Stimulation Of Fastigial Nucleus Research Articles

Transcranial ultrasound with electrical stimulation of the cerebello-parietal nucleus on cerebral blood flow and limb function in patients with stroke.

To investigate the efficacy of transcranial ultrasound stimulation (TUS) combined with Fastigial nucleus stimulation (FNS) on cerebral blood flow and limb function in patients in the acute phase of ischemic stroke. A total of 90 patients in the acute phase of ischemic stroke were randomly divided into an FNS, TUS, and TUS + FNS group (30 patients each), and all patients also received conventional treatment. The FNS group was treated with FNS alone. The TUS group was treated with TUS alone. The TUS + FNS group was treated with both TUS and FNS. The three groups were treated once a day for 6 days a week. The simplified Fugl-Meyer Assessment (FMA) and Barthel index scores (BI), and the peak systolic blood flow velocity (Vs) and the mean blood flow velocity (Vm) of the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery, were significantly higher in all three groups compared with before treatment (P < 0.05). The scores for the TUS group were higher than for the FNS group (P < 0.05), and the scores of the TUS + FNS group were higher than the TUS and FNS groups, respectively (P < 0.05). The total effective rate was 63.3%, 70.0%, and 90.0% in the FNS, TUS, and TUS + FNS groups, respectively, and the difference between the three groups was statistically significant (P < 0.05). The FNS and TUS treatments improved the function of and accelerated cerebral blood flow in patients with acute ischemic stroke to different degrees, and the combined use of both treatment types was overall more effective.

Transcriptome analysis reveals the neuroprotective effect of Dlg4 against fastigial nucleus stimulation-induced ischemia/reperfusion injury in rats

BackgroundPrevious studies have demonstrated that electrical stimulation of the cerebellar fastigial nucleus (FNS) can considerably decrease infarction volume and improve neurofunction restoration following cerebral ischemia. Nevertheless, the molecular mechanism of the neuroprotective effect of FNS is still vague.MethodsIn this study, we developed a rat model of ischemia/reperfusion that included 1 h FNS followed by reperfusion for 3, 6, 12, 24, and 72 h. The expression profile of molecular alterations in brain tissues was obtained by transcriptome sequencing at five different time points. The function and pathway of miRNA expression pattern and core genes were annotated by Allen Brain Atlas, STRING database and Cytoscape software, so as to explore the mechanism of FNS-mediated neuroprotection.ResultsThe results indicated that FNS is associated with the neurotransmitter cycle pathway. FNS may regulate the release of monoamine neurotransmitters in synaptic vesicles by targeting the corresponding miRNAs through core Dlg4 gene, stimulate the Alternative polyadenylation (APA) incident’s anti -apoptosis effect on the brain, and stimulate the interaction activation of neurons in cerebellum, cortex/thalamus and other brain regions, regulate neurovascular coupling, and reduce cerebral damage.ConclusionFNS may activate neuronal and neurovascular coupling by regulating the release of neurotransmitters in synaptic vesicles through the methylation of core Dlg4 gene and the corresponding transcription factors and protein kinases, inducing the anti-apoptotic mechanism of APA events. The findings from our investigation offer a new perspective on the way brain tissue responds to FNS-driven neuroprotection.

The Cholinergic Pathway and MitoK ATP Induce UCP4 Expression Involved in Neuroprotection of FN Stimulation in Rats

