[Progressive myoclonic epilepsy: a retrospective study of newly-diagnosed adult patients from a single center].

OBJECTIVE: To retrospectively analyze the clinical phenotype and pathogenic variants in patients with Progressive myoclonus epilepsy (PME). METHODS: Clinical data and results of genetic testing for 11 patients diagnosed with PME at the Department of Neurology, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2017 to December 2022 were collected and analyzed. RESULTS: All of the patients, including 4 males and 7 females, had predominant action myoclonus. Three patients had myoclonus as the initial manifestation, whilst eight were diagnosed through genetic testing, including three cases with NEU1 gene variants, two with EPM2A gene variants (1 was novel), one with MT-TK gene variant, one with ATN1 gene variant, and one with CSTB gene variant. No pathogenic variant was identified in the remaining three cases. Among the eight patients with a genetic diagnosis, three were diagnosed with sialidosis, two with Lafora disease, one with Dentatorubral-pallidoluysian atrophy (DRPLA), one with Unverricht-Lundborg disease (ULD), and one with Myoclonic epilepsy with ragging red fibers (MERRF). CONCLUSION: Compared with pediatric patients, adult patients with PME represent a distinct subtype with slower progression and milder cognitive impairment.

Whole-exome sequencing identifies a novel de novo variant in DYNC1H in a patient with intractable epilepsy.

DYNC1H1 variants are associated with broad phenotypes including Charcot-Marie-Tooth disease, spinal muscular atrophy, and mental retardation. However, DYNC1H1 variants related intractable epilepsy have not yet been described in detail so far. Herein, we describe the detailed clinical manifestations of a female patient, carrying a novel de novo variant in DYNC1H1 (p.H311Y), who presented with malformation of cortical development (MCD), refractory epilepsy, intellectual disability, and lower motor neuron disease. We provide a review of previously reported patients who presented with epilepsy associated with DYNC1H1 variants. Of the patients with epilepsy, the DYNC1H1 variants were distributed, on average, in the tail, linker, and motor domains, rather than being mainly distributed in the tail domain as previously reported.

The long-term outcome of neuropsychological function is favorable in patients with non-malignancy related anti-GABABR encephalitis: a case series.

BACKGROUND: Anti-GABABR encephalitis is a rare type of autoimmune encephalitis, which often presents with memory impairments, behavioral changes and seizures. This case series describes the neuropsychological function recovery pattern in five adult patients with anti-GABABR encephalitis. CASE PRESENTATION: We recruited five patients with clinically confirmed anti-GABABR encephalitis without any accompanying malignancy. Comprehensive neuropsychological evaluation was conducted on each patient. All the five patients were evaluated in the chronic phase. Five age and gender matched healthy adults were recruited as control group. Our study demonstrated that the neuropsychological function of the patients with anti-GABABR encephalitis was no different with respect to the control group during the chronic phase (more than 6 months after onset). Moreover, one patients with neuropsychological evaluation at acute (within 2 months after onset of symptoms), post-acute (2 to 6 months after onset) and chronic phases respectively, presented neuropsychological function recovered as early as in the post-acute phase and only showed cognition impairment in the acute phase. CONCLUSIONS: The results of this retrospective study indicate a favorable long-term neuropsychological function outcome in adult patients with anti-GABABR encephalitis, despite severe memory deficits occurring during the acute phase. These findings improve our understanding related to the prognosis of neuropsychological function in anti-GABABR encephalitis.

Novel NEXMIF gene pathogenic variant in a female patient with refractory epilepsy and intellectual disability.

We identified a novel nonsense de novo pathogenic variant of the NEXMIF gene in a 29 year-old female patient with refractory epilepsy and mild intellectual disability. The patient presented with episodic atypical absence status (AS), the longest duration of her seizures was approximately 36 hr. She also had occasional eyelid myoclonia during absence seizure. EEG highlighted a photosensitivity phenomenon and generalized epileptiform discharges that were induced by eye closure. Whole exome sequencing revealed a novel nonsense pathogenic variant c.1063delC (p.L355*) in exon 3 of the NEXMIF gene. The mRNA expression of NEXMIF in this female patient was below -2 SD from the mean of control group. In addition to adding a novel pathogenic variant type to the NEXMIF variant database and conducting mRNA studies, this report also describes a unique phenotype in a patient with atypical AS associated with a NEXMIF variant. We discuss implications for medication management in similar patients.

Detection of Lesions in Mesial Temporal Lobe Epilepsy by Using MR Fingerprinting.

