Low-frequency Stimulation Research Articles

Low frequency-repetitive transcranial magnetic stimulation combined with Xingnao Kaiqiao acupuncture improves post-stroke cognitive impairment and has better clinical efficacy.

Enhancing post-stroke cognitive impairment (PSCI) is a key aspect of prognosis for stroke patients. Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) is currently a widely utilised method for treating PSCI. With the increasing promotion of traditional Chinese medicine, Xingnao Kaiqiao (XNKQ) acupuncture has been progressively incorporated into clinical treatment. This paper observes the effect of LF-rTMS with XNKQ acupuncture on patients with PSCI. Totally, 192 patients with PSCI were consecutively recruited and treated either with LF-rTMS and XNKQ acupuncture (observation group) or LF-rTMS only (control group) for 4 weeks. The pre- and post-treatment Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, P300 latency and amplitude, inflammatory factor levels were compared and clinical efficacy was assessed. Both groups exhibited increased MMSE/MoCA scores, and P300 amplitude, and shortened P300 latency, and the observation group had higher scores and P300 amplitude, and shorter P300 latency than the control group. Both groups displayed decreased inflammatory factor levels (Tumour necrosis factor-α, interleukin (IL)-6, IL-10, IL-1β) after treatment, which were lower in the observation group than the control group. Inflammatory factor levels in PSCI patients were negatively interrelated with MMSE, MoCA score and P300 amplitude, and positively with P300 latency. The observation group showed an increased number of patients showing cured and significantly effective results, a decreased number of patients showing effective and invalid results, and an observably elevated total effective rate. LF-rTMS with XNKQ acupuncture can improve cognitive function and reduce inflammatory immune response, and has better clinical efficacy in PSCI patients.

Bilateral pulvinar responsive neurostimulation for bilateral multifocal posteriorly dominant drug resistant epilepsy.

To describe four cases of Responsive Neurostimulation (RNS) in the bilateral pulvinar nuclei (PUL) in individuals with drug resistant epilepsy (DRE). This will show that due to widespread PUL connectivity, bilateral PUL RNS may be an option for some individuals with bilateral multifocal epilepsy. This study comprises two centers' experience with bilateral PUL RNS for DRE. Patients treated with bilateral PUL RNS at Westchester Medical Center (Valhalla, NY) and Corewell Health (Grand Rapids, MI) between the years 2019 and 2022 were analyzed and described. Presented here are methods for target selection, device programming, and clinical outcomes. Two patients with Lennox-Gastaut phenotype (aged 13 and 21 years) with posteriorly dominant discharges were implanted with bilateral PUL electrodes. Additionally, two patients (aged 20 and 31 years) with independent left and right occipital bilateral multifocal seizure onsets were implanted with bilateral RNS devices targeting the ipsilateral PUL and ipsilateral occipital cortex. Subclinical and clinical seizures were captured by RNS electrocorticography (ECoG) in all patients. RNS implantation and treatment was well-tolerated without adverse effects in all patients. Relative to baseline, two patients had 25% and 50% reduction in disabling seizures, and two patients had 71% and 100% reduction in disabling seizures. Stimulation paradigms utilized high frequency stimulation in both Lennox-Gastaut phenotype patients. Low frequency (individualized to the terminal ictal frequencies) stimulation was effective in the two bioccipital patients. RNS with electrode placement targeting bilateral PUL is safe, and no adverse effects have been attributable to the pulvinar electrode placement. PUL responsive neurostimulation is potentially effective for patients with bilateral multifocal, posteriorly dominant DRE. Both high and low frequency responsive stimulation are treatment options. Longer follow-up will shed light on the ultimate reduction of seizure burden. We describe four cases where stimulation devices were placed in the Pulvinar area of the thalamus (central sensory area in the brain). This is very unique and different location than where these devices are typically placed. These patients all had great outcomes with marked seizure reduction, demonstrating that this placement is both safe and effective.

Low-frequency stimulation of corpus callosum suppresses epileptiform activity in the cortex through γ-aminobutyric acid type B receptor and slow afterhyperpolarization-mediated reduction in tissue excitability.

