Effect Of Direct Electrical Stimulation Research Articles

Concept: Electrical Cardiac Stimulation is Detected by the Cardiac Autonomic Nervous System with Possible Effects on the Vasovagal Reflex

Abstract A novel concept is described concerning the possible effect of right ventricular pacing stimulation being detected by the cardiac autonomic nervous system and through its afferent neuronal connection to the central autonomic nervous system (spinal cord) causing reversal or attenuation of the vasovagal reflex. This could be a direct effect of electrical stimulation or may occur by the known adverse consequences on ventricular synchrony induced by stimulation which could be right ventricular site and timing in the evolution of the vasovagal reflex dependent.

Abstract 14447: Increased Autophagy Flux May Underline Cardiomyocyte Remodeling in Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling that impairs electrical activation of the atria. Studies have shown that mitochondrial dysfunction underlies cardiomyocyte remodeling. Here, we report a 50% reduction in total mitochondrial DNA in the atria tissue of RAP dogs as compared to control dogs, as assessed by qPCR the levels of mitochondrial DNA including mt-NT-1, mt-NT-4, mt-NT 5, mt-NT 6. This reduction in mitochondrial DNA suggests reduced mitochondria number in RAP dogs. Autophagic flux (LC3 II protein levels) was markedly increased in the atria tissue of the AF dog model (vs control dog).Furthermore, we examined autophagy flux in isolated cardiomyocytes. Results showed that LC3II was remarkably activated when subject to electrical stimulation for 6 hours under 3 Hertz condition, suggesting the direct effect of electrical stimulation on increasing autophagy. There was no change in the mRNA levels of autophagosome genes including Belin 1, ATG8, LC3, Lamp1 in the RAP dog tissue as compared to control, however, ATG7 increased by 2 fold and GNG2 increased by 5 fold. In conclusion, our study suggests that electrical stimulation-induced autophagy, and reduced mitochondria number and function, may underlie cardiomyocyte remodeling in AF. Targeting the autophagy pathway may present new therapeutic targets for AF. Ongoing AAV-mediated knockdown experiments in isolated cardiomyocytes will further elucidate the mechanism of electrical stimulation-induced autophagy.

Stimulation of frontal pathways disrupts hand muscle control during object manipulation.

The activity of frontal motor areas during hand-object interaction is coordinated by dense communication along specific white matter pathways. This architecture allows the continuous shaping of voluntary motor output but, despite extensive investigation in non-human primate studies, remains poorly understood in humans. Disclosure of this system is crucial for predicting and treatment of motor deficits after brain lesions.For this purpose, we investigated the effect of direct electrical stimulation on white matter pathways within the frontal lobe on hand-object manipulation. This was tested in 34 patients (15 left hemisphere, mean age 42 years, 17 male, 15 with tractography) undergoing awake neurosurgery for frontal lobe tumour removal with the aid of the brain mapping technique. The stimulation outcome was quantified based on hand-muscle activity required by task execution. The white matter pathways responsive to stimulation with an interference on muscles were identified by means of probabilistic density estimation of stimulated sites, tract-based lesion-symptom (disconnectome) analysis and diffusion tractography on the single patient level. Finally, we assessed the effect of permanent tract disconnection on motor outcome in the immediate postoperative period using a multivariate lesion-symptom mapping approach.The analysis showed that stimulation disrupted hand-muscle activity during task execution at 66 sites within the white matter below dorsal and ventral premotor regions. Two different EMG interference patterns associated with different structural architectures emerged: (i) an ‘arrest’ pattern, characterized by complete impairment of muscle activity associated with an abrupt task interruption, occurred when stimulating a white matter area below the dorsal premotor region. Local middle U-shaped fibres, superior fronto-striatal, corticospinal and dorsal fronto-parietal fibres intersected with this region. (ii) a ‘clumsy’ pattern, characterized by partial disruption of muscle activity associated with movement slowdown and/or uncoordinated finger movements, occurred when stimulating a white matter area below the ventral premotor region. Ventral fronto-parietal and inferior fronto-striatal tracts intersected with this region. Finally, only resections partially including the dorsal white matter region surrounding the supplementary motor area were associated with transient upper-limb deficit (P = 0.05; 5000 permutations).Overall, the results identify two distinct frontal white matter regions possibly mediating different aspects of hand-object interaction via distinct sets of structural connectivity. We suggest the dorsal region, associated with arrest pattern and postoperative immediate motor deficits, to be functionally proximal to motor output implementation, while the ventral region may be involved in sensorimotor integration required for task execution.

