Cessation Of Stimulation Research Articles

Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI

The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei.

Stimulation-induced transient changes in neuronal activity, blood flow and N-acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS-BOLD study.

Brain activation studies in humans have shown the dynamic nature of neuronal N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) based on changes in their MRS signals in response to stimulation. These studies demonstrated that upon visual stimulation there was a focal increase in cerebral blood flow (CBF) and a decrease in NAA or in the total of NAA and NAAG signals in the visual cortex, and that these changes were reversed upon cessation of stimulation. In the present study we have developed an animal model in order to explore the relationships between brain stimulation, neuronal activity, CBF and NAA. We use "designer receptor exclusively activated by designer drugs" (DREADDs) technology for site-specific neural activation, a local field potential electrophysiological method for measurement of changes in the rate of neuronal activity, functional MRS for measurement of changes in NAA and a blood oxygenation level-dependent (BOLD) MR technique for evaluating changes in CBF. We show that stimulation of the rat prefrontal cortex using DREADDs results in the following: (i) an increase in level of neuronal activity; (ii) an increase in BOLD and (iii) a decrease in the NAA signal. These findings show for the first time the tightly coupled relationships between stimulation, neuron activity, CBF and NAA dynamics in brain, and also provide the first demonstration of the novel inverse stimulation-NAA phenomenon in an animal model.

Reversal of tubo-ovarian atypical epithelial patterns after cessation of ovarian stimulation by letrozole.

Letrozole (LTZ), one of the ovulation induction medications, is increasingly prescribed in various gynaecological conditions. Previous studies have demonstrated its potential hazardous effect on the ovarian surface epithelium (OSE) as well as on tubal epithelial cells (TEC). However, it is not clear whether this effect could be reversed by LTZ cessation. Therefore, the objective of our study was to investigate the effect of stoppage of LTZ on these cells after 12 cycles of ovarian stimulation. A total of 54 Sprague Dawley rats were used in this study, divided equally into control, LTZ12 and CES12 groups (received saline, 12 cycles of LTZ and 12 cycles of cessation post-LTZ12 respectively). Samples from the ovaries as well as fallopian tubes (FTs) were studied histologically for the changes associated with LTZ12 and CES12 respectively. There was evident increase in the proliferative activity and Ki67 immunoexpression in the OSE of LTZ12. The OSE was hyperchromatic, and abnormally frequent deep invaginations, micropapillae and cortical cysts. Their TEC showed frequent multilayering, papillary projections and loss of cilia. Almost all these changes disappeared 12 cycles after LTZ cessation. While the tubal IL-1β, IL-6, TNF-α and serum MCP-1 levels significantly increased in the LTZ12 group compared with the control group, their levels decreased in the CES12 group compared with those of the control. Therefore, the abnormal tubo-ovarian epithelial patterns may completely regress after cessation of LTZ stimulation for a reasonable duration. This is a potentially good omen and a positive indicator of the relatively safe use of LTZ after its intake has been stopped.

Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum

BackgroundRecent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats. MethodsRats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors. ResultsHigh-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala. ConclusionsOur results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction.

Opponent and bidirectional control of movement velocity in the basal ganglia.

For goal-directed behavior it is critical that we can both select the appropriate action and learn to modify the underlying movements (e.g. the pitch of a note or velocity of a reach) to improve outcomes. The basal ganglia are a critical nexus where circuits necessary for the production of behavior, such as neocortex and thalamus, are integrated with reward signaling 1 to reinforce successful, purposive actions 2. Dorsal striatum, a major input structure of basal ganglia is composed of two opponent pathways, direct and indirect, thought to select actions that elicit positive outcomes or suppress actions that do not, respectively 3,4. Activity-dependent plasticity modulated by reward is thought to be sufficient for selecting actions in striatum 5,6. Although perturbations of basal ganglia function produce profound changes in movement 7, it remains unknown whether activity-dependent plasticity is sufficient to produce learned changes in movement kinematics, such as velocity. Here we used cell-type specific stimulation delivered in closed-loop during movement to demonstrate that activity in either the direct or indirect pathway is sufficient to produce specific and sustained increases or decreases in velocity without affecting action selection or motivation. These behavioral changes were a form of learning that accumulated over trials, persisted after the cessation of stimulation, and were abolished in the presence of dopamine antagonists. Our results reveal that the direct and indirect pathways can each bidirectionally control movement velocity, demonstrating unprecedented specificity and flexibility in the control of volition by the basal ganglia.

