Repeated long sessions of transcranial direct current stimulation reduces seizure frequency in patients with refractory focal epilepsy: An open-label extension study.

OBJECTIVE: Although clinical trials have demonstrated that cathodal transcranial direct current stimulation (tDCS) is effective for seizure reduction, its long-term efficacy is unknown. This study aimed to determine the long-term effects of repeated cathodal long tDCS sessions on seizure suppression in patients with refractory epilepsy. METHODS: Patients were recruited to participate in an extended phase of a previous randomized, double-blind, sham-controlled, three-arm, parallel, multicenter study on tDCS. The patients were divided into an active tDCS group (20 min of tDCS per day) and an intensified tDCS group (2 × 20 min of tDCS per day). Each tDCS session lasted 2 weeks and the patients underwent repeated sessions at intervals of 2 to 6 months. The cathode was placed over the epileptogenic focus with the current intensity set as 2 mA. Seizure frequency reduction from baseline was analyzed using the Wilcoxon signed-rank test for two related samples. A generalized estimating equation model was used to estimate group, time, and interaction effects. RESULTS: Among the 19 patients who participated in the extended phase, 11 were in the active tDCS group and underwent 2-16 active tDCS sessions, and eight were in the intensified tDCS group and underwent 3-11 intensified tDCS sessions. Seizure reduction was significant from the first to the seventh follow-up, with a median seizure frequency reduction of 41.7%-83.3% (p < 0.05). Compared to the regular tDCS protocol, each intensified tDCS session substantially decreased seizure frequency by 0.3680 (p < 0.05). One patient experienced an increase of 8.5%-232.8% in the total number of seizures during three treatment sessions and follow-ups. CONCLUSION: Repeated long cathodal tDCS sessions yielded significant and progressive long-term seizure reductions in patients with refractory focal epilepsy.

SCN1A-Related Epilepsy: Novel Mutations and Rare Phenotypes.

Objectives: To expand the genotypes and phenotypes of sodium voltage-gated channel alpha subunit 1 (SCN1A)-related epilepsy. Methods: We retrospectively collected the clinical and genetic information of 22 epilepsy patients (10 males, 12 females; mean: 9.2 ± 3.9 years; 3.9-20.3 years) carrying 22 variants of SCN1A. SCN1A mutations were identified by next-generation sequencing. Results: Twenty-two variants were identified, among which 12 have not yet been reported. The median age at seizure onset was 6 months. Sixteen patients were diagnosed with Dravet syndrome (DS), two with genetic epilepsy with febrile seizures plus [one evolved into benign epilepsy with centrotemporal spikes (BECTS)], one with focal epilepsy, one with atypical childhood epilepsy with centrotemporal spikes (ABECTS) and two with unclassified epilepsy. Fourteen patients showed a global developmental delay/intellectual disability (GDD/ID). Slow background activities were observed in one patient and epileptiform discharges were observed in 11 patients during the interictal phase. Significance: This study enriches the genotypes and phenotypes of SCN1A-related epilepsy. The clinical characteristics of patients with 12 previously unreported variants were described.

Modulating Gamma Oscillations Promotes Brain Connectivity to Improve Cognitive Impairment.

Dementia causes a substantial global economic burden, but effective treatment is lacking. Recently, studies have revealed that gamma-band waves of electrical brain activity, particularly 40 Hz oscillations, are closely associated with high-order cognitive functions and can activate microglia to clear amyloid-ß deposition. Here, we found that compared with sham stimulation, applying 40-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) over the bilateral angular gyrus in patients with probable Alzheimer's disease (AD; n = 37) resulted in up to 8 weeks of significantly improved cognitive function. Power spectral density analysis of the resting-state electroencephalography (EEG) demonstrated that 40-Hz rTMS modulated gamma-band oscillations in the left posterior temporoparietal region. Further testing with magnetic resonance imaging and TMS-EEG revealed the following: 40-Hz rTMS 1) prevented gray matter volume loss, 2) enhanced local functional integration within bilateral angular gyrus, as well as global functional integration in bilateral angular gyrus and the left middle frontal gyrus, 3) strengthened information flow from the left posterior temporoparietal region to the frontal areas and strengthened the dynamic connectivity between anterior and posterior brain regions. These findings demonstrate that modulating gamma-band oscillations effectively improves cognitive function in patients with probable AD by promoting local, long-range, and dynamic connectivity within the brain.