Application of direct electrical stimulation in awake craniotomy for glioma resection in the motor area

Objective To explore the effect of direct electrical stimulation in awake craniotomy for glioma resection in the motor area. Methods We conducted a retrospective analysis of clinical data of 34 patients with gliomas in the motor area who were admitted to Department of Neurosurgery, General Hospital of Southern Theatre Command from March 2015 to July 2017. The tumor was located in the left hemisphere in 16 patients and right hemisphere in 18. The gliomas were in supplementary motor area or premotor cortex in 23 cases, the central area in 9 cases, and supplementary motor area or premotor cortex invading the central area in 2 cases. All patients underwent awake craniotomy under general anesthesia. Neuronavigation and/or intraoperative ultrasound were employed to locate the lesion. Direct electrical stimulation was used for cortical and subcortical mapping of the important eloquent areas. The tumors were removed according to the functional boundary.Neural function and the degree of tumor resection were evaluated after operation. Results Of the 34 patients, 24 had a motor response after direct cortical electrical stimulation, 13 had abnormal sensations, and 10 revealed language-related cortices through mapping. For subcortical electrical stimulation, there were 24 cases of motor response, 1 case of abnormal sensation, and 8 cases of language disorders. A total of 30 cases (88.2%) of tumor removal reached functional boundaries, and subcortical electrical stimulation did not identify functional fiber in the remaining 4 (11.8%) cases which were all high-grade gliomas. Within 48 hours post surgery, the head MRI indicated total resection of tumor in 22 cases (64.7%), subtotal resection in 9 (26.5%), and partial resection in 3 (8.8%). The follow-up time of 34 patients was (23.6 ± 8.6) months (11.3-39.3)months.There were 29 cases (85.3%) which showed early postoperative neurofunctional disorders or worsening of pre-existing neurological deficits. Three cases (8.8%) developed late postoperative neurological dysfunction worse than preoperative conditions, of which 1 case was mild, 1 case was moderate and 1 case (2.9%) was severe. Of the 16 patients with preoperative neurological dysfunction or increased intracranial pressure, 13 had improved neurological function in 3 months after surgery, 2 were maintained in preoperative state and 1 had severe neurological deficits. Conclusions Functional mapping through direct electrical stimulation and continuous monitoring of the cortical and subcortical white fibers in the motor area during awake craniotomy could maximize the safe resection of glioma in the motor area, the incidence of long-term severe neurological deficits is low, and the quality of life could be improved after surgery. Key words: Glioma; Motor area; Supplementary motor area; Pyramid tract; Direct electrical stimulation

Measuring the electrophysiological effects of direct electrical stimulation after awake brain surgery

Objective. Direct electrical stimulation (DES) at 60 Hz is used to perform real-time functional mapping of the brain, and guide tumour resection during awake neurosurgery. Nonetheless, the electrophysiological effects of DES remain largely unknown, both locally and remotely. Approach. In this study, we lowered the DES frequency to 1–10 Hz and we used a differential recording mode of electro-corticographic (ECoG) signals to improve the focality with a simple algorithm to remove the artefacts due to the response of the acquisition chain. Main results. Doing so, we were able to observe different components in the evoked potentials triggered by simulating the cortex or the subcortical white matter pathways near the recording electrodes and by stimulating the cortex remotely from the recording site. More particularly, P0 and N1 components were repeatedly observed on raw ECoG signals without the need to average the data. Significance. This new methodology is important to probe the electrophysiological states and the connectivity of the brain in vivo and in real time, namely to perform electrophysiological brain mapping on human patients operated in the neurosurgical room and to better understand the electrophysiological spreading of DES.

Direct Electrical Stimulation of Premotor Areas: Different Effects on Hand Muscle Activity during Object Manipulation.