Stimulating forebrain communications: Slow sinusoidal electric fields over frontal cortices dynamically modulate hippocampal activity and cortico-hippocampal interplay during slow-wave states

Slow-wave states are characterized by the most global physiological phenomenon in the mammalian brain, the large-amplitude slow oscillation (SO; ~1Hz) composed of alternating states of activity (ON/UP states) and silence (OFF/DOWN states) at the network and single cell levels. The SO is cortically generated and appears as a traveling wave that can propagate across the cortical surface and can invade the hippocampus. This cortical rhythm is thought to be imperative for sleep-dependent memory consolidation, potentially through increased interactions with the hippocampus. The SO is correlated with learning and its presumed enhancement via slow rhythmic electrical field stimulation improves subsequent mnemonic performance. However, the mechanism by which such field stimulation influences the dynamics of ongoing cortico-hippocampal communication is unknown. Here we show – using multi-site recordings in urethane-anesthetized rats – that sinusoidal electrical field stimulation applied to the frontal region of the cerebral cortex creates a platform for improved cortico-hippocampal communication. Moderate-intensity field stimulation entrained hippocampal slow activity (likely by way of the temporoammonic pathway) and also increased sharp-wave ripples, the signature memory replay events of the hippocampus, and further increased cortical spindles. Following cessation of high-intensity stimulation, SO interactions in the cortical-to-hippocampal direction were reduced, while the reversed hippocampal-to-cortical communication at both SO and gamma bandwidths was enhanced. Taken together, these findings suggest that cortical field stimulation may function to boost memory consolidation by strengthening cortico-hippocampal and hippocampo-cortical interplay at multiple nested frequencies in an intensity-dependent fashion.

Electroacupuncture Produces the Sustained Motor Improvement in 6-Hydroxydopamine-Lesioned Mice.

Clinical and research evidence has shown that electroacupuncture (EA) promotes recovery of motor function in patients with Parkinson’s disease (PD). However, the “efficacy span” of EA treatment, especially the long-term effect of EA that is thought to last after the cessation of EA treatment, has not been investigated. The present study thus investigated and compared the effect of EA during and after chronic EA application on motor activity and dopamine lesions in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Chronic EA treatment (30 min a day, 6 days a week for 2 or 4 weeks) significantly attenuated motor deficiency and reduced dopamine neuron degeneration. Remarkably, EA showed a long-lasting effect after the cessation of EA stimulation. At 2 and 4 weeks after the termination of EA, EA continued to improve motor function in 6-OHDA-lesioned mice. Consistent with sustained behavioral effects, EA induced an enduring increase in the dopamine turnover ratio in the striatum 2 weeks after the cessation of EA treatment. Here we demonstrated that the therapeutic effect of EA outlasted the duration of EA application. During a relatively long period of time after the completion of EA treatment, EA is able to continue to improve motor function and enhance dopamine availability in 6-OHDA-lesioned PD mice.

Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury

An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10min after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10min. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS+c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10days, 27min/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor recovery and substantial CST outgrowth with only 27min of daily stimulation compared with 6h, as in our prior study, making it a potential therapy for humans with spinal cord injury.

Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats

Background and objective. Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke. Here, we evaluated the ability of VNS paired with rehabilitative training to improve recovery of forelimb strength when initiated many weeks after a cortical and subcortical ischemic lesion in subjects with stable, chronic motor deficits. Methods. Rats were trained to perform an automated, quantitative measure of voluntary forelimb strength. Once proficient, rats received injections of endothelin-1 to cause a unilateral cortical and subcortical ischemic lesion. Then, 6 weeks after the lesion, rats underwent rehabilitative training paired with VNS (Paired VNS; n = 10), rehabilitative training with equivalent VNS delivered 2 hours after daily rehabilitative training (Delayed VNS; n = 10), or rehabilitative training without VNS (Rehab, n = 9). Results. VNS paired with rehabilitative training significantly improved recovery of forelimb function compared with control groups. The Paired VNS group displayed an 86% recovery of strength, the Rehab group exhibited 47% recovery, and the Delayed VNS group exhibited 42% recovery. Improvement in forelimb function was sustained in the Paired VNS group after the cessation of stimulation, potentially indicating lasting benefits. No differences in intensity of rehabilitative training, lesion size, or MAP-2 expression were observed between groups. Conclusion. VNS paired with rehabilitative training confers significantly greater recovery of forelimb function after chronic ischemic stroke in rats.

Platelet‐derived growth factor receptor‐α‐positive cells: new players in nerve‐mediated purinergic responses in the colon

Platelet‐derived growth factor receptor‐α‐positive cells: new players in nerve‐mediated purinergic responses in the colon

Contribution of impaired myofibril and ryanodine receptor function to prolonged low-frequency force depression after in situ stimulation in rat skeletal muscle.

The aim of this study was to examine whether prolonged low-frequency force depression (PLFFD) that occurs in situ is the result of decreased myofibrillar Ca(2+) sensitivity and/or reduced sarcoplasmic reticulum (SR) Ca(2+) release. Intact rat gastrocnemius muscles were electrically stimulated via the sciatic nerve until force was reduced to ~50% of the initial and dissected 30 min following the cessation of stimulation. Skinned fibre and whole muscle analyses were performed in the superficial region composed exclusively of type IIB fibres. Fatiguing stimulation significantly reduced the ratio of force at low frequency to that at high frequency to 65% in skinned fibres (1 vs. 50 Hz) and 73% in whole muscles (20 vs. 100 Hz). In order to evaluate changes in myofibrillar Ca(2+) sensitivity and ryanodine receptor caffeine sensitivity, skinned fibres were activated in Ca(2+)- and caffeine-containing solutions, respectively. Skinned fibres from fatigued muscles displayed decreased caffeine sensitivity together with increased myofibrillar Ca(2+) sensitivity. Treatment with 2,2'-dithiodipyridine and reduced glutathione induced a smaller increase in myofibrillar Ca(2+)sensitivity in fatigued than in rested fibres. In fatigued muscles, S-glutathionylation of troponin I was increased and submaximal SR Ca(2+) release, induced by 4-chloro-m-cresol, was decreased. These findings suggest that in the early stage of PLFFD that occurs in fast-twitch muscles of exercising animals and humans, S-glutathionylation of troponin I may attenuate PLFFD by increasing myofibrillar Ca(2+) sensitivity and that under such a circumstance, PLFFD may be ascribable to failure of SR Ca(2+) release.

Electrical Stimulation of the Nucleus Accumbens Shell Reduces Voluntary Ethanol Consumption in Bulbectomized Rats

Background: Alcoholism is often accompanied by depression. It has been shown that deep electrical stimulation of the nucleus accumbens is effective in the treatment of alcoholism. Objective: Despite the promising results of clinical trials, the mechanisms underlying its effects are still unclear. To elucidate these mechanisms, valid animal models are needed. Methods: We investigated the effects of electrical stimulation of the nucleus accumbens shell (NAS) and nucleus accumbens core (NAC) on alcohol intake in bulbectomized rats. Bilateral removal of the olfactory bulbs (OBX) is considered a valid animal model of depression. Results: It was shown that electrical stimulation of the NAS with the described stimulus parameters significantly reduced voluntary ethanol intake in OBX rats. After the cessation of stimulation, this effect became insignificant. In contrast, stimulation of the NAC did not modify voluntary ethanol intake. In sham-bulbectomized animals, voluntary ethanol intake was negligible and ethanol consumption did not alter as a result of electrical stimulation of the NAC or NAS Conclusions: Our study underlines the relevance of the OBX model in the study of depression comorbid alcohol intake. Moreover, it might be useful in the study of the mechanisms underlying the clinical effectiveness of electrical stimulation of the NAS in the treatment of alcoholism.

