Multisession Anodal Transcranial Direct Current Stimulation Enhances Adult Hippocampal Neurogenesis and Context Discrimination in Mice.

Transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory treatment option for multiple neurologic and psychiatric disorders, but its mechanism of action is still poorly understood. Adult hippocampal neurogenesis (AHN) continues throughout life and is crucial for preserving several aspects of hippocampal-dependent cognitive functions. Nevertheless, the contribution of AHN in the neuromodulatory effects of tDCS remains unexplored. Here, we sought to investigate whether multisession anodal tDCS may modulate AHN and its associated cognitive functions. Multisession anodal tDCS were applied on the skull over the hippocampus of adult male mice for 20 min at 0.25 mA once daily for 10 d totally. We found that multisession anodal tDCS enhances AHN by increasing the proliferation, differentiation and survival of neural stem/progenitor cells (NSPCs). In addition, tDCS treatment increased cell cycle reentry and reduced cell cycle exit of NSPCs. The tDCS-treated mice exhibited a reduced GABAergic inhibitory tone in the dentate gyrus compared with sham-treated mice. The effect of tDCS on the proliferation of NSPCs was blocked by pharmacological restoration of GABAB receptor-mediated inhibition. Functionally, multisession anodal tDCS enhances performance on a contextual fear discrimination task, and this enhancement was prevented by blocking AHN using the DNA alkylating agent temozolomide (TMZ). Our results emphasize an important role for AHN in mediating the beneficial effects of tDCS on cognitive functions that substantially broadens the mechanistic understanding of tDCS beyond its well-described in hippocampal synaptic plasticity.SIGNIFICANCE STATEMENT Transcranial direct current stimulation (tDCS) has been shown to effectively enhance cognitive functions in healthy and pathologic conditions. However, the mechanisms underlying its effects are largely unknown and need to be better understood to enable its optimal clinical use. This study shows that multisession anodal tDCS enhances adult hippocampal neurogenesis (AHN) and therefore contributes to enhance context discrimination in mice. Our results also show that the effect of tDCS on AHN is associated with reduced GABAergic inhibition in the dentate gyrus. Our study uncovers a novel mechanism of anodal tDCS to elicit cognitive-enhancing effects and may have the potential to improve cognitive decline associated with normal aging and neurodegenerative disorders.

Loss of oxytocin receptors in hilar mossy cells impairs social discrimination.

Hippocampal oxytocin receptor (OXTR) signaling is crucial for discrimination of social stimuli to guide social recognition, but circuit mechanisms and cell types involved remain incompletely understood. Here, we report a role for OXTR-expressing hilar mossy cells (MCs) of the dentate gyrus in social stimulus discrimination by regulating granule cell (GC) activity. Using a Cre-loxP recombination approach, we found that ablation of Oxtr from MCs impairs discrimination of social, but not object, stimuli in adult male mice. Ablation of MC Oxtr increases spontaneous firing rate of GCs, synaptic excitation to inhibition ratio of MC-to-GC circuit, and GC firing when temporally associated with the lateral perforant path inputs. Using mouse hippocampal slices, we found that bath application of OXTR agonist [Thr4,Gly7]-oxytocin causes membrane depolarization and increases MC firing activity. Optogenetic activation of MC-to-GC circuit ameliorates social discrimination deficit in MC OXTR deficient mice. Together, our results uncover a previously unknown role of MC OXTR signaling for discrimination of social stimuli and delineate a MC-to-GC circuit responsible for social information processing.

The clinical outcome of balloon-assisted maturation procedure between autogenous radiocephalic fistula and brachiocephalic fistula in a single-center experience.