Dorsal and ventral premotor (dPM and vPM) areas are crucial in control of hand muscles during object manipulation, although their respective role in humans is still debated. In patients undergoing awake surgery for brain tumors, we studied the effect of direct electrical stimulation (DES) of the premotor cortex on the execution of a hand manipulation task (HMt). A quantitative analysis of the activity of extrinsic and intrinsic hand muscles recorded during and in absence of DES was performed. Results showed that DES applied to premotor areas significantly impaired HMt execution, affecting task-related muscle activity with specific features related to the stimulated area. Stimulation of dorsal vPM induced both a complete task arrest and clumsy task execution, characterized by general muscle suppression. Stimulation of ventrocaudal dPM evoked a complete task arrest mainly due to a dysfunctional recruitment of hand muscles engaged in task execution. These results suggest that vPM and dPM contribute differently to the control of hand muscles during object manipulation. Stimulation of both areas showed a significant impact on motor output, although the different effects suggest a stronger relationship of dPM with the corticomotoneuronal circuit promoting muscle recruitment and a role for vPM in supporting sensorimotor integration.

Direct Stimulation of Human Hippocampus During Verbal Associative Encoding Enhances Subsequent Memory Recollection.

Previous studies have reported conflicting results regarding the effect of direct electrical stimulation of the human hippocampus on memory performance. A major function of the hippocampus is to form associations between individual elements of experience. However, the effect of direct hippocampal stimulation on associative memory remains largely inconclusive, with most evidence coming from studies employing non-invasive stimulation. Here, we therefore tested the hypothesis that direct electrical stimulation of the hippocampus specifically enhances hippocampal-dependent associative memory. To test this hypothesis, we recruited surgical patients with implanted subdural electrodes to perform a word pair memory task during which the hippocampus was stimulated. Our results indicate that stimulation of the hippocampus during encoding helped to build strong associative memories and enhanced recollection in subsequent trials. Moreover, stimulation significantly increased theta power in the lateral middle temporal cortex during successful memory encoding. Overall, our findings indicate that hippocampal stimulation positively impacts performance during a word pair memory task, suggesting that successful memory encoding involves the temporal cortex, which may act together with the hippocampus.

Auras localized to the temporal lobe disrupt verbal memory and learning — Causal evidence from direct electrical stimulation of the hippocampus

Auras (focal aware seizure; FAS) are subjective ictal events with retained consciousness. Epileptiform activities can disrupt cognitive tasks, but studies are limited to seizures with impaired awareness. As a proof of concept, we examined the cognitive effects of direct electrical stimulation to the left hippocampus which induced a habitual FAS in a patient with left mesial temporal lobe epilepsy. During the induced habitual FAS, verbal memory performance declined significantly as compared to pre-stimulation testing. Tasks measuring auditory working memory and psychomotor processing speed were not affected by the stimulation. The study confirms that FAS can impair episodic verbal memory and learning.

Electrical Stimulation Modulates High γ Activity and Human Memory Performance.

Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with "poor" memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation.

A Method for Removal of Deep Brain Stimulation Artifact From Local Field Potentials.

This paper presents a signal processing method for the electrophysiology simultaneously recorded during deep brain stimulation (DBS) as a research tool. Regarding the local field potential (LFP) signals recorded during stimulation, a novel method was proposed for removal of stimulation artifacts caused by the much stronger stimulating pulse compared to typical LFP. This artifact suppression method was tested and evaluated in an in vitro situation. The results indicate that the stimulation artifacts are well suppressed by this method. Secondly, this method was tested in vivo in Parkinson's disease (PD) patients. It was used to process the LFP signals recorded intraoperatively from PD patients to preliminarily explore the quantitative dependencies of beta band synchronization variations in the subthalamic nucleus (STNs) on the applied DBS parameters, including stimulation voltage, frequency and pulse width. The results confirm that DBS therapy can suppress excessive beta frequency activity and that the degree of attenuation increases with increasing DBS voltage within a range of 1-3 V and increasing DBS frequency within a range of 60-120 Hz. The proposed artifact suppression method provides technical support for exploring the direct effect of electrical stimulation on the brain activities.

