Neurostimulatory Effects Research Articles

Novel Insights into the Role of Probiotics in Respiratory Infections, Allergies, Cancer, and Neurological Abnormalities.

In recent years, probiotics have attracted public attention and transformed the social perception of microorganisms, convening a beneficial role/state on human health. With aging, the immune system, body physiology, and intestinal microbiota tend to change unfavorably, resulting in many chronic conditions. The immune-mediated disorders can be linked to intestinal dysbiosis, consequently leading to immune dysfunctions and a cluster of conditions such as asthma, autoimmune diseases, eczema, and various allergies. Probiotic bacteria such as Lactobacillus and Bifidobacterium species are considered probiotic species that have a great immunomodulatory and anti-allergic effect. Moreover, recent scientific and clinical data illustrate that probiotics can regulate the immune system, exert anti-viral and anti-tumoral activity, and shields the host against oxidative stress. Additionally, microbiota programming by probiotic bacteria can reduce and prevent the symptoms of respiratory infections and ameliorate the neurological status in humans. This review describes the most recent clinical findings, including safe probiotic therapies aiming to medicate respiratory infections, allergies, cancer, and neurological disorders due to their physiological interconnection. Subsequently, we will describe the major biological mechanism by which probiotic bacteriotherapy expresses its anti-viral, anti-allergic, anticancer, and neuro-stimulatory effects.

Inhaling muscle spray: A rising trend of abuse.

Ethyl chloride was popular as an inhalant recreational drug in the 1980s. It is easily available in pharmacies as well as sold online as a topical anesthetic spray for pain relief. In recent times, its use is gaining popularity again among the youth as an inhalant drug due to its neuro-stimulatory effects. To avoid the risks associated with use of illegal drugs, and ease of availability of ethyl chloride without restrictions, there is a rising trend to use it as a “substitute” drug of abuse. In this paper, we try to highlight to the critical care and emergency physicians that majority of these cases present with predominant neurological symptoms, with occasional involvement of the cardiovascular system. The diagnosis of ethyl chloride poisoning is primarily clinical and supportive care is the mainstay of treatment, along with subsequent counseling. Ethyl chloride abuse should be considered as a differential diagnosis in young patients presenting with predominant neurological symptoms. Alongside raising public awareness, the manufacturers and retail distributors of these products have an important role to play in reducing the risk of abuse.

Photobiomodulation effects on active brain networks during a spatial memory task

Photobiomodulation (PBM) or the use of red to near-infrared irradiation spectrum, is a non-invasive intervention that produces neurostimulatory effects and reaches benefits in several pathologies as well as in healthy subjects. The main objective of this study was to evaluate and compare the effects of PBM in a rat brain network on basal state and functional activity during the execution of a reversal task. Twenty-eight rats were divided into four groups: control group (n = 7), control photobiomodulation group (n = 8), behavioural group (n = 6) and behavioural photobiomodulation group (n = 7). Reversal memory was assessed using a Morris water maze and cytochrome c oxidase (CCO) was used as a brain metabolic activity marker. After five days of PBM, the control photobiomodulation group showed a decrease of CCO levels in the striatum, medial septum, entorhinal, hippocampus, amygdala, thalamus, mammillary nuclei and VTA. Both behavioural groups performed the task correctly, however, the behavioural photobiomodulation group displayed CCO reduction in some regions involved in the execution of the reversal task: septum, entorhinal, CA1, CA3, central amygdala and supramammilar, along with higher levels in accumbens. These results could show the effect of PBM on active brain networks. Further studies will be necessary to elucidate its effects in different brain networks that are involved in the execution of other memory tasks.

