Anti-nociceptive and anti-inflammatory potentials of fractions from the extract of Tetracarpidium conophorum leaf in rats and mice

Tetracarpidium conophorum (TC) (Euphorbiaceae) is a perennial woody climbing shrub in low bush forest of some parts of West Africa and used among the natives for relief of ailments accompanying pain and inflammation. In this study, the analgesic and anti-inflammatory effects of the methanolic extract (METC) and fractions (ethyl acetate, F1 and n-hexane, F2) of Tetracarpidium conophorum leaf were evaluated in rat and mice. The analgesic activity was evaluated using acetic acid-induced writhing, formalin-induced paw licking and hot plate test models. Carrageenan-induced paw oedema was used to assess anti-inflammatory activity in rats. The mechanism of action of (TC) was explored by the use of naloxone, a non-selective opioid receptor blocker. The highest analgesic effect was observed in F2 extract at 57.21% inhibition and was further studied on various analgesic and anti-inflammatory models in graded doses. F2 significantly inhibited the late phase of formalin-induced paw licking and prolong hot plate latency at 55±1°C. The n-hexane fraction also significantly inhibited carrageenan-induced paw oedema in rats at 100 and 200mg/kg doses significantly (p< 0.001) and reduced paw licking response by 85.08% compared with control. Naloxone, an opioid receptor antagonist, did not significantly affect the changes observed with n-hexane fraction, thus ruling out the possibility of the involvement of opioid receptors in the analgesic actions of Tetracarpidium conophorum. Phytochemical screening showed that the leaf extracts contain alkaloids, tannins, saponins and cardenolides. The investigations showed that Tetracarpidium conophorum possesses significant anti-nociceptive and anti-inflammatory activities that should be explored.

Tear Secretion Induced by Selective Stimulation of Corneal and Conjunctival Sensory Nerve Fibers

Purpose. To measure the increase in tear secretion evoked by selective stimulation of the different populations of sensory receptors of the cornea and conjunctiva by using moderate and intense mechanical, chemical, and cold stimuli. Methods. Six healthy subjects participated in the study. Tear secretion was measured in both eyes by the Schirmer’s test conducted under control conditions and after stimulation of the center of the cornea and the temporal conjunctiva with a gas esthesiometer. Mechanical stimulation consisted in three pulses of 3 seconds’ duration of warmed air (at 34°C on the eye surface) applied at moderate (170 mL/min) and high (260 mL/min) flow rates. Cold thermal stimulation was made with cooled air that produced a corneal temperature drop of −1°C or −4.5°C. Chemical (acidic) stimulation was performed with a jet of gas containing a mixture of 80% CO2 in air. Results. The basal volume of tear secretion increased significantly (P < 0.05, paired t-test) after stimulation of the cornea with high-flow mechanical stimuli (260 mL/min), intense cooling pulses (−4.5°C), and chemical stimulation (80% CO2). The same stimuli were ineffective when applied to the conjunctiva. Moderate mechanical (170 mL/min) and cold (−1°C) stimulation of the cornea or the conjunctiva did not change significantly the volume of tear secretion. Conclusions. Reflex tear secretion caused by corneal stimulation seems to be chiefly due to activation of corneal polymodal nociceptors, whereas selective excitation of corneal mechanonociceptors or cold receptors appears to be less effective in evoking an augmented lacrimal secretion. Conjunctival receptors stimulated at equivalent levels do not evoke an increased tear secretion.

A Closed Loop Brain-machine Interface for Epilepsy Control Using Dorsal Column Electrical Stimulation

Although electrical neurostimulation has been proposed as an alternative treatment for drug-resistant cases of epilepsy, current procedures such as deep brain stimulation, vagus, and trigeminal nerve stimulation are effective only in a fraction of the patients. Here we demonstrate a closed loop brain-machine interface that delivers electrical stimulation to the dorsal column (DCS) of the spinal cord to suppress epileptic seizures. Rats were implanted with cortical recording microelectrodes and spinal cord stimulating electrodes, and then injected with pentylenetetrazole to induce seizures. Seizures were detected in real time from cortical local field potentials, after which DCS was applied. This method decreased seizure episode frequency by 44% and seizure duration by 38%. We argue that the therapeutic effect of DCS is related to modulation of cortical theta waves, and propose that this closed-loop interface has the potential to become an effective and semi-invasive treatment for refractory epilepsy and other neurological disorders.