OBJECTIVE: Balloon-assisted maturation (BAM) by an endovascular method plays an important role in treating an immature arteriovenous fistula. However, the results between radiocephalic fistula and brachiocephalic fistula were rarely reported. This retrospective study aimed to investigate the effectiveness and outcome of BAM in different sites of autogenous arteriovenous fistulas. METHODS: This single-center retrospective study included patients who underwent BAM procedures from January 2015 to December 2016. Of 148 patients, 117 and 31 patients had a radiocephalic fistula (RC) and a brachiocephalic fistula (BC), respectively. The primary outcome was BAM success. Data regarding fistula lesions, balloon types and size, frequency of procedures, and maturation time were collected for BAMs. The secondary outcome was the patency of a fistula in the follow-up period. RESULTS: No difference was observed in procedure of BAM frequency between the RC and BC groups. The total success rate was 77.7%, without significant difference between the RC and BC groups (81.20% vs 64.50%; P = .055). Within the procedures, the culprit lesion of juxta-anastomosis segment (73.5% vs 25.5%; P < .001) and arterial inlet (21.2% vs 7.8%; P = .04) were more common in the RC group, whereas the venous outlet was more common in the BC group (88.2% vs 57.7%; P < .001). Both groups had an equivalent patency rate after the BAM within the follow-up period (P = .272). CONCLUSIONS: BAM was an effective procedure for immature fistulas, without significant difference between RCs and BCs. Through the procedure, the culprit lesions causing non-maturation were found to be different between the two groups. The patency rate between the two groups after surgery seems to be equivalent within the follow-up period.

Reversible M-M Bonding by Alkaline Earth Metals (Mg, Ca, Sr, Ba) in Graphite Intercalation Compounds.

The alkaline earth metals (M=Mg, Ca, Sr, and Ba) exhibit a +2 oxidation state in nearly all known stable compounds, but MI dimeric complexes with M-M bonding, [M2 (en)2 ]2+ , (en=ethylenediamine) of all these metals can be stabilized within the galleries of donor-type graphite intercalation compounds (GICs). These metals can also form GICs with more conventional metal (II) ion complexes, [M(en)2 ]2+ . Here, the facile interconversion between dimeric-MI and monomeric-MII intercalates upon the addition/removal of en are reported. Thermogravimetry, powder X-ray diffraction, and pair distribution function analysis of total scattering data support the presence of either [M2 (en)2 ]2+ or [M(en)2 ]2+ guests. This phase conversion requires coupling graphene and metal redox centers, with associated reversible M-M bond formation within graphene galleries. This chemistry allows the facile isolation of unusual oxidation states, reveals M0 →M2+ reaction pathways, and present new opportunities in the design of hybrid conversion/intercalation materials for applications such as charge storage.

Cortical Excitability by Transcranial Magnetic Stimulation as Biomarkers for Seizure Controllability in Temporal Lobe Epilepsy.

OBJECTIVE: To investigate whether indicators of cortical excitability are good biomarkers of seizure controllability in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Three groups of subjects were recruited: those with poorly controlled (PC) TLE (N = 41), well-controlled (WC) TLE (N = 71), and healthy controls (N = 44). Short- and long-latency recovery curves were obtained by paired-pulse transcranial magnetic stimulation. Linear mixed effect models were used to study the effects of group, interstimulus interval (ISI), and antiepileptic drugs on long-interval intracortical inhibition (LICI) and short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). RESULTS: The mixed effect model that did not incorporate antiepileptic drugs showed that group and ISI were significant factors for LICI and SICI/ICF. LICI in the healthy control group was greater than in the two epilepsy groups, and the difference was significant at ISIs of 50, 150, and 200 msec. In contrast, SICI/ICF in the PC group was greater than in the healthy control and WC groups, and the difference was significant at an ISI of 15 msec. However, due to large variance, it was difficult to identify a cutoff value with both good sensitivity and good specificity. Incorporating the information of antiepileptic drugs to the mixed effect model did not change the overall results. CONCLUSIONS: Although LICI and SICI/ICF parameters were significantly different at the group level, they may not be suitable biomarkers for the controllability of TLE at the subject level.