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Effect of direct electrical stimulation on decolorization and degradation of azo dye reactive brilliant red X-3B in biofilm-electrode reactors

The degradation of azo dye Reactive Brilliant Red (RBR) X-3B in biofilm-electrode reactors (BERs) with graphite rod as anode and activated carbon fiber attached to steel as cathode was studied. The electrical stimulating effect in terms of cell growth was obtained when the cultivating voltage was between 1.0 and 2.5V, and higher decolorization efficiencies and COD removal were also obtained in this condition. There was long-term effect of cultivating voltage on performance of BERs even if the electrical power was shut off. As the dye concentration was higher than 100mgL−1, the decolorization efficiency and COD removal in the BER were significantly higher than the sum of the same values in a single biological reactor and a single electrochemical reactor, which indicated that there was a synergistic effect between the electrode reaction and biodegradation. Kinetic analysis of color removal of RBR X-3B indicated that the rapid adsorption by microorganisms was weak and the decolorization process with time followed first-order kinetics. GC–MS analysis of the degradation products suggested that the main reaction mechanism of RBR X-3B degradation was the reduction of N=N bonds on the biofilm cathode.

P.1.g.020 Effect of reversal of light–dark cycle on dentate gyrus of hippocampal formation in vivo

We have previously described a population of 5-hydroxytryptamine neurons which repetitively fires bursts of usually two (but occasionally three or four) action potentials, with a short (<20 ms) interspike interval within a regular low-frequency firing pattern. Here we used a paradigm of electrical stimulation comprising twin pulses (with 7- or 10-ms inter-pulse intervals) to mimic this burst firing pattern, and compared the effects of single- and twin-pulse electrical stimulations in models of pre- and postsynaptic 5-hydroxytryptamine function. Firstly, we measured the effect of direct electrical stimulation (2 Hz for 2 min) of rat brain slices on efflux of preloaded [3H]5-hydroxytryptamine. In this in vitro model, twin-pulse stimulation increased the efflux of tritium by about twice as much as did single-pulse stimulation. This effect was evident in the medial prefrontal cortex (area under the curve: 2.59±0.34 vs 1.28±0.22% relative fractional release), as well as in the caudate–putamen (3.93±0.65 vs 2.17±0.51%) and midbrain raphe nuclei (5.42±1.05 vs 2.51±0.75%). Secondly, we used in vivo microdialysis to monitor changes in endogenous extracellular 5-hydroxytryptamine in rat medial prefrontal cortex in response to electrical stimulation (3 Hz for 10 min) of the dorsal raphe nucleus. In this model, twin-pulse stimulation of the dorsal raphe nucleus increased 5-hydroxytryptamine by approximately twice as much as did single-pulse stimulation at the same frequency (area under the curve: 50.4±9.0 vs 24.2±4.4 fmol). Finally, we used in vivo extracellular recording to follow the response of postsynaptic neurons in the rat medial prefrontal cortex to 5-hydroxytryptamine released by dorsal raphe stimulation. Electrical stimulation of the dorsal raphe nucleus (1 Hz) induced a clear-cut poststimulus inhibition in the majority of cortical neurons tested. In these experiments, the duration of poststimulus inhibition following twin-pulse stimulation was markedly longer than that induced by single-pulse stimulation (200±21 vs 77±18.5 ms).Taken together, the present in vitro and in vivo data suggest that in 5-hydroxytryptamine neurons, short bursts of action potentials will propagate along the axon to the nerve terminal and will enhance both the release of 5-hydroxytryptamine and its postsynaptic effect.

Low-intensity electrical stimulation ameliorates disruption of transverse tubules and neuromuscular junctional architecture in denervated rat skeletal muscle fibers

We determine the effects of direct electrical stimulation (ES) on the histological profiles in atrophied skeletal muscle fibers after denervation caused by nerve freezing. Direct ES was performed on the tibialis anterior (TA) muscle after denervation in 7-week-old rats divided into groups as follows: control (CON), denervation (DN), or denervation with direct ES (subdivided into a 4 mA (ES4), an 8 mA (ES8), or a 16 mA stimulus (ES16). The stimulation frequency was set at 10 Hz, and the voltage was set at 40 V (30 min/day, 6 days/week, for 3 weeks). Ultrastructural profiles of the membrane systems involved in excitation-contraction coupling, and four kinds of mRNA expression profiles were evaluated. Morphological disruptions occurred in transverse (t)-tubule networks following denervation: an apparent disruption of the transverse networks, and an increase in the longitudinal t-tubules spanning the gap between the two transverse networks, with the appearance of pentads and heptads. These membrane disruptions seemed to be ameliorated by relatively low intensity ES (4 mA and 8 mA), and the area of longitudinally oriented t-tubules and the number of pentads and heptads decreased significantly (P < 0.01) in ES4 and ES8 compared to the DN. The highest intensity (16 mA) did not improve the disruption of membrane systems. There were no significant differences in the (alpha1s)DHPR and RyR1 mRNA expression among CON, DN, and all ES groups. After 3 weeks of denervation all nerve terminals had disappeared from the neuromuscular junctions (NMJs) in the CON and ES16 groups. However, in the ES4 and ES8 groups, modified nerve terminals were seen in the NMJs. The relatively low-intensity ES ameliorates disruption of membrane system architecture in denervated skeletal muscle fibers, but that it is necessary to select the optimal stimulus intensities to preserve the structural integrity of denervated muscle fibers.

