critical hub in the thalamo-cortical circuit, the human thalamus engages in a spectrum of fundamental and advanced brain functions through widely distributed circuits. Clinically, dysfunction of thalamo-cortical circuits is shown to be profoundly implicated in a wide range of neurological and psychiatric diseases. Nevertheless, the neuroanatomical substrates governing these functions of the thalamus have rarely been directly mapped in humans. Here, we overviewed the acute responses of direct electrical stimulation (DES) delivered to the distributed thalamus sites in 52 epilepsy patients admitted for presurgical stereoelectroencephalography. Specifically, DES of the thalamus evoked a broad spectrum of in-situ responses spanning fundamental functions such as sensory and motor processing, extending to complex neural operations encompassing neurovegetative regulation, cognitive processing, emotional modulation, and multimodal responsiveness. Moreover, through the integration of DES with functional human connectome (n = 1000), we found an intra-thalamic intrinsic functional network associated with each specific clinical response. Our data provide direct substantiation for the complex functional architecture of the human thalamus, advancing current understanding of its role and potentially culminating in targeted therapeutic strategies tailored to ameliorate symptom-specific neural circuit disorders.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with diverse imaging manifestations. Isolated involvement of the caudate nucleus is rare and can be easily misdiagnosed, especially in the early stages when inflammatory symptoms are not apparent. This report describes a pediatric case of severe anti-NMDAR encephalitis with predominant involvement of the caudate nucleus. Case presentation: A 15-year-old male initially presented with stroke-like episodes, misdiagnosed as cerebral infarction. Subsequently, he developed seizures, recurrent low-grade fever, psychiatric symptoms, involuntary orofacial movements, autonomic dysfunction, loss of speech, and inability to perform activities of daily living. Brain MRI revealed a lesion in the left caudate nucleus. The diagnosis was confirmed by positive serum and cerebrospinal fluid anti-NMDAR IgG antibodies. Targeted positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG) and the 18F-DPA-714 tracer for the 18kDa translocator protein (TSPO) identified a core inflammatory area and extensive regions of neuronal dysfunction. The patient's condition gradually improved following immunotherapy and symptomatic treatment. Conclusion: This case provides valuable insights into the pathogenesis of anti-NMDAR encephalitis, particularly its selective involvement of specific brain regions such as the caudate nucleus. The unique imaging features compel us to explore mechanisms beyond the traditional model of direct antibody-mediated pathogenicity.

BACKGROUND:The high risk of resection surgery for hypothalamic hamartoma (HH) epilepsy drives interest in minimally invasive treatment. Stereo-electroencephalography-guided three-dimensional radiofrequency thermocoagulation (SEEG-3D RFTC) offers an alternative option. We investigated this technology's efficacy, safety, and prognostic risk factors. METHODS:Patients with HH who underwent SEEG-3D RFTC were retrospectively analyzed. A high-density focal stereo-array electrode implantation was adopted. SEEG-3D RFTC was performed between two contiguous contacts of the same electrode or adjacent contacts of different electrodes. Outcomes were separately evaluated for clinical seizures, gelastic seizures (GS), and non-gelastic seizures (nGS). Kaplan-Meier survival analysis was used to assess treatment effectiveness. Risk factors were analyzed using log-rank tests and Cox regression analyses. RESULTS:Sixty-nine patients were enrolled. The mean follow-up was 41.00 ± 18.19 months. Seizure freedom was obtained by 48/69 (69.57%) patients for clinical seizures, 50/62 (80.65%) patients for GS, and 41/54 (75.93%) patients for nGS. Surgical procedures were well tolerated. In this study, the proportion of patients experiencing long-term complications was 10.14%. The percentages of HH ablation (p = 0.003; hazard ratio 0.956, 95% confidence interval 0.928-0.985) and HH attachment ablation (p = 0.001; hazard ratio 0.931, 95% confidence interval 0.892-0.970) were significantly associated with seizure outcomes. CONCLUSIONS:Optimized SEEG-3D RFTC is an effective and safe option for HH-related epilepsy and is especially suitable for use where laser interstitial thermal therapy is unavailable. Complete ablation of the HH and attachment site is essential for good outcomes.