Background Electrical stimulation of the cerebellar fastigial nucleus (FN) reduces the infarct size induced by middle cerebral artery occlusion in rats. FN stimulation confers long‐lasting protection from brain injury; however, its underlying mechanism is not yet understood. We aimed to elucidate the mechanism by which FN stimulation exerts neuroprotection. We hypothesized that the neuroprotective effect of FN stimulation involves activation of cholinergic pathways, which increases reactive oxygen species (ROS) production by opening mitochondrial K + ATP channels, thus leading to an increase in UCP4 (uncoupling protein 4) expression and subsequent neuroprotection. Methods FN stimulation was performed for 1 hour in rats. The UCP4 protein and mRNA levels were measured by western blot, dot blot, and in situ hybridization. Carbachol was applied following UCP4‐promoter tdTomato reporter vector transfection of the rat primary cortical cell culture (in vitro) and rat brain (in vivo). We observed cellular UCP4 expression using fluorescence microscopy. UCP4 expression in the cell culture in response to diazoxide application was determined by a reverse transcription‐polymerase chain reaction and western blotting. Results Whereas FN stimulation increased UCP4 protein and mRNA levels, carbachol administration induced UCP4 expression in vitro and in vivo. The attenuation of this effect by atropine suggests that FN‐induced UCP4 expression involves the cholinergic pathway. The opening of mitochondrial K + ATP channels with diazoxide increased the production of ROS and led to increased UCP4 expression. In contrast, quenching ROS with superoxide dismutase reversed the effect of diazoxide on UCP4 expression. Therefore, the opening of mitochondrial K + ATP channels increased ROS production, which subsequently enhanced UCP4 expression and attenuated ROS generation. Conclusion Neuroprotective effect of FN stimulation involves activation of the cholinergic pathways, which increases ROS production by opening mitochondrial K + ATP channels, leading to increased expression of neuroprotective UCP4.

Effect of Fastigial Nucleus Stimulation on Serum Inflammatory Factors in Patients with Coronary Heart Disease

Objective: To observe the effect of Fastigial Nucleus Stimulation (FNS) on serum inflammatory factors in patients with coronary heart disease. Methods: 144 patients with coronary heart disease were randomly divided into the experimental group (n = 72) and the control group (n = 72). The control group received conventional medication for coronary heart disease. The experimental group was given the cerebellar nucleus electrical stimulation on the basis of routine medication. High-sensitivity C-reactive protein (hs-CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor α (TNF-α), Lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured before and after treatment in both groups. Results: There were no significant differences in serum hs-CRP, TNF-α, IL-6 and Lp-PLA2 between the two groups before treatment (p &gt; 0.05). After treatment, serum hs-CRP, TNF-α, IL-6 and Lp-PLA2 were significantly lower in the two groups than before treatment (p &lt; 0.01). The levels of serum hs-CRP, TNF- α , IL-6 and Lp-PLA2 in the experimental group were significantly lower than those in the control group (p &lt; 0.05). Conclusion: FNS can effectively reduce the level of serum inflammatory factors in patients with coronary heart disease. (Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT04121715).

Increased cerebral cortex activation in stroke patients during electrical stimulation of cerebellar fastigial nucleus with functional near-infrared spectroscopy.

Electrical stimulation of the cerebellar fastigial nucleus (FNS) has been shown to protect animals against cerebral ischemic injury. However, the changes in cortical activation as a response to FNS have not been illustrated in humans. This study aims to detect functional connectivity changes in the brain of stroke patients, and investigate the cortical activation caused by FNS through measuring the oxygenated hemoglobin concentration (HBO) in the cerebral cortex of stroke patients and healthy controls (HCs). This study recruited 20 patients with stroke and 20 HCs with all the following factors matched: age, gender and BMI. The experiment session was made up of the pre-task baseline, FNS task period, and post-task baseline. FNS task period contains 5 blocks, each block encompassing the resting state (30 s) and the FNS state (30 s). HBO signals were acquired by functional near-infrared spectroscopy (fNIRS) from the Prefrontal Cortex (PFC), the Motor Cortex (MC) and the Occipital Cortex (OC) throughout the experiment. The Pearson correlation coefficient was used to calculate the resting-state functional connectivity strength between the two groups, and the general linear model (GLM) was used to calculate the activation of 39 fNIRS channels during FNS in stroke patients and HCs, respectively. The coupling strength of stroke patients were significantly decreased in the following regions: right MC and left MC (t = 4.65, p = 0.0007), right MC and left OC (t = 2.93, p = 0.04), left MC and left OC (t = 2.81, p = 0.04). In stroke patients, the changes in cerebral oxygenated hemoglobin (ΔHBO) among 12 channels (CH) in the bilateral PFC and bilateral MC regions were significantly increased during the FNS state (FDR corrected p < 0.05) compared with the resting state. In HCs, only 1 channel was increased (FDR corrected p < 0.05) in the left PFC during FNS. By using the FNS and fNIRS techniques, the characteristics of functional connectivity were found to decrease in stroke patients. It was also noticed that FNS activates the PFC and MC regions. These findings may help to guide functional rehabilitation in stroke patients.