Purpose To improve diagnosis of hippocampal sclerosis (HS) in patients with mesial temporal lobe epilepsy (MTLE) by using MR fingerprinting and compare with visual assessment of T1- and T2-weighted MR images. Materials and Methods For this prospective study performed between April and November 2016, T1 and T2 maps were obtained and tissue segmentation performed in consecutive patients with drug-resistant MTLE with unilateral or bilateral HS. T1 and T2 maps were compared between 33 patients with MTLE (23 women and 10 men; mean age, 32.6 years; age range, 16-60 years) and 30 healthy participants (20 women and 10 men; mean age, 28.8 years; age range, 18-40 years). Differences in individual bilateral hippocampi were compared by using a Wilcoxon signed rank test, whereas the Wilcoxon rank-sum test was used for difference analysis between healthy control participants and patients with MTLE. Results The diagnosis rate (ie, ratio of HS diagnosed on the basis of a 2.5-minute MR fingerprinting examination compared with standard methods: MRI, electroencephalography, and PET) was 32 of 33 (96.9%; 95% confidence interval: 84.9%, 100%), reflecting improved accuracy of diagnosis (P = 1.92 × 10-12) over routine MR examinations that had a diagnostic rate of 23 of 33 (69.7%; 95% confidence interval: 51.5%, 81.6%). The comparison between atrophic and normal-appearing hippocampus in 33 patients with MTLE and healthy control participants demonstrated that both T1 and T2 values in HS lesions were higher than those of normal hippocampal tissue of healthy participants (T1: 1361 msec ± 85 vs 1249 msec ± 59, respectively; T2: 135 msec ± 15 vs 104 msec ± 9, respectively; P < .0001). Conclusion MR fingerprinting allowed for multiparametric mapping of temporal lobe within 2.5 minutes and helped to identify lesions suspicious for HS in patients with MTLE with improved accuracy.

Brain rhythmic abnormalities in convalescent patients with anti-NMDA receptor encephalitis: a resting-state EEG study.

Objective: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is autoimmune encephalitis with a characteristic neuropsychiatric syndrome and persistent cognition deficits even after clinical remission. The objective of this study was to uncover the potential noninvasive and quantified biomarkers related to residual brain distortions in convalescent anti-NMDARE patients. Methods: Based on resting-state electroencephalograms (EEG), both power spectral density (PSD) and brain network analysis were performed to disclose the persistent distortions of brain rhythms in these patients. Potential biomarkers were then established to distinguish convalescent patients from healthy controls. Results: Oppositely configured spatial patterns in PSD and network architecture within specific rhythms were identified, as the hyperactivated PSD spanning the middle and posterior regions obstructs the inter-regional information interactions in patients and thereby leads to attenuated frontoparietal and frontotemporal connectivity. Additionally, the EEG indexes within delta and theta rhythms were further clarified to be objective biomarkers that facilitated the noninvasive recognition of convalescent anti-NMDARE patients from healthy populations. Conclusion: Current findings contributed to understanding the persistent and residual pathological states in convalescent anti-NMDARE patients, as well as informing clinical decisions of prognosis evaluation.

Lateralization of temporal lobe epileptic foci with automated chemical exchange saturation transfer measurements at 3 Tesla.

BACKGROUND: Magnetic Resonance Imaging (MRI) is an indispensable tool for the diagnosis of temporal lobe epilepsy (TLE). However, about 30% of TLE patients show no lesion on structural MRI (sMRI-negative), posing a significant challenge for presurgical evaluation. This study aimed to investigate whether chemical exchange saturation transfer (CEST) MRI at 3 Tesla can lateralize the epileptic focus of TLE and study the metabolic contributors to the CEST signal measured. METHODS: Forty TLE subjects (16 males and 24 females) were included in this study. An automated data analysis pipeline was established, including segmentation of the hippocampus and amygdala (HA), calculation of four CEST metrics and quantitative relaxation times (T1 and T2), and construction of prediction models by logistic regression. Furthermore, a modified two-stage Bloch-McConnell fitting method was developed to investigate the molecular imaging mechanism of 3 T CEST in identifying epileptic foci of TLE. FINDINGS: The mean CEST ratio (CESTR) metric within 2.25-3.25 ppm in the HA was the most powerful index in predicting seizure laterality, with an area under the receiver-operating characteristic curve (AUC) of 0.84. And, the combination of T2 and CESTR further increased the AUC to 0.92. Amine and guanidinium moieties were the two leading contributors to the CEST contrast between the epileptogenic HA and the normal HA. INTERPRETATION: CEST at 3 Tesla is a powerful modality that can predict seizure laterality with high accuracy. This study can potentially facilitate the clinical translation of CEST MRI in identifying the epileptic foci of TLE or other localization-related epilepsies. FUNDING: National Natural Science Foundation of China, Science Technology Department of Zhejiang Province, and Zhejiang University.