Modulating the interference effect on spatial working memory by applying transcranial direct current stimulation over the right dorsolateral prefrontal cortex.

Spatial working memory (SWM) is the ability to temporarily store and manipulate spatial information. It has a limited capacity and is quite vulnerable to interference. Dorsolateral prefrontal cortex (DLPFC) has been shown to be a part of the SWM network but its specific functional role still remains unknown. Here we applied transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique that provides polarity-specific stimulation over the targeted region, to investigate the specific role of the right DLPFC in resolving interference in SWM. A forward- and backward-recall computerized Corsi Block Tapping task (CBT), both with and without a concurrent motor interference task (the modified Luria manual sequencing task) was used to measure SWM capacity and reaction time. The results showed that motor interference impeded accuracy and prolonged reaction time in forward and backward recall for SWM. Anodal tDCS over right DLPFC yielded the tendency to shorten participants' reaction time in the conditions with interference (forward with interference, and backward with interference). Most importantly, anodal tDCS significantly improved participants' SWM span when cognitive demand was the highest (the "backward-recall with motor interference" condition). These results suggest that (1) the right DLPFC plays a crucial role in dealing with the cross-domain motor interference for spatial working memory and (2) the anodal tDCS over right DLPFC improved SWM capacity particularly when task difficulty demands more complex mental manipulations that could be due to the facilitatory effect of anodal tDCS which enhanced the DLPFC function within central executive system at the top-down attentional level.

Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice.

Inflammatory bowel disease (IBD) is a relapsing-remitting disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. Anxiety symptoms are commonly observed in patients with IBD, but the mechanistic link between IBD and anxiety remains elusive. Here, we sought to characterize gut-to-brain signaling and brain circuitry responsible for the pathological expression of anxiety-like behaviors in male dextran sulfate sodium-induced (DSS-induced) experimental colitis mice. We found that DSS-treated mice displayed increased anxiety-like behaviors, which were prevented by bilateral GI vagal afferent ablation. The locus coeruleus (LC) is a relay center connecting the nucleus tractus solitarius to the basolateral amygdala (BLA) in controlling anxiety-like behaviors. Chemogenetic silencing of noradrenergic LC projections to the BLA reduced anxiety-like behaviors in DSS-treated mice. This work expands our understanding of the neural mechanisms by which IBD leads to comorbid anxiety and emphasizes a critical role of gastric vagal afferent signaling in gut-to-brain regulation of emotional states.

Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications.

Vagus nerve stimulation (VNS) is a technology that provides electrical stimulation to the cervical vagus nerve and can be applied in the treatment of a wide variety of neuropsychiatric and systemic diseases. VNS exerts its effect by stimulating vagal afferent and efferent fibers, which project upward to the brainstem nuclei and the relayed circuits and downward to the internal organs to influence the autonomic, neuroendocrine, and neuroimmunology systems. The neuroimmunomodulation effect of VNS is mediated through the cholinergic anti-inflammatory pathway that regulates immune cells and decreases pro-inflammatory cytokines. Traditional and non-invasive VNS have Food and Drug Administration (FDA)-approved indications for patients with drug-refractory epilepsy, treatment-refractory major depressive disorders, and headaches. The number of clinical trials and translational studies that explore the therapeutic potentials and mechanisms of VNS is increasing. In this review, we first introduced the anatomical and physiological bases of the vagus nerve and the immunomodulating functions of VNS. We covered studies that investigated the mechanisms of VNS and its therapeutic implications for a spectrum of brain disorders and systemic diseases in the context of neuroimmunomodulation.

Factors associated with mortality in patients with super-refractory status epilepticus.