English

Kola seeds are highly valued in most African communities due to their medicinal benefits and socio-cultural application during ceremonies. Apart from their neuro-stimulatory effect, the other health benefits such as antioxidant activities which are closely associated with the level of phenolic constituents have also been widely reported. The main purpose of this study is to determine the quantity of quercetin, caffeic acid, gallic acid, ferulic acid, rutin and chlorogenic acid in Cola nitida, Garcinia kola and Buchholzia coriacea using HPLC-DAD. Ethanolic extracts of the selected kola plants was obtained by cold maceration and analysed by HPLC-DAD in accordance with standard methods. The regression coefficient (r2) from the calibration curve for caffeic acid = 0.999, chlorogenic acid = 0.998, gallic acid = 0.999, ferulic acid = 0.998, quercetin = 0.996 and rutin = 0.997. The repeatability gave % RSD of 0.6, 1.63, 0.44, 1.55, 3.65 and 4.67 for caffeic acid, chlorogenic acid, gallic acid, ferulic acid, quercetin and rutin respectively. The quantity of these compounds in C. nitida was caffeic acid (101.24 mg/g), chlorogenic acid (36.35 mg/g), gallic acid (16.99 mg/g) ferulic acid (1.47 mg/g) while quercetin and rutin were not detected. In Garcinia kola, caffeic acid was (0.84 mg/g), gallic acid (1.02 mg/g), ferulic acid (21.83 mg/g), quercetin (53.24 mg/g), rutin (0.49 mg/g) and chlorogenic acid was not detected. B. coriaceae had caffeic acid (1.03 mg/g), chlorogenic acid (0.33 mg/g), gallic acid (1.07 mg/g) while ferulic acid, quercetin and rutin were not detected. Using this analytical method, the quantities of some phenolics and flavonoids compounds were determined, and the most abundant compound in the three species of kola was caffeic acid in C. nitida and quercetin in Garcinia kola. This study also showed that C. nitida contains high amounts of phenolics compounds as compare to the other species of kola seeds investigated in the study. Key word: Phenolic acids, flavonoids, high-performance liquid chromatography- diode-array detector (HPLC-DAD), Cola nitida, Garcinia cola, Buchholzia coriacea.

PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons.

Glucagon-like peptide (GLP-1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper-activation of the hypothalamic-pituitary-adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP-1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP-1 receptor agonist, exendin-4 (Ex-4). Colonic contractile activity was assessed using organ bath physiological recordings. Ex-4 induced an elevation of intracellular calcium arising from store release and influx via voltage-gated calcium channels. Ex-4 activated both ERK-MAPK and PI 3-kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin-releasing factor (CRF) potentiated the neuronal response to Ex-4, and the functional effects of Ex-4 on colonic circular muscle activity were not altered. Ex-4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex-4 were dependent upon activation of PI 3-kinase and ERK-MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.

Differentiation of stem cells from apical papilla into neural lineage using graphene dispersion and single walled carbon nanotubes.

Stem cell-based therapies are considered a promising treatment modality for many medical conditions. Several types of stem cells with variable differentiation potentials have been isolated from dental tissues, among them stem cells from apical papilla (SCAP). In parallel, new classes of biocompatible nanomaterials have also been developed, including graphene and carbon nanotube-based materials. The aim of the study was to assess whether graphene dispersion (GD) and water-soluble single walled carbon nanotubes (ws-SWCNT), may enhance SCAPs capacity to undergo neural differentiation. SCAPs cultivated in neuroinductive medium supplemented with GD and ws-SWCNT, separately and in combination, were subjected to neural marker analysis by real-time polymerase chain reaction (neurofilament medium [NF-M], neurogenin-2 [ngn-2], β III-tubulin, microtubule-associated protein 2) and immunocytochemistry (NeuN and β III-tubulin). GD, ws-SWCNT, and their combination, had neuro-stimulatory effects on SCAPs, as judged by the production of neural markers. Compared to cells grown in nanomaterial free medium, cells with GD showed higher production of B3T, cells with ws-SWCNT had higher production of ngn-2 and NF-M, while the combination of nanomaterials gave similar levels of both B3T and NF-M as the neuroinductive medium alone, but with the finest neuron-like morphology. In conclusion, GD and ws-SWCNT seem to enhance neural differentiation of SCAP. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2653-2661, 2018.

Ghrelin sensitises colonic myenteric neurons to the neurostimulatory effects of glucagonlike peptide‐1 in Sprague Dawley and Wistar Kyoto rats.

Irritable Bowel Syndrome (IBS) is a common functional bowel disorder affecting approximately 10–20% of the population with many experiencing post‐prandial exacerbation of symptoms. Although IBS pathophysiology remains elusive, dysfunctional endocrine signalling has been implicated. Ghrelin is an orexigenic hormone which peaks prior to food ingestion. Glucagon‐like peptide‐1 (GLP‐1) is secreted by L‐cells in the mucosa of the small and large intestine in response to the arrival of nutrients. Previous studies have shown that ghrelin directly primes L‐cells to secrete GLP‐1 and increases GLP‐1 release (Gagnon et al., 2014). The aims of this study were to investigate if ghrelin sensitises colonic enteric neurons for GLP‐1 mediated signalling in two animal models; Sprague Dawley (control) and Wistar Kyoto (stress model of IBS).Immunofluorescence was used to stain for ghrelin and GLP‐1 receptors. Colonic motility was assessed in organ baths, using SD and WKY colonic segments, in response to a GLP‐1 mimetic before and after ghrelin stimulation.Ghrelin and GLP‐1 receptors were expressed in discrete co‐localised clusters in myenteric neurons. GLP‐1 reduced contractile activity in both SD and WKY rat colons. However, this response was potentiated by prior exposure to ghrelin in both circular and longitudinal muscle in Sprague Dawley ((p=0.0116), (p=0.0093), respectively) and Wistar Kyoto ((p= 0.0129), (p=0.0006), respectively) rat colonic segments.Ghrelin sensitises the colon to GLP‐1‐evoked contractile activity. Although similar mechanisms of action were evidence in both species, the baseline contractile activity was aberrant in WKY rats.Support or Funding InformationFunded by UCC TRAP funding and the Department of Physiology, University College of CorkThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague-Dawley rats.