Deep brain stimulation, particularly low-frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug-resistant epilepsy (DRE) and for generalized epilepsy, both of which pose significant treatment challenges. LFS diffusely suppresses seizures in the cortex when applied to fiber tracts like the corpus callosum (CC). Nevertheless, the specific processes responsible for suppressing epileptic activity in the cortex induced by LFS remain unclear. This study investigates the mechanisms underlying the antiepileptic effect in the cortex of LFS of the CC in coronal rodent brain slices. An invitro 4-aminopyridine (4-AP) seizure model of cortical seizures was generated. LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in artificial cerebrospinal fluid, 4-AP, and in the presence of various specific and nonspecific γ-aminobutyric acid type B (GABAB) and slow afterhyperpolarization (sAHP) antagonists. LFS significantly suppressed seizure activity in the cortex, with an optimal frequency of 5 Hz (76.5%). Tissue excitability during LFS reduces across a wide range of interstimulus intervals, with a maximum reduction at 200 ms. Notably, the tissue excitability remains depressed at 1000 ms. LFS, in the presence of GABAB antagonists, had diminished seizure reduction (<15%) and failed to reduce tissue excitability in the 50-400-ms range. Tissue excitability measured with paired pulses in the 600-1000-ms range was depressed in the presence of GABAB antagonists, suggesting a different antiepileptic mechanism was active. Upon administering sAHP antagonists, seizure reduction was once again diminished (<15%). Upon administration of both sAHP and GABAB antagonists, LFS failed to provide any meaningful seizure reduction (<5%). LFS of the CC provides an antiepileptic effect in the cortex with well-understood mechanisms and could be an alternative to surgical intervention for patients suffering from DRE.

Developmental spike timing-dependent long-term depression requires astrocyte D-serine at L2/3-L2/3 synapses of the mouse somatosensory cortex.

Spike timing-dependent plasticity (STDP) is a learning rule important for synaptic refinement and for learning and memory during development. While different forms of presynaptic t-LTD have been deeply investigated, little is known about the mechanisms of somatosensory cortex postsynaptic t-LTD. In the present work, we investigated the requirements and mechanisms for induction of developmental spike timing-dependent long-term depression (t-LTD) at L2/3-L2/3 synapses in the juvenile mouse somatosensory cortex. We found that P13-21 mice of either sex show t-LTD at L2/3-L2/3 synapses induced by pairing single presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz) is expressed postsynaptically, and requires the activation of ionotropic postsynaptic NMDA-type glutamate receptors containing GluN2B subunits. In addition, it requires postsynaptic Ca2+, Ca2+ release from internal stores, calcineurin, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signalling to release the gliotransmitter d-serine to activate postsynaptic NMDARs to induce t-LTD. These results show direct evidence of the mechanism involved in developmental postsynaptic t-LTD at L2/3-L2/3 synapses, revealing a central role of astrocytes and their release of D-serine in its induction.Significance statement We show here the mechanisms and role of astrocytes and gliotransmitters in a postsynaptic spike timing dependent long-term depression (t-LTD) form defined at layer (L)2/3-L2/3 synapses of the somatosensory cortex. We have discovered that this form of plasticity involves N-methyl D-aspartate receptors (NMDAR) containing the GluN2B subunit and requires astrocytes and the gliotransmitter D-serine to co-activate (together with glutamate) postsynaptic NMDAR to mediate LTD. This can be a general mechanism in the brain to define different forms of plasticity. Defining the mechanisms of synaptic plasticity may have important implications for brain repair, sensorial recovery, the treatment of neurodevelopmental disorders and even, for educational policy.

One-step synthesis of a piezoelectric hybrid BNNT/BaTiO3 composite and its application in bone tissue engineering

Nanomaterials with piezoelectric properties can significantly improve the applicability of polymers used in tissue engineering applications. In this study, we report the one-step synthesis of a novel hybrid piezoelectric composite comprising barium titanates and boron nitride nanotubes. This composite is distinguished by its unique microstructures, including nanoflakes, triangular boron nitride structures, and fiber-like boron nitride nanotube configurations, which contribute to its enhanced piezoelectric properties. The composite was incorporated into a chitosan-based tissue scaffold and evaluated in vitro. Electric-responsive Human Osteoblast cells cultured on the scaffolds are exposed to low-frequency ultrasound stimulation during cell growth. The biocompatibility, cell adhesion, alkaline phosphatase activities, and mineralization of osteoblast cells on the piezo-composite scaffolds were evaluated. The results show that the hybrid piezoelectric composite significantly enhances the properties of chitosan-based scaffold.

Closed-loop Low-frequency stimulation: seizure reduction and more

Closed-loop Low-frequency stimulation: seizure reduction and more

Amelioration of Focal Hand Dystonia via Low-Frequency Repetitive Somatosensory Stimulation.

Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high-frequency repetitive somatosensory stimulation (RSS; HF-RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low-frequency RSS (LF-RSS) increases them. However, direct testing on affected body parts was not conducted. This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms. We applied HF-RSS and LF-RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired-pulse somatosensory evoked potentials, spatial lateral inhibition measured by double-pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function. Both synchronous and asynchronous low-frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired-pulse somatosensory evoked potentials. Opposite effects were observed with high-frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low-frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high-frequency stimulation operated in an opposite direction. Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low-frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) in anejaculation: A randomized controlled trial.

Anejaculation represents significant psychological distress and sexual and reproductive challenges among male individuals and couples. Effective fertility management options are available to address the reproductive challenges associated with anejaculation. However, there is a lack of methods to reverse the condition itself. This study aims to assess the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in patients suffering from anejaculation. A total of 94 patients with anejaculation individuals were randomly assigned to receive high-frequency (HF) stimulation on the left dorsolateral prefrontal cortex (DLPFC), low-frequency (LF) stimulation on the right DLPFC, and sham stimulation for 4 weeks, with daily sessions of stimulation occurring on five consecutive weekdays each week. After 4 weeks of rTMS treatment, the patients in both the HF and LF groups exhibited a similar reduction in their male sexual health questionnaire for ejaculatory dysfunction bother/satisfaction score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, and Pittsburgh Sleep Quality Inventory score, which were statistically significant compared with sham treatment. Additionally, there were no significant differences observed in erectile function and cognitive function across the three groups. However, there were notable disparities in the cure rates between HF- and LF-group patients (16.1% vs. 54.8%, p=0.001). Additionally, it is worth noting that only two HF group patients and one LF group patient experienced spontaneously resolving minor adverse effects during the treatment process. At the 8-week follow-up, among patients who initially responded to the treatment, only one from the HF group experienced a relapse. The findings of this study demonstrate that rTMS represents a secure and efficacious remedy for anejaculation patients.

Efficacy of subthalamic deep brain stimulation programming strategies for gait disorders in Parkinson's disease: a systematic review and meta-analysis.

Patients with advanced Parkinson's disease often suffer from severe gait and balance problems, impacting quality of live and persisting despite optimization of standard therapies. The aim of this review was to systematically review the efficacy of STN-DBS programming techniques in alleviating gait disturbances in patients with advanced PD. Searches were conducted in PubMed, Embase, and Lilacs databases, covering studies published until May 2024. The review identified 36 articles that explored five distinct STN-DBS techniques aimed at addressing gait and postural instability in Parkinson's patients: low-frequency stimulation, ventral STN stimulation for simultaneous substantia nigra activation, interleaving, asymmetric stimulation and a short pulse width study. Among these, 21 articles were included in the meta-analysis, which revealed significant heterogeneity among studies. Notably, low-frequency STN-DBS demonstrated positive outcomes in total UPDRS-III score and FOG-Q, especially when combined with dopaminergic therapy. The most favorable results were found for low-frequency STN stimulation. The descriptive analysis suggests that unconventional stimulation approaches may be viable for gait problems in patients who do not respond to standard therapies.

Patient-derived tau and amyloid-β facilitate long-term depression in vivo: role of tumour necrosis factor-α and the integrated stress response.

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.

Retrospective Evaluation of the Efficacy of Electrophysiological Appropriate Techniques for Nocturia Following Radical Prostatectomy.

This study retrospectively examines the effectiveness of low-frequency electrical stimulation for addressing nocturia in patients experiencing urinary incontinence after undergoing radical prostatectomy. We reviewed the outcomes of 32 patients who had undergone radical prostatectomy and subsequently experienced urinary incontinence. These patients were divided into the control group (n = 16) who received pelvic floor muscle training and the treatment group (n = 16) who underwent electrophysiological appropriate technique treatment in conjunction with pelvic floor muscle training. We assessed changes in nocturnal voided volume, polyuria index, and nocturia-related quality of life at three different time points: before treatment, after 2 weeks, and at the 3-month follow-up. After 3-month follow-up, both groups exhibit reductions in nocturnal voided volume, and polyuria index compared with baseline and the 2-week mark (p < .05). Treatment group outperformed the control group (p < .05). The quality of life in the treatment group remained consistently high, while the control group did not show a statistically significant difference from baseline (p > .05). The total effective rate was significantly higher in the treatment group (93.75%) than in the control group (75.00%, p = .044). This retrospective analysis suggests that electrophysiological appropriate technique treatment effectively mitigates nocturnal, leading to improved quality of life in patients with urinary incontinence following radical prostatectomy in the near term.

Effects of low-frequency pulsed electrical stimulation at the common peroneal nerve on chronic refractory wounds of the lower limb: A randomized controlled trial.