The Effects of Non-Nutritive Sucking and Pre-Feeding Oral Stimulation on Time to Achieve Independent Oral Feeding for Preterm Infants

Background: The survival rates of preterm infants has increased over the last years, but oral feeding difficulties are the most common problems encountered by them Objectives: This study aimed at comparing the effects of non-nutritive sucking (NNS) and pre-feeding oral stimulation on feeding skills, length of hospital stay and weight gain of 26-32 weeks gestational age preterm infants in NICU, to determine the more effective intervention. Patients and Methods: Thirty-two preterm infants were assigned randomly into three groups. One intervention group received pre-feeding oral stimulation program and the other received non-nutritive sucking stimulation, while the control group received a sham intervention. Gestational age of infants was calculated during 1, 4 and 8 oral feeding and discharge time from NICU. The infants’ weights were measured weekly from birth and at discharge time. Results: Mean gestational age on 8 time oral feeding per day, in 3 groups was not significant (P = 0.282). Although NNS and pre-feeding oral stimulation groups has fulfilled this criterion 7.55 and 6.07 days sooner than the control group, respectively (a result which is of great clinical and economic importance), but the difference did not reach statistical significance. Weight gaining at discharge time in NNS group was significantly higher than control and pre-feeding oral stimulation groups (P < 0.05). Conclusions: This study revealed that pre-feeding oral stimulation and NNS programs both were effective on oral feeding skills and weight gaining of the immature newborns. Yet, it seems that NNS program was more effective than pre-feeding oral stimulation on weight gaining.

Efficacy of neurostimulation to treat symptoms of Mal de Debarquement Syndrome. A preliminary study using repetitive transcranial magnetic stimulation

Mal de debarquement syndrome (MdDS) is a rare and poorly understood condition of perceived continual motion. Using a multiple-case design (n = 13; 8 f; 63.5 ± 12.6 years), this study investigated the efficacy of eight 20-min sessions, over 4 weeks, of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral pre-frontal cortex. Compared to sham, rTMS demonstrated improvement in balance and confidence in daily living activities. rTMS shows promise for the treatment of MdDS. However, larger trials with longer intervention periods are required.

Examining the feasibility and tolerability of a clinically informed multisite, repetitive transcranial magnetic stimulation protocol

BACKGROUND: Multi-site repetitive transcranial magnetic stimulation (rTMS) has been applied experimentally in the treatment of obsessive compulsive disorder (OCD). NEW METHOD: This study was conducted to systematically evaluate the safety, tolerability and neurocognitive effects of rTMS applied to three cortical regions over a period of three months. NEW METHOD: Twenty healthy participants aged 22-33 years were randomly allocated to receive one session of active or sham stimulation of low and high frequency rTMS applied sequentially to the pre-supplementary motor area, right-dorsolateral prefrontal cortex and left-orbitofrontal cortex totalling 9min. Tolerability and safety was evaluated using a standardised safety questionnaire. Neurocognitive functioning was examined using the Cambridge Neuropsychological Test Automated Battery and measures of verbal fluency from the Delis-Kaplan Executive Functioning Test™ at five time points over three months. RESULTS: The protocol was safe and tolerable. Frequencies of minor adverse effects were higher in active (17 endorsements) than sham (1 endorsement) conditions. No between group differences in neurocognitive functioning were identified over three months. COMPARISON WITH EXISTING METHOD: This study is the first to evaluate the feasibility of low and high frequency parameters applied sequentially in a single session to the three selected cortical regions whilst providing neurocognitive data. CONCLUSIONS: rTMS applied sequentially over three cortical regions was found to be safe and tolerable in healthy individuals with no major neurocognitive effects over three months. Such findings can be used to inform the development of rTMS protocols involving multi-site stimulation for OCD.

Osteoclast formation elicited by interleukin-33 stimulation is dependent upon the type of osteoclast progenitor

Osteoclasts are bone resorbing multinucleated cells (MNCs) derived from macrophage progenitors. IL-33 has been reported to drive osteoclastogenesis independently of receptor activator of NFκB ligand (RANKL) but this remains controversial as later studies did not confirm this. We found IL-33 clearly elicited functional dentine-resorbing osteoclast formation from human adult monocytes. However, monocytes from only 3 of 12 donors responded this way, while all responded to RANKL. Human cord blood-derived progenitors and murine bone marrow macrophages lacked an osteoclastogenic response to IL-33. In RAW264.7 cells, IL-33 elicited NFκB and p38 responses but not NFATc1 signals (suggesting poor osteoclastogenic responses) and formed only mononuclear tartrate-resistant acid phosphatase positive (TRAP(+)) cells. Since TGFβ boosts osteoclastogenesis in RAW264.7 cells we employed an IL-33/TGFβ co-treatment, which resulted in small numbers of MNCs expressing key osteoclast markers TRAP and calcitonin receptors. Thus, IL-33 possesses weak osteoclastogenic activity suggesting pathological significance and, perhaps, explaining previous conflicting reports.

Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex

High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200μA; 90μs) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIα/β), glycogen synthase kinase 3 (GSK3α/β) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100μg/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIα/β and GSK3α/β significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIα/β, GSK3α/β, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIα/β, and GSK3α/β in the LHb together with the downregulation of CaMKIIα/β, GSK3α/β, and AMPK in the IL, contribute to the antidepressant actions of DBS.

A miniature energy harvesting rectenna for operating a head-mountable deep brain stimulation device

This paper presents design, implementation, and evaluation of a miniature rectenna for energy harvesting applications. The rectenna produces DC power from a distant microwave energy transmitter. The generated DC power is then utilized to operate a head-mountable deep brain stimulation device. The rectenna consists of a miniature three-layer planar inverted-F antenna and a Schottky-diode-based bridge rectifier. The antenna has a volume of π × 6 × 1.584 mm3, a resonance frequency of 915 MHz with a simulated bandwidth of 18 MHz (907-925 MHz), and a measured bandwidth of 18 MHz (910-928 MHz) at the return loss of -10 dB. A dielectric substrate of FR-4 of εr = 4.5 and δ = 0.02 is used for simulation and fabrication of the antenna and the rectifier due to its low cost. An L-section impedance matching circuit is employed between the antenna and the rectifier to reduce the mismatch loss. The impedance matching circuit operates as a low-pass filter eliminating higher order harmonics. A deep brain stimulation device is successfully operated by the rectenna at a distance of 20 cm away from a microwave energy transmitter of power 26.77 dBm. The motivation of this paper includes creation of a deep brain stimulation device that operates indefinitely without a battery. From the application standpoint, the developed energy harvesting rectenna facilitates long-term deep brain stimulation of laboratory animals for preclinical research investigating neurological disorders.

Anodal transcranial direct current stimulation of the motor cortex increases cortical voluntary activation and neural plasticity

INTRODUCTION: We examined the cumulative effect of 4 consecutive bouts of non-invasive brain stimulation on corticospinal plasticity and motor performance, and whether these responses were influenced by the brain-derived neurotrophic factor (BDNF) polymorphism.

METHODS: In a randomized double-blinded cross-over design, changes in strength and indices of corticospinal plasticity were analyzed in 14 adults who were exposed to 4 consecutive sessions of anodal and sham transcranial direct current stimulation (tDCS). Participants also undertook a blood sample for BDNF genotyping (N=13).

RESULTS: We observed a significant increase in isometric wrist flexor strength with transcranial magnetic stimulation revealing increased corticospinal excitability, decreased silent period duration, and increased cortical voluntary activation compared to sham tDCS.

DISCUSSION: The results show that 4 consecutive sessions of anodal tDCS increased cortical voluntary activation manifested as an improvement in strength. Induction of corticospinal plasticity appears to be influenced by the BDNF polymorphism.

Cerebral responses to innocuous somatic pressure stimulation following aerobic exercise rehabilitation in chronic pain patients: a functional magnetic resonance imaging study

Objective: The purpose of this research was to assess the functional brain activity and perceptual rating of innocuous somatic pressure stimulation before and after exercise rehabilitation in patients with chronic pain.

Materials and methods: Eleven chronic pain patients and eight healthy pain-free controls completed 12 weeks of supervised aerobic exercise intervention. Perceptual rating of standardized somatic pressure stimulation (2 kg) on the right anterior mid-thigh and brain responses during functional magnetic resonance imaging (fMRI) were assessed at pre- and postexercise rehabilitation.

Results: There was a significant difference in the perceptual rating of innocuous somatic pressure stimulation between the chronic pain and control groups (P=0.02) but no difference following exercise rehabilitation. Whole brain voxel-wise analysis with correction for multiple comparisons revealed trends for differences in fMRI responses between the chronic pain and control groups in the superior temporal gyrus (chronic pain > control, corrected P=0.30), thalamus, and caudate (control > chronic, corrected P=0.23). Repeated measures of the regions of interest (5 mm radius) for blood oxygen level-dependent signal response revealed trend differences for superior temporal gyrus (P=0.06), thalamus (P=0.04), and caudate (P=0.21). Group-by-time interactions revealed trend differences in the caudate (P=0.10) and superior temporal gyrus (P=0.29).

Conclusion: Augmented perceptual and brain responses to innocuous somatic pressure stimulation were shown in the chronic pain group compared to the control group; however, 12-weeks of exercise rehabilitation did not significantly attenuate these responses.