What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.

BackgroundTranscranial focused ultrasound (FUS) is gaining momentum as a novel non-invasive brain stimulation method, with promising potential for superior spatial resolution and depth penetration compared to transcranial magnetic stimulation or transcranial direct current stimulation. We examined the presence of tactile sensations elicited by FUS stimulation of two separate brain regions in humans—the primary (SI) and secondary (SII) somatosensory areas of the hand, as guided by individual-specific functional magnetic resonance imaging data.ResultsUnder image-guidance, acoustic stimulations were delivered to the SI and SII areas either separately or simultaneously. The SII areas were divided into sub-regions that are activated by four types of external tactile sensations to the palmar side of the right hand—vibrotactile, pressure, warmth, and coolness. Across the stimulation conditions (SI only, SII only, SI and SII simultaneously), participants reported various types of tactile sensations that arose from the hand contralateral to the stimulation, such as the palm/back of the hand or as single/neighboring fingers. The type of tactile sensations did not match the sensations that are associated with specific sub-regions in the SII. The neuro-stimulatory effects of FUS were transient and reversible, and the procedure did not cause any adverse changes or discomforts in the subject’s mental/physical status.ConclusionsThe use of multiple FUS transducers allowed for simultaneous stimulation of the SI/SII in the same hemisphere and elicited various tactile sensations in the absence of any external sensory stimuli. Stimulation of the SII area alone could also induce perception of tactile sensations. The ability to stimulate multiple brain areas in a spatially restricted fashion can be used to study causal relationships between regional brain activities and their cognitive/behavioral outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0303-6) contains supplementary material, which is available to authorized users.

Ultrasonic stimulation of peripheral nervous tissue: an investigation into mechanisms

Neuro-stimulation has wide ranging clinical and research potential but this is currently limited either by low resolution, penetration or by highly invasive procedures. It has been reported in previous studies that ultrasound is able to elicit a neuro-stimulatory effect at a higher resolution than other non-invasive approaches but both the underlying mechanism that makes this possible and the practical details of how it can be implemented are still poorly understood. The current study has identified the main issues that need to be resolved in the field, proposing several different approaches to tackling these areas. An isolated in vitro peripheral nerve bundle was chosen as a simple model to demonstrate and investigate the neuro-stimulatory effect after preliminary results showed successful stimulation in a skin-nerve preparation. Early results from the nerve bundle show successful neurostimulation, indicating that structures in the peripheral nerve axon are sensitive to ultrasound. Further research using this model should reveal more precisely what structures are being affected and how to optimise the effect, helping to inform the design of future procedures and devices used in in vivo applications.

Modulation of enteric neurons by interleukin‐6 and corticotropin‐releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome

The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5mgkg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10mgkg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P<0.01) and visceral pain sensitivity (P<0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.

Fronto-tectal white matter connectivity mediates facilitatory effects of non-invasive neurostimulation on visual detection

The causal ability of pre-target FEF activity to modulate visual detection for perithreshold stimuli has been recently demonstrated in humans by means of non-invasive neurostimulation. Yet in spite of the network-distributed effects of these type of techniques, the white matter (WM) tracts and distant visual nodes contributing to such behavioral impact remain unknown. We hereby used individual data from a group of healthy human subjects, who received time-locked pulses of active or sham Transcranial Magnetic Stimulation (TMS) to the right Frontal Eye Field (FEF) region, and experienced increases in visual detection sensitivity. We then studied the extent to which interindividual differences in visual modulation might be dependent on the WM patterns linking the targeted area to other regions relevant for visuo-attentional behaviors. We report a statistically significant correlation between the probability of connection in a right fronto-tectal pathway (FEF-Superior Colliculus) and the modulation of visual sensitivity during a detection task. Our findings support the potential contribution of this pathway and the superior colliculus in the mediation of visual performance from frontal regions in humans. Furthermore, we also show the ability of a TMS/DTI correlational approach to contribute to the disambiguation of the specific long-range pathways driving network-wide neurostimulatory effects on behavior, anticipating their future role in guiding a more efficient use of focal neurostimulation.