A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1.

BACKGROUND: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. RESULTS: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. CONCLUSIONS: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.

Wide therapeutic time-window of low-frequency stimulation at the subiculum for temporal lobe epilepsy treatment in rats.

Low-frequency stimulation (LFS) has been considered as an option for the treatment of intractable epilepsy. However, previous data showed that LFS of certain brain regions only exerts its effect within a very narrow therapeutic time window, which lasts from seconds to tens of seconds, thus restricting its clinical application. The present study was designed to determine whether there exists a target with a wider therapeutic window for LFS treatment. Therefore, evoked seizures in the rat were induced by amygdala kindling and spontaneous seizures were induced by pilocarpine. The effects of different modes of LFS at the subiculum on the progression and severity of evoked seizures and the frequency of spontaneous seizure were evaluated. We found that (i) LFS at 1Hz delivered to the subiculum before and immediately after the kindling stimulations, or after the cessation of afterdischarge (afterdischarge duration, ADD) decreased the seizure stages and shortened the ADD both in seizure acquisition and expression in amygdaloid-kindled seizures. In addition, even LFS delivered after duration of double the ADD prolonged the kindling progression. (ii) LFS delivered at 1Hz, but not 0.5, 3 or 130Hz, immediately after the cessation of kindling stimulations retarded the progression of kindling seizures. (iii) Pilocarpine-induced spontaneous seizures were completely inhibited by 1Hz LFS. Thus, these results demonstrated that LFS of the subiculum has a wide therapeutic time-window for temporal lobe epilepsy treatment in rats, suggesting that the subiculum may be a promising and suitable target for clinical application.

Case report: Moderate therapeutic response to Bevacizumab in late-onset Labrune syndrome.

Labrune syndrome (LS) is caused by SNORD118 gene mutations with a particular neuroimaging of white matter disease, intracranial calcification, and cysts. There was no effective treatment until now. An 18-year-old man with infancy-onset LS was first treated with vascular endothelial growth factor (VEGF) inhibitor Bevacizumab for 1 year, resulting in significant clinical and radiological improvements. We adopted a similar regimen in a patient with late-onset LS and demonstrated moderate cognitive improvements but without changes in imaging. As such, Bevacizumab could potentially be clinically effective in adult-onset LS with great safety.

Abnormal Brain Activation During Verbal Memory Encoding in Postacute Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

Background: Patients with postacute anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis are often left with permanent memory impairments. Given that NMDA receptors are essential to memory encoding, and encoding processes have been suggested to contribute to the success of memory retrieval, we investigate whether postacute anti-NMDA receptor encephalitis leads to abnormal brain activation during verbal memory encoding and its potential effects on subsequent memory retrieval performance. Methods: To address this issue, this study recruited 21 adult patients with anti-NMDA receptor encephalitis past the acute stage and 22 healthy controls (HCs). Functional magnetic resonance imaging (fMRI) data were collected when they completed an episodic memory task. Results: At the neural level, the patients showed higher brain activation than the HCs in the bilateral hippocampus/parahippocampus (HG/PHG), right superior temporal gyrus (STG), and right thalamus during memory encoding. At the behavioral level, the patients showed worse memory retrieval performance than the HCs. Importantly, greater brain activation in the left HG/PHG during memory encoding was significantly associated with worse memory retrieval performance among the patients. Conclusion: Our findings indicate that postacute anti-NMDA receptor encephalitis is likely related to altered brain activation during memory encoding. Particularly, less memory retrieval performance often observed in patients with postacute anti-NMDA receptor encephalitis may result from abnormal activation in HG during encoding. These observations may enhance our understanding of NMDA receptor dysfunction in the human brain. Impact statement Patients with anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis are often left with permanent memory impairments. In this study, brain activation during verbal memory encoding and its potential effects on subsequent memory retrieval performance are addressed using 21 adult patients with postacute anti-NMDA receptor encephalitis and 22 healthy controls. Greater brain activation in the left hippocampus/parahippocampus during memory encoding was significantly associated with worse memory retrieval performance among the patients. These observations enhance our understanding of NMDA receptor dysfunction in the human brain.

Altered executive control network connectivity in anti-NMDA receptor encephalitis.