OBJECTIVES:Localization of the network underlying drug-resistant focal epilepsy in individuals considering surgical treatment with unremarkable MRI is challenging. Concordance rates of 40%-69% have been reported with FDG-PET image statistical parametric mapping (SPM). We investigated the efficacy of postprocessing specific to cortices by cortex-based mapping (CBM) on hybrid PET/MR images with healthy subjects to localize sites of seizure onset. METHODS:We retrospectively examined the PET/MR images of 42 MRI-negative individuals with drug-resistant focal epilepsy who had surgery and 23 healthy subjects. Visual interpretation of standardized uptake value ratios (SUVRs), voxelwise mapping with a two-sample t-test of SUVRs (t-map, SPM), and the proposed z-transformation of the SUVR of patients compared with those of healthy subjects acquired with CBM were compared with the surgical field. Kappa tests, conclusive concordance (CC), partial concordance (PC), and discordance were estimated, with McNemar's test determining the superiority. RESULTS:After an average follow-up of 37.2 months, in people who were seizure-free (n = 31; functionally silent cortices in 26), the CC rate with CBM was 87.10%. Performance was CBM (CC:PC = 27:1), t-map (CC:PC = 15:1), and SUVR (CC:PC = 0:17). The sensitivity, specificity, and kappa scores were 0.87, 0.91, and 0.717 (p < 0.001) for CBM and 0.48, 0.73, and 0.153 (p = 0.288) for t-maps, respectively. The CBM approach was superior to the t-map (p < 0.001) in most extratemporal epilepsies. The average Pearson's r of CBM and t-map to artifacts was 0.08 ± 0.02 and 0.33 ± 0.02, respectively. INTERPRETATION:By eliminating intersubject morphological variations and explicit statistics at the cortex, CBM localized the seizure origin in MRI-negative epilepsy patients with superior efficiency.

BACKGROUND:Cingulate epilepsy is rare and can manifest with variable semiology features. The symptomatic diversity elucidates ictal involvement of certain subregions of the cingulate gyrus and early spread patterns. Knowledge of the features of cingulate epilepsy is important for better localization and surgical strategy. OBJECTIVE:The purpose of this study was to characterize the electroclinical features and report our experience in the diagnosis and surgical treatment of patients with focal epilepsy originating from the cingulate gyrus. METHODS:Thirty-one patients with epilepsy were retrospectively analyzed (mean age, 21; range 2-48), who had a mean epilepsy duration of 10 years (range 1-23). We report the clinical semiology, the scalp electroencephalography (EEG)/stereo-electroencephalography (SEEG) findings, surgical strategy, and postoperative follow-up (mean 48 months; range 12-136). RESULTS:Twelve patients (38.7 %) had circumscribed lesions on magnetic resonance imaging (MRI). All patients underwent noninvasive presurgical evaluation, and 26 (83.9 %) underwent invasive recordings with SEEG (n = 18) or subdural electrodes (n = 8). The ictal patterns of scalp EEG were various. The anterior cingulate epilepsy (ACE) patients showed ipsilateral frontal, frontal-temporal, or bifrontal regions discharges. The ictal discharges involved the ipsilateral frontal, temporal, or central-parietal regions in patients with middle cingulate epilepsy (MCE), and the posterior cingulate epilepsy (PCE) patients showed ipsilateral temporal, occipital-temporal, bitemporal-parietal, or generalized discharges. Secondary generalization seizures originated from each subregion of the cingulate gyrus. The ACE patients showed hypermotor seizures, including twisting trunk, pedaling, and flailing. Limbs or body trembling was observed in both MCE and PCE patients, and dialeptic seizures were observed in PCE patients. 58.1 % of patients were seizure-free, and 77.4 % had a satisfactory surgical outcome (Engel I and II). CONCLUSIONS:Cingulate epilepsy is a rare and diagnostically challenging form of epilepsy with diverse and variable electroclinical features. In patients with non-lesional MRI, invasive recording is required to identify defined seizure focus, and the surgical outcome of 1-year follow-up is favorable.

