Increased Thalamic Connectivity in Juvenile Myoclonic Epilepsy Based on Electroencephalography Source-Level Analysis.

Background: This study investigated alterations in the intrinsic thalamic network of patients with juvenile myoclonic epilepsy (JME) based on an electroencephalography (EEG) source-level analysis. Materials and Methods: We enrolled patients newly diagnosed with JME as well as healthy controls. The assessments were conducted in the resting state. We computed sources based on the scalp electrical potentials using a minimum-norm imaging method and a standardized, low-resolution, brain electromagnetic tomography approach. To create a functional connectivity matrix, we used the Talairach atlas to define thalamic nodes and applied the coherence method to measure brain synchronization as edges. We then calculated the intrinsic thalamic network using graph theory. We compared the intrinsic thalamic network of patients with JME with those of healthy controls. Results: This study included 67 patients with JME and 66 healthy controls. EEG source-level analysis revealed significant differences in the intrinsic thalamic networks between patients with JME and healthy controls. The measures of functional connectivity (radius, diameter, and characteristic path length) were significantly lower in patients with JME than in healthy controls (radius: 2.769 vs. 3.544, p = 0.015; diameter: 4.464 vs. 5.443, p = 0.024; and characteristic path length: 2.248 vs. 2.616, p = 0.046). Conclusions: We demonstrated alterations in the intrinsic thalamic network in patients with JME compared with those in healthy controls based on the EEG source-level analysis. These findings indicated increased thalamic connectivity in the JME group. These intrinsic thalamic network changes may be related to the pathophysiology of JME.

Altered dynamic functional connectivity of striatal-cortical circuits in Juvenile Myoclonic Epilepsy.

OBJECTIVE: To investigate whether the dynamic functional connectivity (dFC) of striatal-cortical circuits changes in juvenile myoclonic epilepsy (JME). METHODS: The resting-state EEG-fMRI and the sliding-window approach were adopted to explore the dynamic striatal-cortical circuitry in thirty JME patients compared with 30 well-matched health controls (HCs). Six pairs of striatal seeds were selected as regions of interests. The correlation analysis was performed to reveal the relationship between the altered dFC variability and clinical variables in JME group. RESULTS: JME patients exhibited increased dFC variability mainly involved in fronto-striatal and striatal-thalamic networks; decreased dFC variability between striatum subdivisions and default mode network (DMN) regions compared with HCs (p<0.05, GRF corrected). In addition, the hypervariability between left ventral-rostral putamen and left medial superior frontal gyrus was positively (r= 0.493, p=0.008) correlated with the mean frequency score of myoclonic seizures in JME group. CONCLUSION: JME presented altered dFC variability in striatal-cortical circuits. The pattern of altered circuits showed increased variability in fronto-striatal and striatal-thalamic networks and decreased variability in striatal-DMN. These results provide novel information about the dynamic neural striatal-cortical circuitry of JME.

Comparative analysis of background EEG activity in juvenile myoclonic epilepsy during valproic acid treatment: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study.

BACKGROUND: By definition, the background EEG is normal in juvenile myoclonic epilepsy (JME) patients and not accompanied by other developmental and cognitive problems. However, some recent studies using quantitative EEG (qEEG) reported abnormal changes in the background activity. QEEG investigation in patients undergoing anticonvulsant treatment might be a useful approach to explore the electrophysiology and anticonvulsant effects in JME. METHODS: We investigated background EEG activity changes in patients undergoing valproic acid (VPA) treatment using qEEG analysis in a distributed source model. In 17 children with JME, non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions. RESULTS: VPA reduced background EEG activity in the low-frequency (delta-theta) bands across the frontal, parieto-occipital, and limbic lobes (threshold log-F-ratio = ±1.414, p < 0.05; threshold log-F-ratio= ±1.465, p < 0.01). In the delta band, comparative analysis revealed significant current density differences in the occipital, parietal, and limbic lobes. In the theta band, the analysis revealed significant differences in the frontal, occipital, and limbic lobes. The maximal difference was found in the delta band in the cuneus of the left occipital lobe (log-F-ratio = -1.840) and the theta band in the medial frontal gyrus of the left frontal lobe (log-F-ratio = -1.610). CONCLUSIONS: This study demonstrated the anticonvulsant effects on the neural networks involved in JME. In addition, these findings suggested the focal features and the possibility of functional deficits in patients with JME.