Super-refractory status epilepticus (SRSE) is a critical condition in which seizures persist despite anesthetic use for 24 h or longer. High mortality has been reported in patients with SRSE, but the cause of death remains unclear. We investigated the factors associated with mortality, including clinical characteristics, SE etiologies and severities, treatments, and responses in patients with SRSE in a 13-year tertiary hospital-based retrospective cohort study comparing these parameters between deceased and surviving patients. SRSE accounted for 14.2% of patients with status epilepticus, and 28.6% of SRSE patients died. Deceased patients were mostly young or middle-aged without known systemic diseases or epilepsy. All deceased patients experienced generalized convulsive status epilepticus and failure of anesthetic tapering-off, significantly higher than survivors. An increased number of second-line anesthetics besides midazolam was observed in the deceased (median, 3, interquartile range 2-3) compared to surviving (1, 1-1; p = 0.0006) patients with prolonged use durations (p = 0.047). For mortality, the cut-off number of second-line anesthetics was 1.5 (AUC = 0.906, p = 0.004). Deceased patients had significantly higher renal and cardiac complications and metabolic acidosis than survivors. In SRSE management, multi-anesthetic use should be carefully controlled to avoid systemic complications and mortality.

Somatosensory rub evoked reflex epilepsy of a temporal lobe origin.

Somatosensory rub reflex epilepsy, evoked by prolonged or repetitive cutaneous contact of a circumscribed body area, is an unusual form of reflex epilepsy. The peculiar complaints and the negative interictal electroencephalographic (EEG) recordings make it difficult to identify the epileptic origin. Here we report an unusual case whose seizures would be evoked by a touch or rub on a unilateral arm and shoulder, with a contralateral temporal lobe origin, demonstrated in immediate postictal single-photon emission computed tomography (SPECT).

Direct observation of Au/Ga2O3 peapodded nanowires and their plasmonic behaviors.

Gold-peapodded Ga(2)O(3) nanowires were fabricated successfully in a well-controlled manner by thermal annealing of core-shell gold-Ga(2)O(3) nanowires. During the heating process, the core gold nanowires were broken up into chains of nanoparticles at sufficiently high temperature by the mechanism of Rayleigh instability. In addition, the size, shape, and interspacing between the particles can be manipulated by varying the annealing time and/or the forming gas. The plasmonic behaviors of these nanostructures are investigated by optical spectroscopy. A single nanowire optical device was designed, and its photonic characteristics were investigated. A remarkably high on/off photocurrent ratio in response to a 532 nm Nd:YAG laser light was found. As the size of the particle (pea) increases, the corresponding spectra are red-shifted. In addition, morphological changes of the peas lead to a distinct spectral response. The results may usher in the diverse applications in optoelectronics and biosensing devices with peapod nanostructures.

Near UV LEDs made with in situ doped p-n homojunction ZnO nanowire arrays.

Catalyst-free p-n homojunction ZnO nanowire (NW) arrays in which the phosphorus (P) and zinc (Zn) served as p- and n-type dopants, respectively, have been synthesized for the first time by a controlled in situ doping process for fabricating efficient ultraviolet light-emitting devices. The doping transition region defined as the width for P atoms gradually occupying Zn sites along the growth direction can be narrowed down to sub-50 nm. The cathodoluminescence emission peak at 340 nm emitted from n-type ZnO:Zn NW arrays is likely due to the Burstein-Moss effect in the high electron carrier concentration regime. Further, the electroluminescence spectra from the p-n ZnO NW arrays distinctively exhibit the short-wavelength emission at 342 nm and the blue shift from 342 to 325 nm is observed as the operating voltage further increasing. The ZnO NW p-n homojunctions comprising p-type segment with high electron concentration are promising building blocks for short-wavelength lighting device and photoelectronics.

Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures.