OBJECTIVE: The goal of this study was to examine whether the static functional connectivity (FC) of the executive control network (ECN) and the temporal properties of dynamic FC states in the ECN can characterize the underlying nature of anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis and their correlations with cognitive functions. METHODS: In total, 21 patients with anti-NMDA receptor encephalitis past the acute stage and 23 healthy controls (HCs) underwent a set of neuropsychological tests and participated in a resting-state fMRI study to analyse the static FC of the ECN and the temporal properties of dynamic FC states in the ECN. In addition, correlation analyses were performed to determine the correlations between the FC metrics and cognitive performance. RESULTS: Patients with anti-NMDA receptor encephalitis past the acute stage showed significant cognitive impairments compared to HCs. In accord with the results of neuropsychological tests, static intrinsic FC alterations and changed dynamic FC metrics of ECN were observed in the patients. Importantly, we observed significant correlations between altered ECN metrics and working memory, information processing speed, executive function performance in the patients. INTERPRETATION: Our findings suggest that cognitive impairments in patients with anti-NMDA receptor encephalitis past the acute stage are likely related to altered static and dynamic ECN connectivity. These observations may enhance our understanding of the pathophysiological mechanisms underlying cognitive function in this population.

Therapeutic time window of low-frequency stimulation at entorhinal cortex for amygdaloid-kindling seizures in rats.

The present study was designed to determine whether low-frequency stimulation (LFS) of the entorhinal cortex(EC) has an anticonvulsive effect, and whether LFS delivered at different times plays different roles. We found that LFS of the EC immediately or 4 s after kindling stimulation had an anticonvulsive effect, and that the latter had a better effect on both kindling and kindled seizures. However, LFS delivered after the cessation of afterdischarge or 10 s after the kindling stimulation, augmented the epileptic activity. So the EC is a potential target for LFS to interfere with epilepsy. Our findings suggest that even in the duration of afterdischarge, there exists a "time window" for LFS treatment, indicating that the time delay of closed-loop stimulation is crucial for LFS treatment.

TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35.

OBJECTIVE: To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6. METHODS: Neurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype. RESULTS: The proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals. CONCLUSIONS: The nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35.

In vitro activity of Impatiens balsamina L. against multiple antibiotic-resistant Helicobacter pylori.

Impatiens balsamina L. has been used as indigenous medicine in Asia for the treatment of rheumatism, fractures, and fingernail inflammation. In this study, anti-H. pylori activity of I. balsamina L. was investigated. The MICs, MBCs, time-kill assay, and effect of environmental pH for the plant extracts were determined. The test H. pylori strains have resistance to clarithromycin (CLR), metronidazole (MTZ), and levofloxacin (LVX). From our results, all part (root/stem/leaf, seed, and pod) extracts of I. balsamina L. exhibited bactericidal H. pylori activity. Specifically, the pod extract had significantly lower MICs and MBCs (1.25-2.5 and 1.25-5.0 microg/ml, respectively). Of the five pod-extraction solvents, both ethyl acetate and acetone were the most efficient for the anti-H. pylori compounds of the pod extraction. The dose-dependency of the pod extract's bactericidal activity was H. pylori strain-dependent. Bactericidal H. pylori activity of the pod extract was not affected by the environmental pH (2-8). In summary, the acetone and ethyl acetate pod extracts of I. balsamina L. exhibited very strong anti-H. pylori activity. This activity exceeded that of MTZ and approximated to that of AMX.

Early second-line therapy is associated with improved episodic memory in anti-NMDA receptor encephalitis.

OBJECTIVE: To investigate whether the early administration of intravenous second-line immunotherapy correlates with improved long-term cognition and the potential mechanisms via imaging in adult patients with moderate-to-severe anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. METHODS: Sixteen adult patients with moderate-to-severe anti-NMDA receptor encephalitis past the acute stage and 15 healthy controls (HCs) performed a set of comprehensive neuropsychological tests, and underwent a resting-state fMRI study to analyze resting state functional connectivity (FC). In addition, correlation analyses were performed between hippocampal FC and cognitive performance. All patients were received intravenous first-line immunotherapy, and nine of them were also given intravenous second-line immunotherapy within 3 months of disease onset. RESULTS: The patients who only received first-line immunotherapy showed significant verbal episodic memory impairments compared with HCs and those who received second-line immunotherapy, while no significant differences were noted between the patients with second-line immunotherapy and the HCs. In line with the results of neuropsychological tests, significant changes in bilateral hippocampal FC were observed in the patients who only received first-line immunotherapy compared with both HCs and those who received second-line immunotherapy. However, no significant differences in hippocampal FC were observed in the patients with second-line immunotherapy compared with the HCs. Importantly, hippocampal-medial prefrontal cortex (mPFC) connectivity positively correlated with memory performance. INTERPRETATION: In the long term, early administration of intravenous second-line immunotherapy may be associated with more favorable verbal episodic memory outcomes in patients with moderate-to-severe anti-NMDA receptor encephalitis. These results may provide some evidence and guidance for the use of immunotherapy in this population.