Therapeutic effect of fastigial nucleus stimulation is mediated by the microRNA-182 & microRNA-382/BDNF signaling pathways in the treatment of post-stroke depression

The deregulation of Brain-Derived Neurotrophic Factor (BDNF) was reported to be responsible for the development of post-stroke depression (PSD), while the stimulation of the fastigial nucleus (FN) can be used to treat PDS by down-regulating the expression of miR-182 and miR-382. Therefore, we aim to test the hypothesis that the therapeutic effect of FN stimulation obtained in the treatment of PSD is mediated by the miR-382&miR-182/BDNF mRNA signaling pathways. Rat models of PSD were established and divided into sham, stroke, PSD and PSD + FNS groups to receive different treatments. Post-stroke depression-like behaviors were observed after the initiation of the treatments. TUNEL assay, Western Blot, IHC assay, real-time PCR, bioinformatics tools and luciferase assays were performed to examine the effect of FN stimulation on the expression of miR-182, miR-382 and BDNF mRNA/protein, as well as to further clarify the role of miR-382&miR-182/BDNF mRNA signaling pathways in FN stimulation. Post-stroke depression-like behaviors were significantly reduced in PSD rats. In contrary, the treatment by FN stimulation alleviated the symptoms of PSD and reduced the apoptosis index in the PSD group. Furthermore, in the PSD group, BDNF mRNA/protein levels were suppressed while the miR-382/miR-182 levels were both significantly up-regulated. After the treatment of FN stimulation, BDNF mRNA/protein levels were partly recovered, while miR-382/miR-182 levels was decreased. Furthermore, BDNF was identified as a virtual target of miR-382 and miR-182. In conclusion, FN stimulation increases the expression of BDNF via down-regulating the expression of miR-382/miR-182, thus exhibiting a positive effect in the management of PSD.

PRIMED2 Preclinical Evidence Scoring Tool to Assess Readiness for Translation of Neuroprotection Therapies

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous, multidimensional quality assessment of the totality of preclinical evidence supporting a therapy prior to conducting human trials. A consensus panel of stroke preclinical model and human clinical trial experts assessed candidate items for the translational readiness scale, compiled from prior instruments (STAIR, ARRIVE, CAMARADES, RoB 2) based on importance, reliability, and feasibility. Once constructed, the tool was applied by two independent raters to four current candidate acute stroke therapies, including two pharmacologic agents [nerinetide and trans-sodium crocetinate] and two device interventions [cathodal transcranial direct current stimulation and fastigial nucleus stimulation]. The Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices (PRIMED2) assessment tool rates the totality of evidence available from all reported preclinical animal stroke model studies in 11 domains related to diversity of tested animals, time windows, feasibility of agent route of delivery, and robustness of effect magnitude. Within each content domain, clearly operationalized rules assign strength of evidence ratings of 0–2. When applied to the four assessed candidate agents, inter-rater reliability was high (kappa = 0.88), and each agent showed a unique profile of evidentiary strengths and weaknesses. The PRIMED2 assessment tool provides a multidimensional assessment of the cumulative preclinical evidence for a candidate acute stroke therapy on factors judged important for successful basic-to-clinical translation. Further evaluation and refinement of this tool is desirable to improve successful translation of therapies for acute stroke.

Abstract WP389: Anatomical Trajectory for Focused Ultrasound Stimulation of Fastigial Nucleus for Neuroprotection in Human Cerebral Ischemia