Functional connectivity disturbances of ascending reticular activating system and posterior thalamus in juvenile myoclonic epilepsy in relation with photosensitivity: A resting-state fMRI study.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is typified by the occurrence of myoclonic seizures after awakening, though another common trait is myoclonic seizures triggered by photic stimulation. We aimed to investigate the functional connectivity (FC) of nuclei in the ascending reticular activating system (ARAS), thalamus and visual cortex in JME with and without photosensitivity. METHODS: We examined 29 patients with JME (16 photosensitive (PS), 13 non- photosensitive-(NPS)) and 28 healthy controls (HCs) using resting-state functional magnetic resonance imaging (rs-fMRI). Seed-to-voxel FC analyses were performed using 25 seeds, including the thalamus, visual cortex, and ARAS nuclei. RESULTS: Mesencephalic reticular formation seed revealed significant hyperconnectivity between the bilateral paracingulate gyrus and anterior cingulate cortex in JME group, and in both JME-PS and JME-NPS subgroups compared to HCs (pFWE-corr < 0.001; pFWE-corr < 0.001; pFWE-corr = 0.002, respectively). Locus coeruleus seed displayed significant hyperconnectivity with the bilateral lingual gyri, intracalcarine cortices, occipital poles and left occipital fusiform gyrus in JME-PS group compared to HCs (pFWE-corr <0.001). Additionally, locus coeruleus seed showed significant hyperconnectivity in JME-PS group compared to JME-NPS group with a cluster corresponding to the bilateral lingual gyri and right intracalcarine cortex (pFWE-corr < 0.001). Lastly, the right posterior nuclei of thalamus revealed significant hyperconnectivity with the right superior lateral occipital cortex in JME-PS group compared to HCs (pFWE-corr < 0.002). CONCLUSIONS: In JME, altered functional connectivity of the arousal networks might contribute to the understanding of myoclonia after awakening, whereas increased connectivity of posterior thalamus might explain photosensitivity.

Thalamic and cortical hyperexcitability in juvenile myoclonic epilepsy.

OBJECTIVES: Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy marked by cortical hyperexcitability. Recent neuroimaging data suggested also a thalamic role in sustaining epileptic propensity in JME. However, thalamic hyperexcitability was not demonstrated so far. Low-frequency (LF-SEPs) and high-frequency somatosensory evoked potentials (HF-SEPs) are very sensitive to thalamic (early HF-SEPs burst, eHFO) and cortical (late HF-SEPs burst, lHFO) excitability. The aim of our experiment was to explore and discern the role of thalamic and cortical excitability in epileptic susceptibility of JME through a LF-SEPs and HF-SEPs study. METHODS: Twenty-three subjects with JME (11 females, 30.2 ± 9.8-year-old) and 23 healthy control subjects (12 females, age: 34.7 ± 7.7-year-old) underwent right median LF-SEPs scalp recordings. Cp3'-Fz traces were filtered (400-800 Hz) to reveal HF-SEPs. All JME patients were on drug treatment and seizure free, except for sporadic myoclonus. RESULTS: N20 LF-SEPs amplitude (p < 0.009), areas of totHFO, eHFO and lHFO (all p < 0.005) and totHFO duration (p = 0.013) were increased in JME respect to healthy subjects. totHFO area was negatively correlated with the number of antiepileptic drugs (rho = -0.505, sig.: 0.027), while eHFO area was positively correlated with the myoclonus frequency (rho = 0.555, sig = 0.014). CONCLUSIONS: We demonstrated that in JME the thalamic hyperexcitability assists the cortical one in sustaining epileptic susceptibility. SIGNIFICANCE: Our results support the concept of JME as a network and genetic disorder.

Rhythmic Network Modulation to Thalamocortical Couplings in Epilepsy.