Control of abnormal synchronization in neurological disorders.

In the nervous system, synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson’s disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR) neuromodulation, we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, non-linear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP), CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from an abnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved.

Second Generation Direct-Acting Antiviral Agents Eradicate Hepatitis C Virus (HCV) but Exacerbate Thrombocytopenia in a Patient with HCV-Associated Immune Thrombocytopenic Purpura (ITP): Case Report

BackgroundLymphotropism of HCV induces chronic immune stimulation, facilitating production of wide variety of autoantibodies, leading to HCV driven autoimmunity. Immune thrombocytopenic purpura (ITP) is one of extra hepatic manifestations of autoimmune diseases in HCV infection.The treatment landscape of hepatitis C virus infection has been dramatically altered in 2013 with the approvals of the second-generation protease inhibitor simeprevir and the nucleotide polymerase inhibitor sofosbuvir. In most patients treated with the direct-acting antiviral agent (DAA), HCV RNA became undetectable.However a little is known about how DAA therapy affects autoimmune diseases associated with HCV, especially in ITP. Cessation of immune stimulation by HCV following the treatment may alter immune responses and may modify autoimmune diseases.We report here a case of acute exacerbation of ITP following DAA treatment. DAA therapy appears to precipitate acute exacerbation of thrombocytopenia and ITP became refractory to all treatments including the measures that used to induce remission prior to DAA treatment.Case reportA 67-year-old man was diagnosed chronic HCV infection, genotype 1b, in 1997. He failed treatment with Interferons. Chronic active hepatitis subsequently progressed into cirrhosis with portal hypertension. His ITP required frequent treatments with Prednisone and IVIG. It became severe in early 2013. His platelet counts were low at 10,000. He responded well to high dose Prednisone but could not continue because of worsening diabetes. He also failed Rituxan. He received multiple treatments including eltrombopag and romiplostin which he did not respond well to. His ITP finally stabilized with monthly infusion of WinRho as maintenance therapy with platelet counts hovering around 40.000 for 6 months.In March 2014, he was started on HCV treatment with simeprevir, sofosbuvir and ribavirin. His baseline platelet count prior to the new treatment was in the 50000’s. It plummeted to below 10.000 two weeks into treatment. He developed multiple ecchymosis and blood blisters in the mouth. He completed his HCV treatment on June 3, 2014. His viral load was no longer detectable.However, ITP remained refractory and severe with platelet counts around 10,000. High dose Prednisone or WinRho which had been effective in raising platelet counts previously were no longer effective after DAA therapy. During this acute exacerbation of ITP, he was treated with IVIG 3 times a week and low dose Prednisone and NPlate weekly with increasing dosage. He developed frequent blood blisters in mouth and gum bleeding requiring emergency room visits and hospitalization where he received platelet transfusions along with IVIGG and high dose Prednisone. His hemoglobin was stable throughout. IVIGG was reduced to 2 times a week. At 8 weeks following completion of DAAs, his platelet count improved to 40.000s range without clinical sign of bleeding.DiscussionIt has been shown that the frequency of B-cell production of anti- GPIIb-IIIa antibody, an antibody against the major platelet surface autoantigen (BP IIb-IIIa) recognized by anti-platelet antibodies in patients with idiopathic thrombocytopenic purpura (ITP), was greater in HCV-ITP (9). An inverse correlation was found between platelet count and B-cell anti–GPIIb-IIIa Ab production in 51 patients with liver cirrhosis (73% with hepatitis C).In our patient, ITP was stable with maintenance infusion of WinRho for 6 months. Acute exacerbation of ITP 2 weeks into DAA therapy suggests that it was triggered by the DAAs. Thrombocytopenia is a well-recognized complication of interferon therapy for treatment of viral hepatitis. Simeprevir and sofosbuvir however, are not well known to affect the platelet count.A little is known on effect of DAAs on thrombocytopenia. Immune alteration following eradication of HCV and subsequent modification of autoimmunity could affect course of ITP associated with HCV infection. Meanwhile, it is important for physicians and patients to be aware of potentially dangerous complications of these second generation DAAs. DisclosuresNo relevant conflicts of interest to declare.