Introduction: In multiple animal models of ischemic stroke, cerebellar fastigial nucleus stimulation (FNS) via implanted electrode has been shown to exert strong neuroprotective and collateral enhancement effects. Translational studies of FNS have been precluded due to the invasive nature of direct electrical stimulation. Recently, low-intensity focused ultrasound pulsation (LIFUP) has been used to stimulate deep hemispheric targets. Identifying achievable anatomic trajectories for LIFUP delivery is required for human trials. Method: Sagittal brain MRI T1 from 10 patients were analyzed. Potential pathways from the suboccipital (SO) region (transducer placement site) to the roof of the 4 th ventricle (location of FN) were traced, evaluating paths both via the thinnest portion of the occipital bone (OB) and via the transforaminal window (TFW). Interindividual variations in trajectory distances (cm), thickness of the OB through which the beam passes (cm), and the projected neck flexion degree from neutral position required to achieve a TFW path were measured. Results: An achievable anatomic pathway for stimulation of the FN via LIFUP was identified in 100% of patients (Fig 1). In standard MR positioning, 90% had an available path through thin portions of the OB and 10% had a projected path through TFW. The mean distance from the skin at the SO region to the roof of 4 th ventricle/FN was 7.2 cm (± 0.64cm). The mean OB thickness traversed by the beam was 0.3cm (±0.1). The projected required neck flexion to enable a TFW in all subjects was mean 9.3° (±5°). Conclusions: The distance for the LIFUP beam to travel from skin surface to FN via a suboccipital approach is well within the LIFUP penetration depth and all individuals had an accessible trajectory via the TFW through attainable degrees of head flexion, affording minimal ultrasonic energy dispersion and maximal focality. Ultrasound stimulation of fastigial nucleus is a feasible treatment strategy in human acute ischemic stroke.

Abstract WP310: PRIMED Preclinical Evidence Scoring Tool to Assess Readiness for Translation of Neuroprotection Therapies

Introduction: Multiple neuroprotective therapies (NPT’s) for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous quality assessment of all the cumulative preclinical evidence supporting an NPT prior to conducting human trials. There is a need for an updated translational readiness assessment tool to assess candidate therapies that combines desirable elements of existing instruments (STAIR 2.0, CAMARADES, RoB2) and include additional important elements. Methods: Candidate items for the intervention translational readiness scale, based on prior instruments, were rated by importance, reliability, and feasibility. For illustrative purposes, the assessment tool was applied to four NPT in current development, including two pharmacologic agents [uric acid (UA) and trans sodium crocetinate (TSC)] and two neuromodulatory device interventions [cathodal direct current stimulation (C-DCS) of ischemic hemisphere and fastigial nucleus stimulation (FSN)]. Results: The final Preclinical evidence of Readiness In stroke Models Evaluating Drugs/Devices (PRIMED) assessment tool rates evidence available from all reported animal studies in 10 domains (Fig1). Among the four assessed candidate NPT’s, the scores for two pharmacologic NPT’s indicated high translational readiness (UA and TSC 17) and the two neuromodulatory NPT’s had intermediate readiness-for-translation (C-DCS 12, FNS 8). Conclusion: The PRIMED assessment tool is an updated, multidimensional tool that provides a detailed assessment of multiple important readiness features across all preclinical experiments testing an NPT to assess readiness for translation, applicable to both pharmocologic and device therapies for acute stroke, providing both qualitative profiling of agent strengths and weaknesses and a quantitative summary score. Based on this tool, translational readiness is high for UA and TSC and intermediate for C-DCS and FNS.

Central Nervous System Electrical Stimulation for Neuroprotection in Acute Cerebral Ischemia: Meta-Analysis of Preclinical Studies.

Background and Purpose- Brain electrical stimulation, widely studied to facilitate recovery from stroke, has also been reported to confer direct neuroprotection in preclinical models of acute cerebral ischemia. Systematic review of controlled preclinical acute cerebral ischemia studies would aid in planning for initial human clinical trials. Methods- A systematic Medline search identified controlled, preclinical studies of central nervous system electrical stimulation in acute cerebral ischemia. Studies were categorized among 6 stimulation strategies. Three strategies applied different stimulation types to tissues within the ischemic zone (cathodal hemispheric stimulation [CHS], anodal hemispheric stimulation, and pulsed hemispheric stimulation), and 3 strategies applied deep brain stimulation to different neuronal targets remote from the ischemic zone (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation). Random-effects meta-analysis assessed electrical stimulation modification of final infarct volume. Study-level risk of bias and intervention-level readiness-for-translation were assessed using formal rating scales. Results- Systematic search identified 28 experiments in 21 studies, including a total of 350 animals, of electrical stimulation in preclinical acute cerebral ischemia. Overall, in animals undergoing electrical stimulation, final infarct volumes were reduced by 37% (95% CI, 34%-40%; P<0.001), compared with control. There was evidence of heterogeneity of efficacy among stimulation strategies (I2=93.1%, Pheterogeneity<0.001). Among the within-ischemic zone stimulation strategies, only CHS significantly reduced the infarct volume (27 %; 95% CI, 22%-33%; P<0.001); among the remote-from ischemic zone approaches, all (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation) reduced infarct volumes by approximately half. On formal rating scales, CHS studies had the lowest risk of bias, and CHS had the highest overall quality of intervention-level evidence supporting readiness to proceed to clinical testing. Conclusions- Electrical stimulation reduces final infarct volume across preclinical studies. CHS shows the most robust evidence and is potentially appropriate for progression to early-stage human clinical trial testing as a promising neuroprotective intervention.