Disparity in Context: Understanding how monocular image content interacts with disparity processing in human visual cortex.

Horizontal disparities between the two eyes' retinal images are the primary cue for depth. Commonly used random ot tereograms (RDS) intentionally camouflage the disparity cue, breaking the correlations between monocular image structure and the depth map that are present in natural images. Because of the nonlinear nature of visual processing, it is unlikely that simple computational rules derived from RDS will be sufficient to explain binocular vision in natural environments. In order to understand the interplay between natural scene structure and disparity encoding, we used a depth-image-based-rendering technique and a library of natural 3D stereo pairs to synthesize two novel stereogram types in which monocular scene content was manipulated independent of scene depth information. The half-images of the novel stereograms comprised either random-dots or scrambled natural scenes, each with the same depth maps as the corresponding natural scene stereograms. Using these stereograms in a simultaneous Event-Related Potential and behavioral discrimination task, we identified multiple disparity-contingent encoding stages between 100 ~ 500 msec. The first disparity sensitive evoked potential was observed at ~100 msec after an earlier evoked potential (between ~50-100 msec) that was sensitive to the structure of the monocular half-images but blind to disparity. Starting at ~150 msec, disparity responses were stereogram-specific and predictive of perceptual depth. Complex features associated with natural scene content are thus at least partially coded prior to disparity information, but these features and possibly others associated with natural scene content interact with disparity information only after an intermediate, 2D scene-independent disparity processing stage.

The Correlation of ELP4-PAX6 With Rolandic Spike Sources in Idiopathic Rolandic Epilepsy Syndromes.

Objective: To study the single nucleotide polymorphism rs662702 of ELP4-PAX6 in patients with idiopathic rolandic epilepsy syndromes (IRES) in China and explore the relationship between the distribution of rolandic spike sources and the single nucleotide polymorphism rs662702 in ELP4-PAX6. Methods: First, clinical information was obtained from patients diagnosed with IRES. Next, the single nucleotide polymorphism rs662702 of ELP4 was analyzed by using the Sanger method. Resting-state magnetoencephalography data were collected from 17 patients. We analyzed the epileptic spike sources using the single equivalent current dipole (SECD) model and determined the spike distributions across the whole brain. Finally, Fisher's test was performed to assess the correlation between the single nucleotide polymorphism rs662702 of ELP4-PAX6 and rolandic spike sources. Results: ELP4 rs662702 T alleles were found in 10.7% of IRES patients and occurred four times more frequently in these patients than in the healthy controls. TT homozygosity was found in one IRES patient (1.3%), while no TT homozygosity was found in the healthy control group. The IRES rolandic spike sources were unilateral in sixteen patients (94.1%) and were mainly located in the anterior central gyrus (58.8%). The spike source of patients without the ELP4 rs662702 T allele was correlated with the central region (p < 0.05). The rolandic spikes sources were significant correlated with the non-central gyrus (frontal and temporal lobes) in patients with the ELP4 rs662702 T allele (p < 0.05). Conclusion: The rolandic spike sources of the IRES patients with the ELP4 rs662702 T allele were significantly associated with the non-central gyrus, including the frontal and temporal lobes. Our study confirmed for the first time in vivo that ELP4 rs662702 T allele overexpression is correlated with the rolandic spike distribution in patients with IRES and provides important insights into how genetic abnormalities can lead to brain dysfunction and into the precise targeting of abnormal discharge sources in the brain.

Comprehensive genetic, clinical and electrophysiological studies of familial cortical myoclonic tremor with epilepsy 1 highlight the role of gene configurations.