Importance:Perampanel (PER) is used less extensively in children than in adults. Currently, there is a lack of data from PER clinical studies with large sample sizes in Chinese children and adolescents with epilepsy, especially those with refractory epilepsy. Objective:To evaluate the effectiveness, retention, and safety of PER in the treatment of children and adolescents with epilepsy in China. Methods:This was a multicenter, prospective, observational study. Children and adolescents with epilepsy who received PER as adjunctive therapy were included. The primary effectiveness endpoint was the proportion of patients achieving a ≥50% reduction in seizure frequency after 6 months of treatment compared to baseline. The secondary effectiveness endpoints included retention and seizure-free rates. The safety outcome was the incidence of treatment-emergent adverse events (TEAEs). Results:A total of 240 patients with epilepsy were enrolled in the study. Prior to initiating PER treatment, approximately 87.9% of them took two or more antiseizure medications. After a 6-month treatment regimen with PER, 70.4% of the patients experienced a reduced seizure frequency of at least 50%, and 22.1% achieved complete seizure freedom. The retention rate was 90.2%. TEAEs were reported by 89 patients, leading to the discontinuation of PER in seven cases. No severe TEAEs were observed in this study. Interpretation:Under routine clinical conditions, PER demonstrated good effectiveness and retention in Chinese children with epilepsy, particularly in those with refractory epilepsy.

OBJECTIVE:Although the hippocampus is critical for memory processes, recent studies have suggested that amnesic patients with hippocampal lesions can still acquire some types of memory by distributed learning rather than by massed learning. However, as these studies recruited patients with developmental amnesia, whether lesion onset influenced the spacing effect was unclear. In addition, the extent to which the prefrontal cortex (PFC) supports the spacing effect has not been explored. METHOD:Patients with hippocampal lesions at early onset and late onset and PFC lesions were enrolled. The participants learned face-scene pairs under single learning (i.e., once in 1 day), massed learning (i.e., four times in 1 day), and distributed learning (i.e., four times in 2 days, twice per day). Then, they performed associative recognition tasks 20 min and 1 day later. RESULTS:The results showed that the spacing effect was significantly higher than baseline (d = 2.91) and comparable with the control groups for hippocampal lesions at early onset patients at 1 day. However, the spacing effect was significantly impaired for hippocampal lesions at late onset (d = -1.84) and PFC patients (d = -1.48) when compared with the normal groups. The repetition effect (massed vs. single learning) was significantly impaired for PFC patients at 20 min when compared with the controls (d = -1.15). CONCLUSIONS:These findings clarified the roles of the hippocampus and PFC in distributed learning and repetitive learning and suggest that early-onset hippocampal damage induces a significant reorganization in the human brain to support memory formation and retention. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Introduction Anterior temporal lobectomy (ATL) is the standard surgical treatment for drug-resistant mesial temporal lobe epilepsy (MTLE); however, it is associated with cognitive decline and visual field deficits. In the current era of personalized medicine and quality-of-life-focused care, minimally invasive surgical strategies are increasingly needed. Optimized stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RF-TC) is a promising option for preserving cognitive and visual function while providing effective seizure control. Objectives Methods: This assessor-blinded randomized, controlled pilot trial enrolled patients with drug-resistant MTLE at Xuanwu Hospital between August 2019 and October 2022. Participants were randomly allocated (1:1) to the ATL or SEEG-guided RF-TC groups. The primary outcome was the change in cognitive function at the 1-year follow-up, assessed using the Chinese version of the Wechsler Adult Intelligence Scale-IV (WAIS-IV-C). Secondary outcomes included the Wechsler Memory Scale-IV (WMS-IV-C), seizure control (Engel classification), visual fields (Humphrey perimetry), quality of life (QOLIE-89), and adverse events. Results Thirty-eight patients (19 male [50.0 %]; mean [standard deviation] age, 28.3 [7.1] years) were enrolled, with 20 and 18 patients assigned to the ATL and RF-TC groups, respectively. At 1 year, the overall WAIS-IV-C scores did not differ between the ATL and RF-TC groups (P > 0.050). However, patients who underwent dominant-side RF-TC demonstrated superior preservation in the full-scale intelligence quotient (96.91 ± 15.83 vs. 113.44 ± 17.50, P = 0.040), cognitive productivity index (97.36 ± 15.64 vs. 116.89 ± 16.54, P = 0.014), working memory index (97.73 ± 12.89 vs. 115.56 ± 18.80, P = 0.022) and processing speed index (97.91 ± 15.44 vs. 115.00 ± 18.41, P = 0.036) compared to the ATL group. Visual field defects occurred more frequently in the ATL group (15/20, 75.0 %) than in the RF-TC group (3/18, 16.7 %; P < 0.010). The 1-year seizure freedom (Engel I) was comparable (ATL vs. RF-TC, 85.0 % vs. 72.2 %, P = 0.440; Engel IA: 65.0 % vs. 33.3 %, P = 0.103). The RF-TC group experienced fewer adverse events than the ATL group. Conclusions Optimized SEEG-guided RF-TC preserved cognitive and visual function better in dominant-side MTLE than in ATL, with comparable seizure control and quality of life outcomes. Further multicenter studies with larger sample sizes and extended follow-up are needed to validate its efficacy and long-term safety.Trial registration: Clinicaltrials.gov Identifiers: NCT03941613.