Cerebellar Fastigial Nucleus Stimulation in a Chronic Unpredictable Mild Stress Rat Model Reduces Post-Stroke Depression by Suppressing Brain Inflammation via the microRNA-29c/TNFRSF1A Signaling Pathway.

BackgroundWe previously reported that cerebellar fastigial nucleus stimulation reduced post-stroke depression in a rat model by reducing inflammation. This study aimed to investigate the molecular inflammatory signaling pathways associated with cerebellar fastigial nucleus stimulation in an established rat model of post-stroke depression.Material/MethodsTwenty-four Sprague-Dawley rats included a sham group (N=6), an untreated stroke group (N=6), an untreated post-stroke depression model group (PSD) (N=6), and the model group treated with cerebellar fastigial nucleus stimulation (FNS) (N=6). The rat stroke model involved occlusion of the middle cerebral artery occlusion (MCAO). Post-stroke depression model was established using chronic unpredictable mild stress treatment and was verified using an open field test. Real-time polymerase chain reaction (PCR) and Western blot compared expression levels of microRNA-29c (miR-29c), miR-676, TNFRSF1A, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in cerebellar tissue. U251 human glioblastoma cells and SH-SY5Y human neuroblastoma cells were studied in vitro.ResultsCerebellar fastigial nucleus stimulation reduced behaviors associated with depression in the rat model, upregulated the expression of miR-29c, and reduced the expression of TNFRSF1A and inflammatory cytokines, and mildly reduced neuronal apoptosis. Bioinformatics data analysis identified a regulatory relationship between miR-29c and TNFRSF1A. SH-SY5Y cells treated with a miR-29c mimic, or TNFRSF1A short interfering RNA (siRNA), identified a negative regulatory relationship between TNFRSF1A and miR-29c.ConclusionsIn a rat model, cerebellar fastigial nucleus stimulation reduced the expression of TNFRSF1A by upregulating miR-29c expression, which suppressed the expression of inflammatory cytokines, resulting in reduced severity of post-stroke depression.

Fastigial nucleus stimulation ameliorates cognitive impairment via modulating autophagy and inflammasomes activation in a rat model of vascular dementia.

It has been reported that the fastigial nucleus (FSN) plays an important role in the development of vascular dementia (VD). Both autophagy and inflammation are functionally involved in the pathogenesis of VD. In this study, we aimed to evaluate the therapeutic effect of electrical cerebellar fastigial nucleus stimulation (FNS) in VD treatment, as well as the effect of FNS on autophagy and inflammation. A Morris water maze was used to evaluate the effect of FNS on the learning and memory ability of VD rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to study the apoptosis status of neuron cells in different groups of rats. In addition, immunohistochemistry (IHC) assay, real-time polymerase chain reaction, and Western blot analysis were carried out to measure the expression of various factors involved in autophagy and inflammation. Rats with artery occlusion or FSN damages showed longer escape latency and spent less time in the target quadrant. In addition, FNS treatment could help to partly recover the lost learning and memory ability in VD rats. Meanwhile, FNS treatment could alleviate neuron cell apoptosis by downregulating light chain 3-II expression and NLRP3 expression. In addition, the expression of caspase-1, interleukin 1β (IL-1β), and IL-18 was markedly reduced in VD rats treated by FNS. FNS treatment exerted a therapeutic effect during VD treatment by suppressing the autophagy process and by inhibiting inflammatory responses, thus alleviating neuron cell apoptosis and reducing the severity of VD.