OBJECTIVES: Two configurations of TTTTA/TTTCA expansion in SAMD12 have been identified in familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1). This study investigated the clinical and neurophysiological features of FCMTE1 and their association with TTTTA/TTTCA expansion patterns. METHODS: In total, 76 patients from 20 Chinese pedigrees were enrolled. Genetic (TTTTA/TTTCA configuration), clinical (e.g., onset, medication, prognosis, and anticipation) and neurophysiological examination (e.g., electroencephalogram and magnetoencephalography) data were evaluated, and associations between these parameters were analyzed. RESULTS: All patients carried the TTTTA/TTTCA expansion mutation, 19 displayed the (TTTTA)exp(TTTCA)exp (type I) configuration and 1 displayed the (TTTTA)exp (TTTCA)exp(TTTTA)exp (type II) configuration. All patients manifested as progressive tremor, but symptoms of patients carrying type II expansion were more severe. The onset of tremor but not generalized tonic and clonic seizures displayed clinical anticipation between generations of 7 pedigrees, but the pedigree carrying the type II mutation did not show anticipation. Nanopore sequencing showed that the repeats expanded during maternal/offspring transmission (pedigree #7) but shrank during paternal/offspring transmission (pedigree #9). Magnetoencephalographic dipoles were localized in the right frontal lobe near the central sulcus in 4 patients carrying the type I mutation and on the left side in one patient carrying the type II mutation. SIGNIFICANCE: We confirmed the causative roles played by TTTTA/TTTCA repeat expansion in the SAMD12 gene in FCTME1. Both the length and the configuration of the repeats contribute to the clinical and neurophysiological characteristics of the disease.

Identifying Morphological Patterns of Hippocampal Atrophy in Patients With Mesial Temporal Lobe Epilepsy and Alzheimer Disease.

Purpose: Mesial temporal lobe epilepsy (MTLE) and Alzheimer's disease (AD) are two distinct neurological disorders associated with hippocampal atrophy. Our goal is to analyze the morphologic patterns of hippocampal atrophy to better understand the underlying pathological and clinical characteristics of the two conditions. Methods: Twenty-five patients with AD and 20 healthy controls with matched age and gender were recruited into the AD group. Twenty-three MTLE patients and 28 healthy controls with matched age and gender were recruited into the MTLE group. All subjects were scanned on 3T-MRI scanner. Automated volumetric analysis was applied to measure and compare the hippocampal volume of the two respective groups. Vertex-based morphologic analysis was applied to characterize the morphologic patterns of hippocampal atrophy within and between groups, and a correlation analysis was performed. Results: Volumetric analysis revealed significantly decreased hippocampal volume in both AD and MTLE patients compared to the controls. In the patients with AD, the mean total hippocampal volume was 32.70% smaller than that of healthy controls, without a significant difference between the left and the right hippocampus (p < 0.05). In patients with MTLE, a significant reduction in unilateral hippocampal volume was observed, with a mean volume reduction of 28.38% as compared with healthy controls (p < 0.05). Vertex-based morphologic analysis revealed a generalized shrinkage of the hippocampi in AD patients, especially in bilateral medial and lateral regions. In MTLE group, atrophy was seen in the ipsilateral head, ipsilateral lateral body and slightly contralateral tail of the hippocampus (FWE-corrected, p < 0.05). Conclusions: MTLE and AD have distinctive morphologic patterns of hippocampal atrophy, which provide new insight into the radiology-pathology correlation in these diseases.