Manipulation of Pre-Target Activity on the Right Frontal Eye Field Enhances Conscious Visual Perception in Humans

The right Frontal Eye Field (FEF) is a region of the human brain, which has been consistently involved in visuo-spatial attention and access to consciousness. Nonetheless, the extent of this cortical site’s ability to influence specific aspects of visual performance remains debated. We hereby manipulated pre-target activity on the right FEF and explored its influence on the detection and categorization of low-contrast near-threshold visual stimuli. Our data show that pre-target frontal neurostimulation has the potential when used alone to induce enhancements of conscious visual detection. More interestingly, when FEF stimulation was combined with visuo-spatial cues, improvements remained present only for trials in which the cue correctly predicted the location of the subsequent target. Our data provide evidence for the causal role of the right FEF pre-target activity in the modulation of human conscious vision and reveal the dependence of such neurostimulatory effects on the state of activity set up by cue validity in the dorsal attentional orienting network.

Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury.

Traumatic brain injury represents a leading cause of morbidity in young individuals and there is an imperative need for neuroprotective treatments limiting the neurologic impairment following such injury. It has recently been demonstrated that bio-liberated gold ions liberated from small metallic gold implants reduce inflammation and neuronal apoptosis, while generating an increased neuronal stem cell response following focal brain damage. In this study mice were subjected to a unilateral traumatic cryo-lesion with concomitant injection of 25-45 microm gold particles near the lesion. Placebo-treated mice subjected to cryo-lesion served as controls. The effects of gold-treatment were investigated by examining gold-induced growth factor expression (VEGF and FGF) in the first two weeks after the insult, and the extent of the neurostimulatory effect of gold was explored by comparing cell proliferation in the subventricular zone as judged by immunohistochemical staining for CDC47. Vimentin staining revealed a decrease in activated microglia and a transient astrogliosis in response to the gold liberation. Moreover, gold ions significantly increase the expression of VEGF and FGF following trauma and a significant increase in cell proliferation in both the ipsilateral and the contralateral subventricular zone was found in response to gold-treatment. we confirmed the previously demonstrated anti-inflammatory effect of bio-liberated gold ions, and further show that metallic gold increases growth factor expression and adult neurogenesis.

Extremely low frequency (ELF) electric and magnetic field exposure limits: Rationale for basic restrictions used in the development of an Australian standard

There are large disparities between basic restrictions for exposure to extremely low-frequency (0-3 kHz) Electric and Magnetic Fields set by two major international bodies. Both bodies agree that these basic restrictions should prevent neuro-stimulatory effects: the retinal phosphene at frequencies up to a few hundred Hertz and peripheral nervous stimulation (PNS) at higher frequencies. The disparity arises from differences in estimated thresholds and frequency dependence, and whether restrictions should be of tissue induced current density or electric field. This paper argues that the latter metric more directly relates to neurostimulatory processes. By analysing available literature, a threshold for retinal phosphenes occurrence is found to be 56 mV/m (95% Confidence Interval 2-1330 mV/m), with a characteristic frequency of 20 Hz. Similarly, the smallest PNS sensation threshold is identified at 2 V/m (characteristic frequency above 3 kHz). In the case of the former, the large range of uncertainty suggests a 'power of ten' value of 100 mV/m. For the latter, because of the small margin between sensation and pain threshold, and because of the large individual variation, the smallest estimate of sensation threshold (2 V/m) represents a basic restriction with precaution incorporated.

Heptachlor epoxide: Effects on calcium-mediated transmitter release from brain synaptosomes in rat

The biochemical processes by which heptachlor epoxide affects transmitter release were studied, using rat brain synaptosomes. Heptachlor epoxide stimulated the release of preloaded [ 14C]glutamate from isolated synaptosomes in the presence of externally available Ca 2+ or a high concentration of K + (71 mM). This stimulatory effect appeared to be independent of the general membrane depolarization, since it could still be observed in a synaptosomal preparation suspended in a high K + concentration (71 mM). Heptachlor epoxide-treated synaptosomes were also found to take up more Ca 2+ and to release less compared to untreated synaptosomes. By using subcellular preparations from disrupted synaptosomes, it was possible to demonstrate that an ATP-dependent Ca 2+ uptake process was inhibited by heptachlor epoxide. Experiments in vivo also confirmed the above observation. It was noted that all these actions of heptachlor expoxide have the same effect of raising the intracellular level of free Ca 2+. A working hypothesis has been proposed, therefore, to explain the neurostimulatory effect of heptachlor expoxide on the basis of its effects on synaptic Ca 2+ regulation, particularly that by Ca 2+-Mg 2+ ATPase.