Direct Effect of Electrical Stimulation on Induction of Brain-Derived Neurotrophic Factor from Cultured Retinal Müller Cells

To investigate the direct effect of electrical stimulation (ES) on the induction of brain-derived neurotrophic factor (BDNF) from cultured retinal Müller cells. Müller cells were isolated from rat retinas. ES was applied to passage 1 Müller cells with biphasic pulses (duration, 1 ms; frequency, 20 Hz; current, 10 mA) for 30 minutes. The changes in gene expression after ES were analyzed with microarrays. The mRNA and protein levels of BDNF were determined at each time point after ES by RT-PCR and ELISA, respectively. RT-PCR was also performed at 3 hours after ES of Müller cells that had been exposed to 1 microM nifedipine, a blocker of L-type voltage-dependent calcium channels (L-VDCCs). Microarray analyses showed an upregulation of 245 genes, including BDNF. The mRNA level of BDNF increased significantly (P < 0.05; by approximately 1.2-fold over that of the control) at 2 and 3 hours after ES. The intracellular protein level was upregulated significantly (by approximately 1.4-fold) at 6 hours after ES, whereas the extracellular level did not change at any time point. The total protein level of BDNF increased significantly ( approximately 1.3-fold) at 6 hours after ES. The increase in the mRNA level of BDNF was fully suppressed by exposure of the Müller cells to nifedipine. These results demonstrate that ES directly upregulates the transcriptional induction of BDNF through L-VDCCs in cultured Müller cells. The ES of Müller cells may be used to supply endogenous BDNF to the retina.

Excitation- and beta(2)-agonist-induced activation of the Na(+)-K(+) pump in rat soleus muscle.

In rat skeletal muscle, Na(+)-K(+) pump activity increases dramatically in response to excitation (up to 20-fold) or beta(2)-agonists (2-fold), leading to a reduction in intracellular Na(+). This study examines the time course of these effects and whether they are due to an increased affinity of the Na(+)-K(+) pump for intracellular Na(+). Isolated rat soleus muscles were incubated at 30 (o)C in Krebs-Ringer bicarbonate buffer. The effects of direct electrical stimulation on (86)Rb(+) uptake rate and intracellular Na(+) concentration ([Na(+)](i)) were characterized in the subsequent recovery phase. [Na(+)](i) was varied using monensin or buffers with low Na(+). In the [Na(+)](i) range 21-69 mM, both the beta(2)-agonist salbutamol and electrical stimulation produced a left shift of the curves relating (86)Rb(+) uptake rate to [Na(+)](i). In the first 10 s after 1 or 10 s pulse trains of 60 Hz, [Na(+)](i) showed no increase, but (86)Rb(+) uptake rate increased by 22 and 86 %, respectively. Muscles excited in Na(+)-free Li(+)-substituted buffer and subsequently allowed to rest in standard buffer also showed a significant increase in (86)Rb(+) uptake rate and decrease in [Na(+)](i). Na(+) loading induced by monensin or electroporation also stimulated (86)Rb(+) uptake rate but, contrary to excitation, increased [Na(+)](i). The increase in the rate of (86)Rb(+) uptake elicited by electrical stimulation was abolished by ouabain, but not by bumetanide. The results indicate that excitation (like salbutamol) induces a rapid increase in the affinity of the Na(+)-K(+) pump for intracellular Na(+). This leads to a Na(+)-K(+) pump activation that does not require Na(+) influx, but possibly the generation of action potentials. This improves restoration of the Na(+)-K(+) homeostasis during work and optimizes excitability and contractile performance of the working muscle.