Transcranial direct current stimulation reduces seizure frequency in patients with refractory focal epilepsy: A randomized, double-blind, sham-controlled, and three-arm parallel multicenter study.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been explored in epilepsy with limited samples, varied parameters, and inconclusive results. We aimed to study the efficacy of tDCS for patients with refractory focal epilepsy. METHOD: We conducted a randomized, double-blind, sham-controlled, and three-arm (Group 1 (sham), Group 2 (20-min), and Group 3 (2 × 20-min)) tDCS parallel multicenter study. The primary outcome measurement was seizure frequencies (SFs). The study consisted of 28-days baseline, 14-days treatment, and 56-days follow-up. The cathode was placed over the epileptogenic focus, and the current intensity was 2 mA. The generalized estimating equations model, one-way analysis of variance, chi-square and Kruskal-Wallis test were used for analysis. RESULTS: Of the 82 enrolled patients, 70 patients were included for final analysis (Group 1, n = 21; Group 2, n = 24; and Group 3, n = 25). There was a significant reduction in SFs for both active tDCS groups compared with the sham group. Patients in Group 2 showed a significantly 50.73-21.91% greater reduction in SFs that lasted for 4 weeks (p = 0.008-0.060). Patients in Group 3 showed a significantly 63.19-49.79% greater reduction in SFs compared with the sham group that lasted for 5 weeks (p = 0.011-0.045). Patients in Group 3 had a 64.98-66.32% greater reduction in SFs at W9-W10, when compared with Group 2 (p = 0.021-0.022). CONCLUSION: Fourteen consecutive days tDCS significantly decreased SFs in patients with refractory focal epilepsy, with 2 × 20-min daily stimulation protocol being superior to 20-min daily stimulation protocol.

Magnetoencephalogram-assisted diagnosis of familial focal epilepsy with variable foci in a Chinese family with a novel DEPDC5 mutation.

Familial focal epilepsy with variable foci (FFEVF) is an autosomal dominant disorder characterized by focal seizures arising from different brain lobes in different family members. Currently, the diagnosis of this syndrome mainly depends on the combination of semiology and EEG after exclusion of other types of familial focal epilepsy. Mutations in dishevelled, Egl-10, and pleckstrin domain-containing protein 5 (DEPDC5) have been recently identified as a common cause of this syndrome. We studied a Chinese four-generation FFEVF family with nine affected individuals. Targeted next-generation sequencing was performed for the proband and the suspected mutation was confirmed by Sanger sequencing. Magnetoencephalography (MEG) was applied to two MRI-negative patients with refractory epilepsy. We identified a novel splice site mutation in DEPDC5 (c.280-1 G>A) in this family. The MEG results showed different dipole-clustered areas in these two patients. This is the first report of the use of MEG to confirm a diagnosis of FFEVF, in a Chinese family with a novel DEPDC5 mutation. Furthermore, the MEG results also revealed the possibility of surgical resection for these two intractable patients.

Tractography optimization using quantitative T1 mapping in the human optic radiation.

Diffusion MRI tractography is essential for reconstructing white-matter projections in the living human brain. Yet tractography results miss some projections and falsely identify others. A challenging example is the optic radiation (OR) that connects the thalamus and the primary visual cortex. Here, we tested whether OR tractography can be optimized using quantitative T1 mapping. Based on histology, we proposed that myelin-sensitive T1 values along the OR should remain consistently low compared with adjacent white matter. We found that complementary information from the T1 map allows for increasing the specificity of the reconstructed OR tract by eliminating falsely identified projections. This T1-filtering outperforms other, diffusion-based tractography filters. These results provide evidence that the smooth microstructural signature along the tract can be used as constructive input for tractography. Finally, we demonstrate that this approach can be applied in a case of multiple sclerosis, and generalized to the HCP-available MRI measurements. We conclude that multimodal MRI microstructural information can be used to eliminate spurious tractography results in the case of the OR.

Determinants of neural responses to disparity in natural scenes.

We studied disparity-evoked responses in natural scenes using high-density electroencephalography (EEG) in an event-related design. Thirty natural scenes that mainly included outdoor settings with trees and buildings were used. Twenty-four subjects viewed a series of trials composed of sequential two-alternative temporal forced-choice presentation of two different versions (two-dimensional [2D] vs. three-dimensional [3D]) of the same scene interleaved by a scrambled image with the same power spectrum. Scenes were viewed orthostereoscopically at 3 m through a pair of shutter glasses. After each trial, participants indicated with a key press which version of the scene was 3D. Performance on the discrimination was >90%. Participants who were more accurate also tended to respond faster; scenes that were reported more accurately as 3D also led to faster reaction times. We compared visual evoked potentials elicited by scrambled, 2D, and 3D scenes using reliable component analysis to reduce dimensionality. The disparity-evoked response to natural scene stimuli, measured from the difference potential between 2D and 3D scenes, comprised a sustained relative negativity in the dominant response component. The magnitude of the disparity-specific response was correlated with the observer's stereoacuity. Scenes with more homogeneous depth maps also tended to elicit large disparity-specific responses. Finally, the magnitude of the disparity-specific response was correlated with the magnitude of the differential response between scrambled and 2D scenes, suggesting that monocular higher-order scene statistics modulate disparity-specific responses.