Temporary sacral nerve stimulation in patients with fecal incontinence owing to rectal hyposensitivity: A prospective, double-blind study

Rectal hyposensitivity (RH) can lead to fecal incontinence (FI). Sacral nerve stimulation (SNS) is known to modulate rectal sensation, but no data about affecting FI owing to RH are available. This prospective study aimed to assess the therapeutic effect of temporary SNS on patients with FI owing to RH. Twenty-four patients with FI owing to RH had temporary SNS (4 weeks on followed by 1 week off). Before SNS (baseline), after 4 weeks of stimulation (on), and at the end of the off week we recorded first constant sensation (FCS), defecatory desire volume (DDV), maximum tolerated volume (MTV), anal pressures, bowel diaries, Wexner incontinence score, and FI quality-of-life score (FIQOL). There were significant decreases in DDV and MTV during the on-treatment period (P < .0001); this decrease was not significant during the off period. FCS was not significantly affected by SNS. FI episodes significantly improved during the on period in 22 patients (from 5.3 to 1.1 per week; P < .0001) and mean Wexner incontinence score improved from 13.3 to 1.7 (P < .0001). Anal pressures (resting and squeeze) significantly increased during the on period but not during the off period. There was significant improvement in FIQOL during the on period only. SNS can be effective in restoring continence and improving QOL in patients with FI owing to RH. Improved continence might be related to improvement of rectal sensation and/or increased anal pressure. The washout effect of SNS on the continence score, DDV, and MTV after cessation of stimulation needs to be explained.

Whole transcriptome RNA sequencing data from blood leukocytes derived from Parkinson's disease patients prior to and following deep brain stimulation treatment.

Recent evidence demonstrates the power of RNA sequencing (RNA-Seq) for identifying valuable and urgently needed blood biomarkers and advancing both early and accurate detection of neurological diseases, and in particular Parkinson's disease (PD). RNA sequencing technology enables non-biased, high throughput, probe-independent inspection of expression data and high coverage and both quantification of global transcript levels as well as the detection of expressed exons and junctions given a sufficient sequencing depth (coverage). However, the analysis of sequencing data frequently presents a bottleneck. Tools for quantification of alternative splicing from sequenced libraries hardly exist at the present time, and methods that support multiple sequencing platforms are especially lacking. Here, we describe in details a whole RNA-Seq transcriptome dataset produced from PD patient's blood leukocytes. The samples were taken prior to, and following deep brain stimulation (DBS) treatment while being on stimulation and following 1 h of complete electrical stimulation cessation and from healthy control volunteers. We describe in detail the methodology applied for analyzing the RNA-Seq data including differential expression of long noncoding RNAs (lncRNAs). We also provide details of the corresponding analysis of in-depth splice isoform data from junction and exon reads, with the use of the software AltAnalyze. Both the RNA-Seq raw (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE42608) and analyzed data (https://www.synapse.org/#!Synapse:syn2805267) may be found valuable towards detection of novel blood biomarkers for PD.

Initiation and modulation of locomotor circuitry output with multisite transcutaneous electrical stimulation of the spinal cord in noninjured humans.