Protective effect and mechanism of injection of glutamate into cerebellum fastigial nucleus on chronic visceral hypersensitivity in rats

AimsWe investigated the effects of chemical stimulation of cerebellum fastigial nucleus (FN) on the chronic visceral hypersensitivity (CVH) and its possible mechanism in rats. Main methodsWe stimulated the FN by microinjecting glutamate into the FN, in order to explore whether the cerebellum fastigial nucleus played a role on CVH in rat. The model of CVH was established by colorectal distension (CRD) in neonatal rats. Abdominal withdrawal reflex (AWR) scores, pain threshold, and amplitude of electromyography (EMG) were used to assess the hyperalgesia. Key findingsWe showed that microinjection of l-glutamate (Glu) into the FN markedly attenuated hyperalgesia. The protective effect of FN was prevented by pretreatment with the glutamate decarboxylase inhibitor, 3-mercaptopropionic acid (3-MPA) into the FN or GABAA receptor antagonist, bicuculline (Bic) into the LHA (lateral hypothalamic area). The expressions of protein Bax, caspase-3 were decreased, but the expression of protein Bcl-2 was increased after chemical stimulation of FN. These results indicated that the FN participated in regulation of CVH, and was a specific area in the CNS for exerting protective effects on the CVH. In addition, LHA and GABA receptor may be involved in this process. SignificanceOur findings might provide a new and improved understanding of the FN function, and might show an effective treatment strategy for the chronic visceral hypersensitivity.

Abstract TP72: Transcranial Direct Current Stimulation (tDCS) for Neuroprotection in Acute Cerebral Ischemia: Meta-analysis of Preclinical Studies and Implications for Human Clinical Trials

Introduction: Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique safe and promising in early human studies of nonacute disorders (depression, OCD, stroke recovery), and also reported to confer direct neuroprotection and vasodilation in animal models of acute cerebral ischemia. Systematic review of preclinical acute cerebral ischemia studies would aid planning for potential initial human clinical trials. Method: A systematic Medline search identified controlled, preclinical studies of tDCS in acute ischemic stroke. Studies were categorized according to stimulation type (hemispheric cathodal; hemispheric anodal; targeted cerebellar fastigial nucleus). Stratified meta-analysis assessed effect of tDCS on final infarct volume. Results: The systematic search identified 17 controlled comparisons of tDCS in preclinical acute cerebral ischemia models, including a total of 256 animals, all with middle cerebral artery occlusion. Hemispheric cathodal stimulation was used in 3 experiments (32 animals), hemispheric anodal stimulation in 1 experiment (8 animals) and fastigial nucleus stimulation in 13 experiments (91 animals). Overall, tDCS reduced final infarct volume by 27.5 cc (95% CI 25.33-29.74, P&lt;0.00001). Heterogeneity of effect by stimulation type was noted (I 2 =90.5%), with the greatest infarct reduction with cathodal - 34.9 cc (95% CI 30.60-39.18, P&lt; 0.00001), followed by targeted fastigial nucleus - 26.8 cc (95% CI 25.33-29.53, P&lt; 0.00001), and anodal - 17.8 cc (95% CI 11.42-24.18, P&lt; 0.00001). In the cathodal studies, stimulation was started 30-45 minutes after ischemia onset. Conclusions: Transcranial direct current stimulation reduces final infarct volume across animal preclinical studies. The greatest neuroprotective effect is observed with hemispheric cathodal stimulation, with treatment initiation in a time frame achievable in human prehospital clinical trials. Human clinical trials of hemispheric cathodal tDCS are warranted.

Oxiracetam or fastigial nucleus stimulation reduces cognitive injury at high altitude.