The Structural Properties of Major White Matter Tracts in Strabismic Amblyopia.

PURPOSE: In order to better understand whether white matter structural deficits are present in strabismic amblyopia, we performed a survey of the tissue properties of 28 major white matter tracts using diffusion and quantitative magnetic resonance imaging approaches. METHODS: We used diffusion-based tensor modeling and a new quantitative T1 protocol to measure fractional anisotropy (FA), mean diffusivity (MD), and myelin-sensitive T1 values. We surveyed tracts in the occipital lobe, including the vertical occipital fasciculus (VOF)-a newly rediscovered tract that bridges dorsal and ventral areas of the occipital lobe, as well as tracts across the rest of the brain. RESULTS: Adults with long-standing strabismic amblyopia show tract-specific elevations in MD. We rank-ordered the tracts on the basis of their MD effect-size. The four most affected tracts were the anterior frontal corpus callosum (ACC), the right VOF, the left inferior longitudinal fasciculus (ILF) and the left optic radiation. CONCLUSIONS: The results suggest that most white matter tissue properties are relatively robust to the early visual insult caused by strabismus. However, strabismic amblyopia does affect MD, not only in occipital tracts, such as the VOF and optic radiation, but also in long range association tracts connecting visual cortex to the frontal and temporal lobes (ILF) and connecting the two hemispheres (ACC).

Hippocampal interplay with the nucleus accumbens is critical for decisions about time.

Human cognition depends upon the capacity to make decisions in the present that bear upon outcomes in the future. The nucleus accumbens, a recipient of direct projections from both the hippocampus and orbitofrontal cortex, is known to contribute to these aspects of decision-making. Here we demonstrate that interaction of the nucleus accumbens with the hippocampus, but not the orbitofrontal cortex, is critical in shaping decisions that involve time trade-offs. Compared with controls, rats with a disrupted hippocampal-accumbens interaction were strongly biased toward choosing stimuli that led to small and immediate food rewards over large and delayed ones. We show that this pattern of behavior cannot be ascribed to the impaired representation of stimulus value, the incapacity to wait, or a general disruption of decision-making. These results identify a hippocampal-accumbens circuit that may underlie a range of problems in which daily decisions are marked by a shift toward immediate gratification.

Holistic processing as a hallmark of perceptual expertise for nonface categories including Chinese characters.

Holistic processing has been associated with perceptual expertise in different domains involving faces, cars, fingerprints, musical notes, English words, etc. Curiously Chinese characters are regarded as an exception, as indicated by reduced holistic processing found for experts with the Chinese writing system as compared with novices. We revisit the issue and examine one type of holistic processing, the obligatory attention to all parts of an object, using the composite paradigm from face perception literature. Chinese readers (experts) and non-Chinese readers (novices) matched the target halves of two characters while ignoring the irrelevant halves. We introduced differential response deadlines for experts and novices in order to match their performance level and to avoid ceiling performance for experts. Both experts and novices showed holistic processing, irrespective of the character structure (left-right or top-bottom) or presentation sequence (sequential or simultaneous matching). Experts' holistic processing also showed some sensitivity to the amount of experience with the characters, as it was larger for characters than noncharacters in some situations. Novices, however, did not show a systematic difference, suggesting that their effects were more related to their inefficient decomposition of a novel, complex pattern into parts. The current results, together with other recent findings of holistic processing for English words and musical notes, indicate that the development of holistic processing is not restricted to faces and objects. Instead it may be a general marker of expertise across a wider domain of visual discrimination than previously thought, including alphabetic and nonalphabetic writing systems.