Thalamus interacts with cortical areas, generating oscillations characterized by their rhythm and levels of synchrony. However, little is known of what function the rhythmic dynamic may serve in thalamocortical couplings. This work introduced a general approach to investigate the modulatory contribution of rhythmic scalp network to the thalamo-frontal couplings in juvenile myoclonic epilepsy (JME) and frontal lobe epilepsy (FLE). Here, time-varying rhythmic network was constructed using the adapted directed transfer function between EEG electrodes, and then was applied as a modulator in fMRI-based thalamocortical functional couplings. Furthermore, the relationship between corticocortical connectivity and rhythm-dependent thalamocortical coupling was examined. The results revealed thalamocortical couplings modulated by EEG scalp network have frequency-dependent characteristics. Increased thalamus- sensorimotor network (SMN) and thalamus-default mode network (DMN) couplings in JME were strongly modulated by alpha band. These thalamus-SMN couplings demonstrated enhanced association with SMN-related corticocortical connectivity. In addition, altered theta-dependent and beta-dependent thalamus-frontoparietal network (FPN) couplings were found in FLE. The reduced theta-dependent thalamus-FPN couplings were associated with the decreased FPN-related corticocortical connectivity. This study proposed interactive links between the rhythmic modulation and thalamocortical coupling. The crucial role of SMN and FPN in subcortical-cortical circuit may have implications for intervention in generalized and focal epilepsy.

Subcortical gray matter changes in pediatric patients with new-onset juvenile myoclonic epilepsy.

OBJECTIVE: The objective of the study was to identify the relationship between subcortical gray matter (GM) volumes and juvenile myoclonic epilepsy (JME). METHODS: We analyzed the brain magnetic resonance imaging (MRI) scans that were performed during the time of the diagnosis of epilepsy by using voxel-based morphometry (VBM) method. The volumetric three-dimensional sequence was used for structural investigation. The volumes of the thalamus, caudate nucleus, pallidum, and putamen were measured in both hemispheres of patients with JME, patients with generalized tonic-clonic seizures alone (GTCS) (as a disease control group) and healthy controls (HCs). All patients were drug-naïve, and treatment had been started after evaluating MRI results. RESULTS: Fifteen patients with JME (9 females, mean age = 16.1 ±â€¯3.2), 18 patients with GTCS (10 females, mean age = 15.5 ±â€¯2.9), and 43 HCs (24 females, mean age = 15.9 ±â€¯2.8) were included in the analysis. No significant difference was found for relative globus pallidus, caudate, and putamen volumes among the groups with JME, GTCS, and the HC group. The relative left and right thalamic volumes were significantly different between groups (Kruskal-Wallis rank test, p = 0.007, p = 0.001). In pairwise comparisons, both right and left relative thalamic volumes were lower in patients with JME than in HCs (right thalamus: means: 0.521 ±â€¯0.066 vs. 0.597 ±â€¯0.058, p < 0.001; left thalamus: means: 0.526 ±â€¯0.088 vs. 0.605 ±â€¯0.057, p < 0.001, Bonferroni post hoc corrections) and in patients with JME than in patients with GTCS (right thalamus: means: 0.521 ±â€¯0.066 vs. 0.578 ±â€¯0.066, p = 0.03; left thalamus: means: 0.526 ±â€¯0.088 vs. 0.592 ±â€¯0.068, p = 0.01, Bonferroni post hoc corrections), whereas there was no significant difference between the HCs and patients with GTCS (right thalamus: means: 0.597 ±â€¯0.058 vs. 0.578 ±â€¯0.066, p = 0.8; left thalamus: means: 0.605 ±â€¯0.057 vs. 0.592 ±â€¯0.068, p = 0.999, Bonferroni post hoc corrections). CONCLUSION: This study allowed us to know that microstructural abnormalities exist from the disease onset, and the thalamus might play a critical role in the pathogenesis of JME.

Alteration of cerebello-thalamocortical spontaneous low-frequency oscillations in juvenile myoclonic epilepsy.

OBJECTIVE: Altered thalamocortical network has been proposed to play a pivotal role in the principal pathophysiology underlying juvenile myoclonic epilepsy (JME). Recently, resting-state fMRI studies have provided converging evidence for thalamocortical dysconnectivity in patients with JME. Herein, we investigated the amplitude and spatial distribution of spontaneous low-frequency oscillations using analysis of fractional amplitude of low-frequency fluctuation (fALFF) in a large group of JME patients in comparison with controls. METHODS: Volumetric MRI and resting-state fMRI were acquired in 75 patients with JME and 62 matched controls. After preprocessing of MRI data, fALFF was computed and then Z-transformed for standardization. fALFF was compared between controls and patients, and correlation analysis between regional fALFF and clinical parameters were performed in patients. RESULTS: Compared with controls, JME patients revealed significant fALFF increases in the bilateral medial thalamus, insular cortex/inferior frontal gyrus, and cerebellum vermis (false discovery rate-corrected P < 0.05). There was no region of fALFF reduction in JME patients relative to controls. No significant correlation was observed between regional fALFF and disease duration or cumulative number of generalized tonic-clonic seizures. CONCLUSIONS: We have shown alterations of low-frequency oscillations in the thalamus, insular cortex/inferior frontal gyrus, and cerebellum in patients with JME, implicating cerebello-thalamocortical network abnormality in the pathophysiology underlying JME. Our results could further support the recent concept that JME is a network epilepsy involving specific cortical and subcortical structures, especially the cerebello-thalamocortical network.