AIMS:Autoscopic phenomena (AP) are distinct manifestations of epileptic seizure semiology and are also identified in diverse psychiatric disorders. Our study aimed to map the brain AP network and characterize its multimodal signatures. METHODS:By performing lesion network mapping using the human connectome dataset (n = 1000), we investigated the brain AP network derived from 25 cases of AP caused by distributed focal brain lesions (n = 19) and direct electrical stimulation (DES) (n = 6). We further studied the multimodal signatures of the AP network, including exploring spatial correlation with human cortical developmental and evolutionary expansions, neurotransmitters, and electrophysiological rhythms. RESULTS:We mapped a common AP network primarily involving the bilateral angular gyrus, posterior medial cortex, intraparietal sulcus, cuneus, fusiform and insula. Specifically, the bilateral thalamic pulvinar were identified as subcortical hubs. We further found a significant negative correlation between the AP network and developmental and evolutionary expansions. Particularly, the spatial density of norepinephrine transporter and the alpha frequency band power were significantly positively correlated with the AP network. CONCLUSION:Our study identified a common brain AP network and uncovered its multimodal signatures. These findings may clarify the network mechanisms underpinning AP, providing novel insights into bodily self-consciousness.

AIM:A total of 30% of individuals with epilepsy are resistant to drug treatment. Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) shows promise for treating drug-resistant epilepsy (DRE), but further research is needed to optimize DBS parameters, including stimulation frequency. This study aimed to reveal the optimal frequency for ANT-DBS by testing the real-time effects of various stimulation frequencies on the ANT among patients undergoing stereoelectroencephalography (SEEG) electrode implantation. METHODS:Eleven patients (8 males; mean age, 24.2 years; mean epilepsy duration, 13.5 years) were enrolled. Postoperative electrode reconstruction identified ANT contacts for bipolar stimulation between 10 Hz and 100 Hz at 10-Hz increments, with a 1-min interval between stimuli. The effects were analyzed on the basis of spike count, power spectral density, and causal flow. RESULTS:Our study revealed that ANT stimulation suppresses seizure focus activity and modulates brain network dynamics, with the effects varying by individual characteristics and frequency. Stimulation at 10-70 Hz reduced spikes (> 50%) and PSD (p < 0.05) in the epileptogenic region while also influencing network connectivity between the epileptogenic zone and adjacent cortical regions, including the frontal, temporal, and insular lobes, as well as the overall brain network. CONCLUSIONS:Instead of using a fixed high frequency for ANT-DBS, the optimal frequency should be selected for each patient. Patients who do not respond well to high-frequency ANT-DBS can use a lower frequency, such as 10-70 Hz.

This study aims to investigate the neuromodulatory effects of interictal short-term high-frequency stimulation on both the epileptogenic zone (EZ) and distributed networks, thereby advancing our understanding of the mechanisms underlying the therapeutic efficacy of chronic subthreshold cortical stimulation in refractory epilepsy. Eight patients with epilepsy undergoing stereoelectroencephalography monitoring during pre-surgical evaluation, with periodic spikes observed during the interictal period, were included. Short-term high-frequency stimulation (STHFS) and incremental current stimulation protocols were applied to the EZ. Spike rate, amplitude and spectral power were quantitatively assessed during the interictal (baseline), stimulation and post-stimulation periods. Functional network connectivity was evaluated using the directed transfer function and partial directed coherence. During STHFS, the spike rate, amplitude and spectral power decreased significantly compared with the baseline period. In the post-stimulation period, the spike rate, amplitude and spectral power rapidly rebounded and fluctuated around the baseline. Incremental current stimulation resulted in a gradual reduction in spike rate and spectral power, with maximal inhibition achieved at a specific current intensity. Functional connectivity exhibited individualized patterns across frequency bands during STHFS. In individual patients, specific brain regions consistently demonstrated reduced functional connectivity throughout the stimulation process. Short-term high-frequency stimulation effectively inhibits neuronal excitability in the EZ, with the degree of inhibition dependent on stimulation intensity. STHFS has an anti-epileptic effect in the local EZ region and stably regulates the distributed network.