BackgroundCognitive impairment is common in people travelling to high altitude. Oxiracetam and electrical stimulation of cerebellar fastigial nucleus may have beneficial impacts. This study was to investigate the effects of preconditioning with Oxiracetam or fastigial nucleus stimulation (FNS) on cognitive decline following the ascension to high altitude.MethodsThe study was conducted on 60 male military voluntary members who were divided into control group, Oxiracetam group, and fastigial nucleus stimulation group. Transcranial doppler sonography, auditory evoked potential, electroencephalogram (EEG), and cognitive assessments were performed.ResultsPeople could still suffer cognitive dysfunction at 4,000 m high altitude despite that they have lived at 1,800 m altitude for several years. The 4,000 m altitude environment also prolonged P300 and N200 latencies. Both Oxiracetam and FNS improved cognitive function, reduced the prolonged latencies of Event Related Potentials (P300 and N200), decreased the average velocity of brain arteries, and enhanced EEG power spectral entropy at 4,000 m altitude.ConclusionsNeurophysiological evidences suggest the underlying mechanism of cognitive impairments. Both Oxiracetam and FNS can reduce cognitive decline post arrival at high altitude. They could be a potential pretreatment method for cognitive dysfunction resulted from high altitude.

Clinical study on treating post-stroke sleep disorders by fastigial nucleus stimulation

Objective To discuss the efficacy and safety of fastigial nucleus stimulation (FNS) in the treatment of post-stroke sleep disorders (PSSD). Methods A total of 69 cases with PSSD were randomly divided into 3 groups: control group (N = 23), sham group (N = 23) and treatment group (N = 23). Control group received routine treatment, sham group received routine treatment plus sham FNS treatment, and treatment group received routine treatment plus FNS treatment. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of patients in 3 groups before and after 4-week treatment. Adverse reactions during the FNS treatment were also observed. Results There was statistical significance in PSQI scores among 3 groups before and after 4-week treatment ( P = 0.020). PSQI score after 4-week treatment in treatment group was significantly lower than control group and sham group ( P = 0.000, 0.000). Compared to before treatment, PSQI scores were significantly decreased in 3 groups after 4-week treatment ( P = 0.000). Conclusions FNS safely and effectively improves the sleep quality of patients with PSSD, thus it can be used as one of the auxiliary treatments for curing PSSD. DOI: 10.3969/j.issn.1672-6731.2017.03.006

Electrical stimulation of cerebellar fastigial nucleus protects against cerebral ischemic injury by PPARγ upregulation

Objective: Cerebellar fastigial nucleus stimulation (FNS) has been shown to protect against cerebral ischemic injury. Peroxisome proliferator activator receptor gamma (PPARγ) has been reported to cause neuroprotection in animal models of stroke. The present study was performed to explore the neuroprotective mechanisms of FNS treatment in experimental stroke.Methodology: Adult male Sprague-Dawley (SD) rats preconditioned through transfection with either PPARγ-small hairpin RNA (shRNA) or lentiviral vector without shRNA and surgically subjected to middle cerebral artery occlusion and reperfusion subsequently received FNS treatment. The expression of PPARγ after FNS treatment was measured using western blotting and immunohistochemistry. Subsequently, the neuronal apoptosis, neurological deficits scores, and cerebral infarction were also evaluated. Additionally, the influence of FNS on the pro-inflammatory cytokines expression were determined by ELISA.Results: We found that FNS significantly upregulated PPARγ expression, attenuated apoptosis and inflammatory response, and reduced infarct volume. The protective effect of FNS was abrogated by PPARγ-shRNA.Conclusion: Our results as described above suggested that FNS confers neuroprotection by upregulated PPARγ.

Migraine prevention by noninvasive electrical fastigial nucleus stimulation: a multi-center, randomized, double-blind, sham-controlled trial