BOLD-fMRI activity informed by network variation of scalp EEG in juvenile myoclonic epilepsy.

Epilepsy is marked by hypersynchronous bursts of neuronal activity, and seizures can propagate variably to any and all areas, leading to brain network dynamic organization. However, the relationship between the network characteristics of scalp EEG and blood oxygenation level-dependent (BOLD) responses in epilepsy patients is still not well known. In this study, simultaneous EEG and fMRI data were acquired in 18 juvenile myoclonic epilepsy (JME) patients. Then, the adapted directed transfer function (ADTF) values between EEG electrodes were calculated to define the time-varying network. The variation of network information flow within sliding windows was used as a temporal regressor in fMRI analysis to predict the BOLD response. To investigate the EEG-dependent functional coupling among the responding regions, modulatory interactions were analyzed for network variation of scalp EEG and BOLD time courses. The results showed that BOLD activations associated with high network variation were mainly located in the thalamus, cerebellum, precuneus, inferior temporal lobe and sensorimotor-related areas, including the middle cingulate cortex (MCC), supplemental motor area (SMA), and paracentral lobule. BOLD deactivations associated with medium network variation were found in the frontal, parietal, and occipital areas. In addition, modulatory interaction analysis demonstrated predominantly directional negative modulation effects among the thalamus, cerebellum, frontal and sensorimotor-related areas. This study described a novel method to link BOLD response with simultaneous functional network organization of scalp EEG. These findings suggested the validity of predicting epileptic activity using functional connectivity variation between electrodes. The functional coupling among the thalamus, frontal regions, cerebellum and sensorimotor-related regions may be characteristically involved in epilepsy generation and propagation, which provides new insight into the pathophysiological mechanisms and intervene targets for JME.

Frontal lobe cognitive functions and electroencephalographic features in juvenile myoclonic epilepsy.

PURPOSE: The study aimed to examine the relationship between frontal lobe functions and interictal electroencephalography (EEG) discharge characteristics of patients with juvenile myoclonic epilepsy (JME). METHOD: Thirty patients with JME who had EEG with asymmetrical generalized discharge (aEEG), 15 patients with JME who had EEG with symmetrical generalized discharge (sEEG), and 15 healthy controls were included in the study. To evaluate attention, the digit span and Corsi block tests were used; to evaluate memory, we applied verbal and visual memory tests; to evaluate frontal lobe functions, we used clock drawing, verbal fluency, the Stroop test, trail making, mental control, and antisaccadic eye movement tests as well as the continuous performance (CPT) tests. ETHICAL CONSIDERATIONS: The research was approved by the Research Ethics Committee of the Bakirkoy Research and Training Hospital for Psychiatry, Neurology, Neurosurgery, with protocol number: 41340010/4891-262, date: 05.02.2013. RESULTS: The mean age of the 45 patients with JME was 22.89 ±â€¯6.77 years, and 34 (75.6%) were female. The age at onset of seizures and disease duration of the patients with JME was 15.56 ±â€¯4.06 years (range, 9-26 years) and 7.20 ±â€¯5.59 years (range, 1-25 years), respectively. All patients were under valproate (VPA) treatment, and the mean VPA dosage was 783.33 ±â€¯379.14 mg/day. Patients with JME scored worse than the control group in attention, memory, and frontal lobe functions. In patients with aEEG, scores of attention, memory, and frontal lobe function tests were lower than in patients with sEEG; however, with the exception of CPT, they were not statistically significant. CONCLUSION: Cognitive functions in JME have been shown to be impaired. Furthermore, we concluded that the frontal lobe cognitive functions may be worse in patients with aEEG than in patients with sEEG. Further studies in patients with JME with aEEG abnormalities may lead to a better understanding of the pathophysiology of JME.