Electrical stimulation (ES) has been shown to substantially enhance the quality of life by alleviating pain in patients with chronic wounds. This study aimed to observe the effects of low-frequency pulsed wearable ES at the common peroneal nerve on chronic refractory wounds of the lower limb. Forty-eight participants were randomly divided into control group (n = 24) and treatment group (n = 24) in this study. The control group received standard wound care (SWC) exclusively, whereas the treatment group was administered both SWC and the wearable low-frequency ES targeting the common peroneal nerve. Measurements of wound area, pain intensity, wound status, and quality of life scores were systematically recorded both before and after 4 weeks treatment. After 4 weeks of intervention, the percentage area reductionwas significantly higher in the treatment group compared to the control group (Z = -3.9, p < 0.001), and the healing rate of the treatment group was significantly higher than that of the control group (33% vs. 4%). Moreover, the visual Analog Scale for Pain score (β = -0.65, p = 0.019), the Bates-Jensen Wound Assessment Tool score (p < 0.05), and the questionnaire on quality of life with chronic wounds (Wound-Qol) score (β = -4.23, p = 0.003) were significantly decreased in the patients in the treatment group compared to the control group. The wearable low-frequency pulsed ES at the common peroneal nerve for the treatment of chronic refractory wounds showed significant improvement and were far superior compared to SWC. Future research should broaden its scope to include a diverse range of wound types and benefit from collaboration across multiple research centers.

Determining Which Hydrostatic Pressure Regimes Promote Osteogenesis in Human Mesenchymal Stem Cells.

Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1h/day over 28days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. Stimulation of the 3D cultures with 0-280kPa cyclic hydrostatic pressure at 1Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280kPa, 0Hz), low-frequency (0.05Hz, 280kPa) or low-magnitude (70kPa, 1Hz) stimulation had no osteogenic effects (< 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure 'switch', which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.

Effectiveness of repetitive transcranial magnetic stimulation combined with intelligent Gait-Adaptability Training in improving lower limb function and brain symmetry after subacute stroke: a preliminary study

ObjectivesPersistent lower limb dysfunction is a major challenge in post-stroke recovery. Repetitive transcranial magnetic stimulation is recognized for addressing post-stroke motor deficits. Our study explores the efficacy of combining rTMS with gait-adaptive training to enhance lower limb function and regulatory mechanisms in subacute stroke. Materials and methodsThis randomized controlled trial enrolled 27 patients with subacute hemiparesis, dividing them into experimental and control groups. Both groups underwent gait-adaptability training 5 times/week for 4 weeks, with the experimental group receiving daily low-frequency transcranial magnetic stimulation before training. Primary outcomes included the pairwise derived brain symmetry index, lower-extremity Fugl-Meyer Assessment, 10-meter walk test, and Berg Balance Scale. Assessments occurred before and after the four-week intervention. ResultsThe experimental and control groups showed significant improvements in the Fugl-Meyer Assessment, 10-meter walk test, and Berg Balance Scale after the 4-week intervention compared to baseline (all p<0.05). However, the experimental group demonstrated significantly greater improvements compared to the control group in the Fugl-Meyer Assessment (p=0.024) and the 10-meter walk test (p=0.033). Additionally, the experimental group exhibited a more pronounced decrease in the pairwise derived brain symmetry index (p=0.026) compared to the control group. Within the experimental group, the cortical subgroup's pairwise derived brain symmetry index was significantly lower than that of the control group (p=0.006). ConclusionsCombining low-frequency transcranial magnetic stimulation with Gait-Adaptive Training effectively enhances lower limb function and Regulatory mechanisms of the cerebral hemisphere in subacute stroke recovery, and it can provide rapid and effective rehabilitation effect compared with gait adaptation training alone.

Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.

We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure. While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases. Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.

Low-frequency Transcranial Magnetic Stimulation Ameliorates Anhedonic Behaviors and Regulates the Gut Microbiome in Mice Exposed to Chronic Unpredictable Mild Stress.

This paper presents a preliminary study on whether low-frequency transcranial magnetic stimulation (LF-TMS) can modulate the gut microbiota in mice with chronic unpredictable mild stress (CUMS). Mice received LF-TMS (1 Hz, 20 mT) for 28 consecutive days under chronic unpredictable mild stress (CUMS). The composition of gut microbiota of stool samples were tested. CUMS caused significant changes in gut microbiotas, specifically in community diversity of gut microbiotas (P < .05). Compared with the stressed group mice, the Chao1 index (P < .05), Observed species index (P < .05), Faith's PD index (P < .05) and Shannon index (P < .05) of the LF-TMS treatment group were significantly increased. Furthermore, 1 Hz LF-TMS-treatment partially recovered chronic stress induced changes of microbiotas, such as the abundance of Chloroflexi, Actinobacteria. These results manifested that LF-TMS treatment can improve the anhedonic behaviors caused by CUMS in mice, which are connected with regulating the related intestinal microbial community disturbance, including species diversity, structure of gut microbiota, and species composition.

Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders.

Bilateral centromedian nucleus of thalamus responsive neurostimulation for pediatric-onset drug-resistant epilepsy.

Neuromodulation therapies offer an efficacious treatment alternative for patients with drug-resistant epilepsy (DRE), particularly those unlikely to benefit from surgical resection. Here we present our retrospective single-center case series of patients with pediatric-onset DRE who underwent responsive neurostimulation (RNS) depth electrode implantation targeting the bilateral centromedian nucleus (CM) of the thalamus between October 2020 and October 2022. Sixteen patients were identified; seizure outcomes, programming parameters, and complications at follow-up were reviewed. The median age at implantation was 13 years (range 3.6-22). Six patients (38%) were younger than 12 years of age at the time of implantation. Ictal electroencephalography (EEG) patterns during patients' most disabling seizures were reliably detected. Ten patients (62%) achieved 50% or greater reduction in seizure frequency at a median 1.3 years (range 0.6-2.6) of follow-up. Eight patients (50%) experienced sensorimotor side effects, and three patients (19%) had superficial pocket infection, prompting the removal of the RNS device. Side effects of stimulation were experienced mostly in monopolar-cathodal configuration and alleviated with programming change to bipolar configuration or low-frequency stimulation. Closed-loop neurostimulation using RNS targeting bilateral CM is a feasible and useful therapy for patients with pediatric-onset DRE.

Neural correlates of approach–avoidance behavior in healthy subjects: Effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex

The dorsolateral prefrontal cortex (dlPFC) is implicated in top-down regulation of emotion, but the detailed network mechanisms require further elucidation. To investigate network-level functions of the dlPFC in emotion regulation, this study measured changes in task-based activation, resting-state and task-based functional connectivity (FC) patterns following suppression of dlPFC excitability by 1-Hz repetitive transcranial magnetic stimulation (rTMS). In a sham-controlled within-subject design, 1-Hz active or sham rTMS was applied to the right dlPFC of 19 healthy volunteers during two separate counterbalanced sessions. Following active and sham rTMS, functional magnetic resonance imaging (fMRI) was conducted in the resting state (rs-fMRI) and during approach–avoidance task responses to pictures with positive and negative emotional content (task-based fMRI). Activation and generalized psychophysiological interaction analyses were performed on task-based fMRI, and seed-based FC analysis was applied to rs-fMRI data. Task-based fMRI revealed greater and more lateralized activation in the right hemisphere during negative picture responses compared to positive picture responses. After active rTMS, greater activation was observed in the left middle prefrontal cortex compared to sham rTMS. Further, rTMS reduced response times and error rates in approach to positive pictures compared to negative pictures. Significant FC changes due to rTMS were observed predominantly in the frontoparietal network (FPN) and visual network (VN) during the task, and in the default mode network (DMN) and VN at rest. Suppression of right dlPFC activity by 1-Hz rTMS alters large-scale neural networks and modulates emotion, supporting potential applications for the treatment of mood disorders.

Unveiling the impact of low-frequency electrical stimulation on network synchronization and learning behavior in cultured hippocampal neural networks

Understanding the dynamics of neural networks and their response to external stimuli is crucial for unraveling the mechanisms associated with learning processes. In this study, we hypothesized that electrical stimulation (ES) would lead to significant alterations in the activity patterns of hippocampal neuronal networks and investigated the effects of low-frequency ES on hippocampal neuronal populations using the microelectrode arrays (MEAs). Our findings revealed significant alterations in the activity of hippocampal neuronal networks following low-frequency ES trainings. Post-stimulation, the neural activity exhibited an organized burst firing pattern characterized by increased spike and burst firings, increased synchronization, and enhanced learning behaviors. Analysis of peri-stimulus time histograms (PSTHs) further revealed that low-frequency ES (1Hz) significantly enhanced neural plasticity, thereby facilitating the learning process of cultured neurons, whereas high-frequency ES (>10Hz) impeded this process. Moreover, we observed a substantial increase in correlations and connectivity within neuronal networks following ES trainings. These alterations in network properties indicated enhanced synaptic plasticity and emphasized the positive impact of low-frequency ES on hippocampal neural activities, contributing to the brain's capacity for learning and memory.