BACKGROUND: Transcranial direct current stimulation (tDCS) provides a noninvasive polarity-specific constant current to treat epilepsy, through a mechanism possibly involving excitability modulation and neural oscillation. OBJECTIVE: To determine whether EEG oscillations underlie the interictal spike changes after tDCS in rats with chronic spontaneous seizures. METHODS: Rats with kainic acid-induced spontaneous seizures were subjected to cathodal tDCS or sham stimulation for 5 consecutive days. Video-EEG recordings were collected immediately pre- and post-stimulation and for the subsequent 2 weeks following stimulation. The acute pre-post stimulation and subacute follow-up changes of interictal spikes and EEG oscillations in tDCS-treated rats were compared with sham. Ictal EEG with seizure behaviors, hippocampal brain-derived neurotrophic factor (BDNF) protein expression, and mossy fiber sprouting were compared between tDCS and sham rats. RESULTS: Interictal spike counts were reduced immediately following tDCS with augmented delta and diminished beta and gamma oscillations compared with sham. Cathodal tDCS also enhanced delta oscillations in normal rats. However, increased numbers of interictal spikes with a decrease of delta and theta oscillations were observed in tDCS-treated rats compared with sham during the following 2 weeks after stimulation. Resuming tDCS suppressed the increase of interictal spike activity. In tDCS rats, hippocampal BDNF protein expression was decreased while mossy fiber sprouting did not change compared with sham. CONCLUSIONS: The inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicates that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability.

Nonketotic hyperglycemia-related reflex epileptic seizures induced by Mah-Jong playing.

Seizures related to nonketotic hyperglycemia (NKH) are often encountered in clinical practice. Among such seizures, reflex seizures are rare, and most of them are movement-induced focal seizures. We describe five patients with NKH and reflex seizures induced exclusively by playing Mah-Jong, a traditional and popular game in Chinese society. Four patients had partial seizures and one had a generalized seizure. All the patients manifested NKH on occurrence of the seizure. During Mah-Jong in the presence of NKH, seizures could arise from the frontal and temporal lobes, which are highly activated during the game. Both avoidance of Mah-Jong playing and control of glucose intake help prevent this disorder.

Fabrication of metal nanostructures by atomic force microscopy nanomachining and related applications.

In this work, the fabrication of metal nanostructures by a combination of atomic force microscopy nanomachining on a thin polymer resist, metal coating and lift-off is presented. Nanodots with sizes down to 20 nm and nanowires with widths ranging between 40 and 100 nm have been successfully created by nanoindenting and nanoscratching. The results exemplify the feasibility and effectiveness of the present technique as an alternative to e-beam lithography. The localized surface plasmon resonance properties of the fabricated nanostructures are characterized. The chemical sensing capability of a single nanowire based on resistance increase is also demonstrated.

Reversible postvaccination paraneoplastic encephalomyelitis in a patient with lung adenocarcinoma.

Encephalomyelitis occurs in paraneoplastic syndrome and acute disseminated encephalomyelitis through different autoimmune mechanisms. No postvaccinal encephalomyelitis other than acute disseminated encephalomyelitis has been reported in patients with malignancy. A 68-year-old woman was admitted because of a headache followed by a gait disturbance and psychomotor retardation 2 days after she had received an influenza vaccination followed by abulia, limb rigidity and hyperreflexia of both legs, and meningeal irritation. Cerebrospinal fluid studies showed increased intracranial pressure, elevated immunoglobulins G and A, and pleocytosis. Contrasted brain magnetic resonance imaging revealed ventriculomegaly and multiple symmetric leptomeningeal enhancement, without demyelinating changes or cortical ribbon signs. Somatosensory evoked potentials and nerve conduction velocity studies suggested myelitis. Encephalomyelitis was diagnosed on the basis of clinical and laboratory examinations. The etiological survey identified a lung adenocarcinoma. Both the encephalomyelitis and the lung adenocarcinoma simultaneously progressed after the vaccination and then, after targeted therapy for lung cancer, simultaneously subsided. In conclusion, postinfluenza-vaccination paraneoplastic encephalomyelitis may occur in patients with lung adenocarcinoma.

Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats.