Magnetic resonance fingerprinting of temporal lobe white matter in mesial temporal lobe epilepsy.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is a network disorder. We aimed to quantify the white matter alterations in the temporal lobe of MTLE patients with hippocampal sclerosis (MTLE-HS) by using magnetic resonance fingerprinting (MRF), a novel imaging technique, which allows simultaneous measurements of multiple parameters with a single acquisition. METHODS: We consecutively recruited 27 unilateral MTLE-HS patients and 22 healthy controls. Measurements including T1, T2, and PD values in the temporopolar white matter and temporal stem were recorded and analyzed. RESULTS: We found increased T2 value in both sides, and increased T1 value in the ipsilateral temporopolar white matter of MTLE-HS patients, as compared with healthy controls. The T1 and T2 values were higher in the ipsilateral than the contralateral side. In the temporal stem, increased T1 and T2 values in the ipsilateral side of the MTLE-HS patients were also observed. Only increased T2 values were observed in the contralateral temporal stem. No significant differences in PD values were observed in either the temporopolar white matter or temporal stem of the MTLE-HS patients. Correlation analysis revealed that T1 and T2 values in the ipsilateral temporopolar white matter were negatively correlated with the age at epilepsy onset. INTERPRETATION: By using MRF, we were able to assess the alterations of T1 and T2 in the temporal lobe white matter of MTLE-HS patients. MRF could be a promising imaging technique in identifying mild changes in MTLE patients, which might optimize the pre-surgical evaluation and therapeutic interventions in these patients.

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation.

AIMS: Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early-life FSs could transmit across generations or not. METHODS: The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects. RESULTS: Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) 1 was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase 1. DNMT inhibitors prevented the high expression of DNMT1 and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs. CONCLUSIONS: Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

Time-dependent effect of low-frequency stimulation on amygdaloid-kindling seizures in rats.

Low-frequency stimulation (LFS) has been considered as a new option for the treatment of intractable epilepsy. The present study was designed to determine whether LFS of the kindling focus given at different time points after seizures exert different roles on kindling seizures. Our results showed that: (i) In kindling animals, LFS delivered immediately after cessation of the kindling stimulus inhibited the seizure stage during kindling acquisition, whereas LFS delivered after the cessation of afterdischarge accelerated the kindling progression to stages 1 and 2. (ii) In fully kindled animals, when using the generalized seizure threshold current as the kindling stimulus, immediate LFS decreased the incidence of generalized seizures and the average seizure stage as well as shortened the cumulative generalized seizure duration (GSD). However, delayed LFS prolonged the cumulative GSD and afterdischarge duration. Our study indicates that there is a time-dependent aspect of LFS treatment, and immediate LFS has anti-epileptogenic action.

Low-frequency stimulation of the tuberomammillary nucleus facilitates electrical amygdaloid-kindling acquisition in Sprague-Dawley rats.

Histamine plays a suppressive role in seizure. The tuberomammillary nucleus (TM) is the only locus of histaminergic neurons in the brain. To determine whether deep brain stimulation (DBS) of the TM provides protection against seizures, we tested the effects of low-frequency stimulation (LFS, 1 Hz), high frequency stimulation (HFS, 100 Hz), and electrolytic lesions of the TM on seizures generated by amygdaloid kindling, pentylenetetrazol (PTZ) and maximal electroshock (MES) in rats. LFS of TM accelerated the progression of behavioral seizure stage and increased the mean afterdischarge duration (ADD) during acquisition of amygdaloid-kindling seizures, but had no considerable anticonvulsive effect in fully kindled animals. It augmented the MES-induced seizures as well, but had no appreciable effects on PTZ-kindled seizures. In addition, both HFS and bilateral lesions of the TM exacerbated the progression of amygdaloid-kindling seizures. These results suggest that specific negative sites for DBS exist in the brain, such as the TM. This study indicates that it is crucial to choose a suitable target for DBS in the clinical treatment of epilepsy.