Aberrant Thalamocortical Connectivity in Juvenile Myoclonic Epilepsy.

The purpose of this study was to investigate the functional connectivity (FC) of thalamic subdivisions in patients with juvenile myoclonic epilepsy (JME). Resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were acquired from 22 JME and 25 healthy controls. We first divided the thalamus into eight subdivisions by performing independent component analysis on tracking fibers and clustering thalamus-related FC maps. We then analyzed abnormal FC in each subdivision in JME compared with healthy controls, and we investigated their associations with clinical features. Eight thalamic sub-regions identified in the current study showed unbalanced thalamic FC in JME: decreased FC with the superior frontal gyrus and enhanced FC with the supplementary motor area in the posterior thalamus increased thalamic FC with the salience network (SN) and reduced FC with the default mode network (DMN). Abnormalities in thalamo-prefrontocortical networks might be related to the propagation of generalized spikes with frontocentral predominance in JME, and the network connectivity differences with the SN and DMN might be implicated in emotional and cognitive defects in JME. JME was also associated with enhanced FC among thalamic sub-regions and with the basal ganglia and cerebellum, suggesting the regulatory role of subcortical nuclei and the cerebellum on the thalamo-cortical circuit. Additionally, increased FC with the pallidum was positive related with the duration of disease. The present study provides emerging evidence of FC to understand that specific thalamic subdivisions contribute to the abnormalities of thalamic-cortical networks in JME. Moreover, the posterior thalamus could play a crucial role in generalized epileptic activity in JME.

Juvenile myoclonic epilepsy may be a disorder of cortex rather than thalamus: An effective connectivity analysis.

Although juvenile myoclonic epilepsy has been considered as a disorder of thalamo-cortical circuit, it is not determined the causality relationship between thalamus and cortex. The aim of this study was to evaluate whether juvenile myoclonic epilepsy is a disorder of thalamus or cortex. Twenty-nine patients with juvenile myoclonic epilepsy and 20 normal controls were enrolled in this study. In addition, we included 10 patients with childhood absence epilepsy as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the structures, including hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. The structural volumes in juvenile myoclonic epilepsy were not different from those in normal controls. There was a statistically significant effective connectivity from the total cortex to the thalamus in the patients with juvenile myoclonic epilepsy. In addition, a significant effective connectivity from the hippocampus to the ipsilateral thalamus was revealed. Unlike the patients with juvenile myoclonic epilepsy, neither the patients with childhood absence epilepsy nor normal controls had a significant effective connectivity from the total cortex to the thalamus or from the thalamus to the cortex. The connectivity of brain in patients with juvenile myoclonic epilepsy could be different from that in patients with childhood absence epilepsy, and the cortex rather than the thalamus might play a critical role in the pathogenesis of juvenile myoclonic epilepsy.

Heterogeneity of anatomic regions by MR volumetry in juvenile myoclonic epilepsy.

OBJECTIVE: To investigate brain volumes in patients with well-characterized juvenile myoclonic epilepsy (JME). MATERIALS AND METHODS: We studied the MRI images of seventeen subjects with EEG and clinically defined JME and seventeen age- and sex-matched controls using voxel-based morphometry (VBM) and automated and manual volumetry. RESULTS: We found no significant group differences in the cortical volumes by automated techniques for all regions or for the whole brain. However, we found a larger pulvinar nucleus in JME using VBM with small volume correction and a larger thalamus with manual volumetry (P = 0.001; corrected two-tailed t-test). By analysing the individual subjects, we determined that considerable heterogeneity exists even in this highly selected group. Histograms of all JME and matched control regions' volumes showed more subjects with JME had smaller hippocampi and larger thalami (P < 0.05; chi-square). Subjects in whom the first seizure was absence were more likely to have smaller hippocampi than their matched control, while those without absences showed no differences (P < 0.05, chi-square). CONCLUSIONS: There is ample evidence for frontal cortical thalamic network changes in JME, but subcortical structural differences were more distinct in this group. Given the heterogeneity of brain volumes in the clinical population, further advancement in the field will require the examination of stringent genetically controlled populations.