Background: Migraine is a global disease with a high morbidity rate, and while there is medication for migraine prevention, it has many side effects. Thus there is a need to find a non-drug therapy to prevent migraine in patients with frequent attacks of migraine, severe pain, and poor drug control. Cortical spreading depression (CSD) is an important pathological mechanism behind migraine. Electrical fastigial nucleus stimulation (FNS) can reportedly inhibit the occurrence and propagation of CSD, and therefore can be used to prevent migraine. Methods/Design: This is a prospective, multi-center, randomized, double-blind, sham-controlled trial. It will be performed at Chengdu Second People's Hospital, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Fourth People's Hospital, the First Affiliated Hospital of Chongqing Medical University, and Chongqing People's Hospital, China. The approach is to randomly allocate 80 eligible migraine patients to undergo 3 months of either noninvasive electrical FNS (pulse width 90 μs, frequency 1.8 kHz, and output current 10 mA) or ineffective sham-stimulation (using the same stimulation equipment; pulse width 90 μs, frequency 10 kHz, and output current 0.18 mA). The primary outcomes are: change in monthly migraine days between the run-in month and 3 rd month of treatment, and percentage of patients having at least a 50% reduction of monthly migraine days in the 3 rd month of treatment. The secondary outcomes are: change between average monthly migraine days across 3 months of treatment and monthly migraine days in the 3 rd month of treatment, Visual Analogue Scale score in the 3 rd month of treatment, change in monthly anti-migraine drug use between the run-in month and 3 rd month of treatment, migraine disability assessment questionnaire score, accompanying symptoms, and adverse reactions. Discussion: In previous studies on electrical FNS for the treatment of various brain injuries, sample sizes have been small with inclusion of only a small number of institutions and non-rigorous trial protocols. Accordingly, the data obtained were not very reliable. In this study, we will validate the efficacy of electrical FNS in migraine prevention using a multi-center, randomized, double-blinded, controlled trial. Our findings will provide evidence for clinical application of this method. Trial registration: The trial protocol was registered at Chinese Clinical Trial Registry ( www.chictr.org.cn ) (registration number: ChiCTR-ICR-15006273) on 5 April 2015. Ethics: This trial was approved by the Ethics Committee of Chengdu Second People's Hospital, China on 9 April 2015 (approval number: 2015010), and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association. Informed consent: Written informed consent will be obtained from participants or their guardians.

MicroRNA involvement in mechanism of endogenous protection induced by fastigial nucleus stimulation based on deep sequencing and bioinformatics.

BackgroundNeurogenic neuroprotection is a promising approach for treating patients with ischemic brain lesions. Fastigial nucleus stimulation (FNS) has been shown to reduce the tissue damage resulting from focal cerebral ischemia in the earlier studies. However, the mechanisms of neuroprotection induced by FNS remain unclear. MicroRNAs (miRNAs) are a newly discovered group of non-coding small RNA molecules that negatively regulate target gene expression and involved in the regulation of pathological process. To date, there is a lack of knowledge on the expression of miRNA in response to FNS. Thus, we study the regulation of miRNAs in the rat ischemic brain by the neuroprotection effect of FNS.MethodsIn this study, we used an established focal cerebral ischemia/reperfusion (IR) model in rats. MiRNA expression profile of rat ischemic cortex after 1 h of FNS were investigated using deep sequencing. Microarray was performed to study the expression pattern of miRNAs. Functional annotation on the miRNA was carried out by bioinformatics analysis.ResultsTwo thousand four hundred ninety three miRNAs were detected and found to be miRNAs or miRNA candidates using deep sequencing technology. We found that the FNS-related miRNAs were differentially expressed according microarray data. Bioinformatics analysis indicated that several differentially expressed miRNAs might be a central node of neuroprotection-associated genetic networks and contribute to neuroprotection induced by FNS.ConclusionsMiRNA acts as a novel regulator and contributes to FNS-induced neuroprotection. Our study provides a better understanding of neuroprotection induced by FNS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0155-4) contains supplementary material, which is available to authorized users.

Improvement of Regional Cerebral Blood Flow After Stimulation of the Nucl. Fastigius in Cerebral Infarction Patients

Experimental studies reported that focal stimulation of the nucl. fastigius (fastigial nucleus stimulation, FNS) increases regional cerebral blood flow (rCBF) and ameliorates disorders of cerebral blood circulation. The aim of our study was to examine the effect of FNS on rCBF in cerebral infarction patients and to estimate correlation of the respective effect with prognosis and treatment. The rCBF of 20 cerebral infarction patients was measured before and after FNS using single-photon emission computed tomography (SPECT), and the data were subjected to semiquantitative analysis. Results of the neural ability defect test were used to evaluate prognosis. In the above patients, different levels of decreased rCBF were observed. Focal FNS noticeably ameliorated disorders of scirculation in both the infarction area and the corresponding contralateral cerebral area (P < 0.05). The SPECT images showed that the improvement of rCBF was more evident in the central region of the lesion than in the surrounding area. Thus, it was demonstrated that FNS treatment enhances rCBF, which is followed by the improvement of clinical symptoms in cerebral infarction patients.