Tactile Discrimination Task Not Disturbed by Thalamic Stimulation

The major pathway of human somatosensation passes through the ventrocaudal nucleus (Vc) of the thalamus. We tested the effect of direct electrical stimulation of the Vc on tactile discrimination in 5 Parkinson patients undergoing stereotactic thalamotomy. Raised gratings with lines 3, 4, or 6 mm apart were used. Patients had to actively touch test patterns placed in the hand contralateral to the thalamus under operation and compare it with a reference 3-mm grating held continuously in their other hand. Their performance was best for 6-mm, followed by 3-mm and then by 4-mm patterns regardless of electrical stimulation. Under Vc stimulation, patients recognized the 4-mm gratings slightly better. This can be explained either by the nature of thalamocortical interaction, which makes it resistant to external noise, or by the involvement of other pathways that circumvent the effect of thalamic stimulation.

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons

We have previously described a population of 5-hydroxytryptamine neurons which repetitively fires bursts of usually two (but occasionally three or four) action potentials, with a short (<20 ms) interspike interval within a regular low-frequency firing pattern. Here we used a paradigm of electrical stimulation comprising twin pulses (with 7- or 10-ms inter-pulse intervals) to mimic this burst firing pattern, and compared the effects of single- and twin-pulse electrical stimulations in models of pre- and postsynaptic 5-hydroxytryptamine function. Firstly, we measured the effect of direct electrical stimulation (2 Hz for 2 min) of rat brain slices on efflux of preloaded [ 3H]5-hydroxytryptamine. In this in vitro model, twin-pulse stimulation increased the efflux of tritium by about twice as much as did single-pulse stimulation. This effect was evident in the medial prefrontal cortex (area under the curve: 2.59±0.34 vs 1.28±0.22% relative fractional release), as well as in the caudate–putamen (3.93±0.65 vs 2.17±0.51%) and midbrain raphe nuclei (5.42±1.05 vs 2.51±0.75%). Secondly, we used in vivo microdialysis to monitor changes in endogenous extracellular 5-hydroxytryptamine in rat medial prefrontal cortex in response to electrical stimulation (3 Hz for 10 min) of the dorsal raphe nucleus. In this model, twin-pulse stimulation of the dorsal raphe nucleus increased 5-hydroxytryptamine by approximately twice as much as did single-pulse stimulation at the same frequency (area under the curve: 50.4±9.0 vs 24.2±4.4 fmol). Finally, we used in vivo extracellular recording to follow the response of postsynaptic neurons in the rat medial prefrontal cortex to 5-hydroxytryptamine released by dorsal raphe stimulation. Electrical stimulation of the dorsal raphe nucleus (1 Hz) induced a clear-cut poststimulus inhibition in the majority of cortical neurons tested. In these experiments, the duration of poststimulus inhibition following twin-pulse stimulation was markedly longer than that induced by single-pulse stimulation (200±21 vs 77±18.5 ms). Taken together, the present in vitro and in vivo data suggest that in 5-hydroxytryptamine neurons, short bursts of action potentials will propagate along the axon to the nerve terminal and will enhance both the release of 5-hydroxytryptamine and its postsynaptic effect.

The effect of electrical stimulation on colonic transit following spinal cord injury in cats.

The effect of direct electrical stimulation on colinic transit and manometric recordings following spinal cord injury were assessed in five adult male cats. Intra-colonic catheters were surgically placed, stimulating electrodes were sutured to the colonic serosa and a laminectomy with spinal cord clamping at a T4 level was done to induce spinal cord injury (SCI). Twenty radiopaque markers were inserted through an intra-colonic catheter located 1 cm distal to the cecum and were monitored with daily fluoroscopy as a measure of colonic transit. Transit measurements were compared before SCI, after SCI and after SCI with electrical stimulation of 40 pps, 1 ms, and 0-50 mA. Colonic transit following SCI was significantly prolonged (P<0.05) when compared to the transit before SCI. Electrical stimulation following SCI improved colonic transit to values not significantly different from those before SCI. Spontaneous colonic phasic motor activity was similar both before and after SCI. Manometric defection patterns were also observed to be similar before SCI and after SCI with electrical stimulation. Based on our scoring criteria, the most frequent response to electrical stimulation was an abdominal contraction. These findings demonstrate that colonic transit is prolonged following SCI and that direct electrical stimulation of the colon following SCI improves colonic transit in an animal model.