High-dose versus low-dose valproate for the treatment of juvenile myoclonic epilepsy: Going from low to high.

Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy accounting for 3-12% of adult cases of epilepsy. Valproate has proven to be the first-choice drug in JME for controlling the most common seizure types: myoclonic, absence, and generalized tonic-clonic (GTC). In this retrospective study, we analyzed seizure outcome in patients with JME using valproate monotherapy for a minimum period of one year. Low valproate dose was considered to be 1000mg/day or lower, while serum levels were considered to be low if they were at or below 50mcg/dl. One hundred three patients met the inclusion criteria. Fifty-six patients (54.4%) were female. The current average age was 28.4±7.4years, while the age of epilepsy onset was 13.6±2.9years. Most patients corresponded to the subsyndrome of classic JME. Forty-six (44.7%) patients were free from all seizure types, and 76 (73.7%) patients were free from GTC seizures. No significant difference was found in seizure freedom among patients using a low dose of valproate versus a high dose (p=0.535) or among patients with low blood levels versus high blood levels (p=0.69). In patients with JME, it seems appropriate to use low doses of valproate (500mg to 1000mg) for initial treatment and then to determine if freedom from seizures was attained.

Modern management of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common genetic epilepsy syndrome usually presenting in adolescence and characterized by myoclonic jerks, predominately in the arms, associated with tonic-clonic seizures and less often generalized absences. Although the evidence base for treating JME is weak, most experts regard sodium valproate as drug of first choice. The recent diktat from the European regulatory agency - recommending that sodium valproate should not be prescribed to female children, adolescents or women of childbearing potential unless other treatments were ineffective or not tolerated - has substantially changed the way JME is being managed in this population. This paper reviews the literature underpinning the pharmacological treatment of JME. Data reporting associated symptoms of frontal lobe dysfunction in some patients with JME are discussed, as is the importance of counselling on lifestyle issues as an essential component of management. Long-term studies examining pharmacological and quality-of-life outcomes are reviewed, indicating a range of different phenotypes and likely genotypes underpinning this fascinating disorder. Lastly, a practical approach to managing JME in young men and women is summarized.

Diffusion tensor imaging abnormalities in photosensitive juvenile myoclonic epilepsy.

BACKGROUND AND PURPOSE: Multiple structural white matter abnormalities have been described in patients with juvenile myoclonic epilepsy (JME). In the present study, the question of whether microstructural variations exist between the two subgroups of JME, with and without photoparoxysmal responses (PPR positive and negative), was addressed using diffusion tensor imaging. METHODS: A selection of 18 patients (eight PPR positive) from a tertiary epilepsy center diagnosed with JME and 27 healthy controls was studied. The following regions of interest were investigated: the ascending reticular activating system, lateral geniculate nucleus, genu of the internal capsule, ventromedial thalamus and inferior cerebellar peduncle. RESULTS: Widespread white matter microstructural abnormalities in JME and in particular in PPR positive cases were identified. PPR positive patients demonstrated increased fractional anisotropy in the ascending reticular activating system and ventromedial thalamus compared to PPR negative patients and healthy controls. Reduced fractional anisotropy of the lateral geniculate nucleus was observed in the entire JME group compared to healthy controls. CONCLUSIONS: Several microstructural variations between PPR positive and negative JME patients have been identified. Our findings highlight the pivotal role of the thalamus in the pathophysiology of primary generalized seizures and suggest that thalamo-premotor connections are both an essential part of epileptic networks and important in the pathogenesis of photosensitivity.

Auditory startle response is normal in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is hypothesized to originate from the dysfunction of thalamo-cortical circuit. We aimed to analyze any changes in auditory startle response in JME patients to determine the role of brainstem in JME. The responses of 18 JME patients to auditory simulation were recorded over the unilateral orbicularis oculi, masseter, sternocleidomastoid, and extremity muscles. Results were compared with those of 18 age and gender matched healthy volunteers. Total auditory startle response frequencies were similar between the two groups (31.1 ± 11.1 % vs. 33.7 ± 8.7 %, p = 0.400). Other parameters over each muscle were also similar. There were no impacts of antiepileptic drug use or disease duration. We may conclude that our findings may provide sufficient evidence for the lack of functional changes of the auditory startle response circuit even in longstanding cases of JME.