Status epilepticus (SE) is a state of prolonged and repeated seizures that can lead to permanent brain damage or life-threatening conditions. Transcranial direct current stimulation (tDCS) non-invasively provides a polarity-specific electric current to modulate brain excitability. Little is known about the therapeutic potential of tDCS in SE. Here, we aim to determine the tDCS effects on seizure severity, EEG and post-SE consequences in rats with kainic acid (KA)-induced SE. Rats were subjected to cathodal tDCS or sham stimulation over the dorsal hippocampus for 5 days. KA was intraperitoneally injected to induce SE. We used continuous video-EEG recording to monitor seizure activity, immunostaining and Timm staining to evaluate neuron counts and mossy fiber sprouting, and ELISA for Brain-derived neurotrophic factor (BDNF) protein measurement. Two featured EEG patterns, gamma ranged high-frequency polyspikes and low-frequency spike-and-wave complexes, were identified in the hippocampal CA1 of KA-induced SE rats. tDCS elicited a significant decrease in severe seizures of Racine stages 4-5 in KA-induced SE rats. tDCS-treated rats manifested diminished high-frequency oscillation during SE, decreased chronic spontaneous spike activities and mossy fiber sproutings compared to sham. tDCS-treated rats also exhibited significantly lower hippocampal BDNF protein levels than sham immediately and 4 weeks after SE. A positive correlation between the hippocampal BDNF level and the seizure severity of SE was found. Altogether, our results show that repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences in KA-induced SE rats, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures.

Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate neuronal excitability via externally applied electric fields. Despite the positive effects of tDCS in a wide range of neurological disorders in humans, its mechanism of action remains poorly understood. Here we investigated cellular and molecular mechanisms underlying the aftereffects of anodal tDCS on the induction of long-term potentiation (LTP), a cellular correlate of learning and memory, at Schaffer collateral-CA1 synapses. We found that hippocampal CA1 LTP was enhanced in slices from rats subjected to anodal tDCS with no significant changes in basal synaptic function. The enhancing effect of tDCS on LTP was still maintained 12 h after stimulation. Treatment of ex vivo hippocampal slices from tDCS-treated rats with tropomyosin receptor kinase B (TrkB) inhibitor ANA-12, but not D1 receptor antagonist SKF-83566 or ß2-adrenergic receptor antagonist propranolol, efficiently prevented tDCS-induced enhancement of LTP. The tDCS-treated rats exhibited higher levels of brain derived neurotrophic factor (BDNF) in the hippocampal CA1 region compared to sham-treated rats. Anodal tDCS also enhances memory performance in hippocampal-dependent passive avoidance learning task, and this enhancement can be blocked by ANA-12 pretreatment. Altogether, our results underscore the importance of BDNF/TrkB-mediated metaplastic effect of anodal tDCS on the induction of hippocampal CA1 LTP.

Sensitive and automated detection of iron-oxide-labeled cells using phase image cross-correlation analysis.

Superparamagnetic iron oxide (SPIO) nanoparticles are increasingly being used to noninvasively track cells, target specific molecules and monitor gene expression in vivo. Contrast changes that are subtle relative to intrinsic sources of contrast present a significant detection challenge. Here, we describe a postprocessing algorithm, called Phase map cross-correlation Detection and Quantification (PDQ), with the purpose of automating identification and quantification of localized accumulations of SPIO agents. The method is designed to sacrifice little flexibility - it works on previously acquired data and allows the use of conventional high-SNR pulse sequences with no extra scan time. We first investigated the theoretical detection limits of PDQ using a simulated dipole field. This method was then applied to three-dimensional (3D) MRI data sets of agarose gel containing isolated dipoles and ex vivo transplanted allogenic rat hearts infiltrated by numerous iron-oxide-labeled macrophages as a result of organ rejection. A simulated dipole field showed this method to be robust in very low signal-to-noise ratio images. Analysis of agarose gel and allogenic rat heart shows that this method can automatically identify and count dipoles while visualizing their biodistribution in 3D renderings. In the heart, this information was used to calculate a quantitative index that may indicate its degree of cellular infiltration.