The mammalian lumbar spinal cord has the capability to generate locomotor activity in the absence of input from the brain. Previously, we reported that transcutaneous electrical stimulation of the spinal cord at vertebral level T11 can activate the locomotor circuitry in noninjured subjects when their legs are placed in a gravity-neutral position (Gorodnichev RM, Pivovarova EA, Pukhov A, Moiseev SA, Savokhin AA, Moshonkina TR, Shcherbakova NA, Kilimnik VA, Selionov VA, Kozlovskaia IB, Edgerton VR, Gerasimenko IU. Fiziol Cheloveka 38: 46-56, 2012). In the present study we hypothesized that stimulating multiple spinal sites and therefore unique combinations of networks converging on postural and locomotor lumbosacral networks would be more effective in inducing more robust locomotor behavior and more selective control than stimulation of more restricted networks. We demonstrate that simultaneous stimulation at the cervical, thoracic, and lumbar levels induced coordinated stepping movements with a greater range of motion at multiple joints in five of six noninjured subjects. We show that the addition of stimulation at L1 and/or at C5 to stimulation at T11 immediately resulted in enhancing the kinematics and interlimb coordination as well as the EMG patterns in proximal and distal leg muscles. Sequential cessation of stimulation at C5 and then at L1 resulted in a progressive degradation of the stepping pattern. The synergistic and interactive effects of transcutaneous stimulation suggest a multisegmental convergence of descending and ascending, and most likely propriospinal, influences on the spinal neuronal circuitries associated with locomotor activity. The potential impact of using multisite spinal cord stimulation as a strategy to neuromodulate the spinal circuitry has significant implications in furthering our understanding of the mechanisms controlling posture and locomotion and for regaining significant sensorimotor function even after a severe spinal cord injury.

A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity.

Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone secreted from gastrointestinal K cells in response to food intake, has an important role in the control of whole-body metabolism. GIP signals through activation of the GIP receptor (GIPR), a G-protein-coupled receptor (GPCR). Dysregulation of this pathway has been implicated in the development of metabolic disease. Here we demonstrate that GIPR is constitutively trafficked between the plasma membrane and intracellular compartments of both GIP-stimulated and unstimulated adipocytes. GIP induces a downregulation of plasma membrane GIPR by slowing GIPR recycling without affecting internalization kinetics. This transient reduction in the expression of GIPR in the plasma membrane correlates with desensitization to the effects of GIP. A naturally occurring variant of GIPR (E354Q) associated with an increased incidence of insulin resistance, type 2 diabetes, and cardiovascular disease in humans responds to GIP stimulation with an exaggerated downregulation from the plasma membrane and a delayed recovery of GIP sensitivity following cessation of GIP stimulation. This perturbation in the desensitization-resensitization cycle of the GIPR variant, revealed in studies of cultured adipocytes, may contribute to the link of the E354Q variant to metabolic disease.

Electropermeabilization of Adherent Cells with Cochlear Implant Electrical Stimulation in vitro

Cochlear implant stimulation creates a reduction in electrode impedance that returns to pre-stimulation levels following cessation of stimulation and is presumed to be associated with the fibrous tissue covering over the electrode array. This study assessed the possibility that transitory impedance reduction originates from a change in the membrane permeability of cells on the electrode (electropermeabilization). These changes can be recorded using the dye propidium iodide, which fluoresces upon entry into the leaky cell. The in vitro model used showed impedance reduction and dye uptake into adherent cells overlying planar gold electrodes stimulated with as little as 5 min of clinically relevant cochlear implant stimulation. The delayed additions of propidium iodide showed a similar dye uptake to those groups with concurrent dye addition, suggesting the electropermeabilization was not reversible. Further understanding of the mechanisms behind these impedance and cell permeability changes with cochlear implant electrical stimulation may provide opportunities for creating long-lasting reductions in electrode impedance.

Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage.

Vagus nerve stimulation (VNS) delivered during rehabilitative training enhances neuroplasticity and improves recovery in models of cortical ischemic stroke. However, VNS therapy has not been applied in a model of subcortical intracerebral hemorrhage (ICH). We hypothesized that VNS paired with rehabilitative training after ICH would enhance recovery of forelimb motor function beyond rehabilitative training alone. Rats were trained to perform an automated, quantitative measure of forelimb function. Once proficient, rats received an intrastriatal injection of bacterial collagenase to induce ICH. Rats then underwent VNS paired with rehabilitative training (VNS+Rehab; n=14) or rehabilitative training without VNS (Rehab; n=12). Rehabilitative training began ≥9 days after ICH and continued for 6 weeks. VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS. The VNS+Rehab group displayed a 77% recovery of function, whereas the Rehab group only exhibited 29% recovery. Recovery was sustained after cessation of stimulation. Both groups performed similar amounts of trials during rehabilitative, and lesion size was not different between groups. VNS paired with rehabilitative training confers significantly improved forelimb recovery after ICH compared to rehabilitative training without VNS.