Frontal and thalamic changes of GABA concentration indicate dysfunction of thalamofrontal networks in juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) has been considered to be a frontal variant of thalamocortical network dysfunction in epilepsy. Changes of γ-aminobutyric acid (GABA)ergic neurotransmission may play a key role in this dysfunction. Magnetic resonance spectroscopy (MRS) is the only noninvasive method to measure GABA concentrations in different brain regions. We measured GABA and other metabolite concentrations in the thalamus and frontal lobe of patients with JME. METHODS: A specific protocol was used for determining GABA concentrations in the thalamus, frontal lobe, and motor cortex contralateral to the handedness in 15 patients with JME and 15 age-matched controls. In addition, we measured concentrations of glutamate and glutamine, N-acetyl-aspartate (NAA), myoinositol, creatine, and choline using MRS with short echo time. JME-related concentration changes were analyzed comparing patients to controls, also considering potential effects of antiepileptic drugs. RESULTS: In patients with JME, GABA and NAA were reduced in the thalamus (p = 0.03 and p = 0.02), whereas frontal GABA and glutamine were elevated (p = 0.046 and p = 0.03). MRS revealed reduced NAA in the thalamic gray matter contralateral to the handedness (p = 0.04 each). These changes were found consistently in patients treated with new antiepileptic drugs and with valproate, although the extent of metabolic changes differed between these treatments. SIGNIFICANCE: Decreased thalamic and increased frontal GABA suggest a dysfunction of GABAergic neurotransmission in these brain regions of patients with JME. The NAA decrease in the gray matter of the thalamus may hint to a damage of GABAergic neurons, whereas frontal increase of GABA and its precursor glutamine may reflect increased density in GABAergic neurons due to subtle cortical disorganization in the thalamofrontal network.

Causal influence of epileptic network during spike-and-wave discharge in juvenile myoclonic epilepsy.

Electroencephalographic (EEG) characteristic of juvenile myoclonic epilepsy (JME) is spike-and-wave discharge (SWD), which is dominant in the frontal region. However, activity in the parietal area, including the precuneus, has also been documented for several seconds before and during SWD. The aim of this study was to identify the role of the parietal region, especially the precuneus, and to clarify the causal dynamics among cortical regions during SWD. EEGs were obtained from seven patients with JME. Each SWD was divided into six distinct temporal phases: spike onset, spike peak, slow-wave onset, slow-wave ascending, slow-wave peak, and slow-wave descending phases. Based on the cortical current source distribution and the results of a previous study, we selected the medial frontal, orbitofrontal, anterior cingulate, and mesial temporal cortices and the precuneus as regions of interest (ROIs). To assess epileptic networks and the causal relationships among ROIs during SWD, the directed transfer function (DTF), a measure of multivariate causality, was calculated for each phase of SWD. During spike onset, the maximal outdegree region in all patients was the precuneus. The spike-peak and slow-wave onset phases did not show a consistently dominant outflow region. Outflow from the anterior cingulate cortex was dominant in four patients during the slow-wave ascending phase, and the precuneus showed the maximal outdegree in six patients during the slow-wave peak. In the slow-wave descending phase, four patients showed maximal outflow from the temporal cortex. Our findings suggest that the precuneus is likely a key region for SWD despite the small amount of neural activity observed. The precuneus was the region with the maximal outdegree during both the spike onset and slow-wave peak phases, indicating that SWD in JME is initiated and sustained by a network involving the frontal cortex, precuneus, and thalamus.

Nodular heterotopia and absence seizures: fMRI evidence that they may be connected.

In this study we used EEG-fMRI to investigate whether peri-ventricular nodular heterotopia (PNH) are connected to the seizure generating network in individuals initially diagnosed with absence seizures (AS) who were later found to have co-existent PNH. We performed event related EEG-fMRI of the patients typical events as well as performing functional connectivity (FC) seeded from the PNH to answer this question. Both subjects demonstrated event related BOLD change in the "core" absence network. Subject 1 also displayed event related BOLD increase in the nodules while FC analysis demonstrated connectivity between the nodules and the thalami and striatum bilaterally. The second subject did not display event related BOLD in the PNH but FC analysis demonstrated strong connections between the PNH and the parietal cortex. This study demonstrates that the peri-ventricular nodules can show connectivity to the absence network in individuals with AS and may be involved in seizure generation.