Sacral nerve stimulation increases gastric accommodation in rats: a spinal afferent and vagal efferent pathway.

Impaired gastric accommodation (GA) has been frequently reported in various gastrointestinal diseases. No standard treatment strategy is available for treating impaired GA. We explored the possible effect of sacral nerve stimulation (SNS) on GA and discovered a spinal afferent and vagal efferent mechanism in rats. Sprague-Dawley rats (450-500 g) with a chronically implanted gastric cannula and ECG electrodes were studied in a series of sessions to study: 1) the effects of SNS with different parameters on gastric tone, compliance, and accommodation using a barostat device; two sets of parameters were tested as follows: parameter 1) 5 Hz, 500 µs, 10 s on 90 s off; 90% motor threshold and parameter 2) same as parameter 1 but 25 Hz; 2) the involvement of spinal afferent pathway via detecting c-fos immunoreactive (IR) cells in the nucleus of the solitary tract (NTS) of the brain; 3) the involvement of vagal efferent activity via the spectral analysis of heart rate variability derived from the ECG; and 4) the nitrergic mechanism, Nω-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor, was given before SNS at 5 Hz. Compared with sham-SNS: 1) SNS at 5 Hz inhibited gastric tone and increased gastric compliance and GA. No difference was noted between the stimulation frequencies of 5 and 25 Hz. 2) SNS increased the expression of c-fos in the NTS. 3) SNS increased cardiac vagal efferent activity and decreased the sympathovagal ratio. 4) l-NAME blocked the relaxation effect of SNS. In conclusion, SNS with certain parameters relaxes gastric fundus and improves gastric accommodation mediated via a spinal afferent and vagal efferent pathway.NEW & NOTEWORTHY Currently, there is no adequate medical therapy for impaired gastric accommodation, since medications that relax the fundus often impair antral peristalsis and thus further delay gastric emptying that is commonly seen in patients with functional dyspepsia or gastroparesis. The advantage of the potential sacral nerve stimulation therapy is that it improves gastric accommodation by enhancing vagal activity, and the enhanced vagal activity would lead to enhanced antral peristalsis rather than inhibiting it.

Effects of electroacupuncture on stress-induced gastric dysrhythmia and mechanisms involving autonomic and central nervous systems in functional dyspepsia.

Electroacupuncture (EA) is widely used as an effective method to treat stress-related disorders. However, its mechanisms remain largely unknown. The aim of this study was to investigate the effects and mechanisms of EA on gastric slow wave (GSW) dysrhythmia and c-Fos expression in the nucleus of the solitary tract (NTS) induced by stress in a rodent model of functional dyspepsia (FD). Rats in the neonatal stage were treated using intragastric iodoacetamide. Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of GSW and electrodes into accupoints ST36 for EA. Autonomic functions were assessed by spectral analysis of heart rate variability. Rats were placed for 30 min in a cylindrical plastic tube for acute restraint stress. The involvement of a central afferent pathway was assessed by measuring c-Fos-immunoreactive cells in the NTS. 1) EA normalized restraint stress-induced impairment of GSW in FD rats. 2) EA significantly increased vagal activity (P = 0.002) and improved sympathovagal balance (P = 0.004) under stress in FD rats. 3) In FD rats under restraint stress, plasma norepinephrine concentration was increased substantially (P < 0.01), which was suppressed with EA. 4) The EA group showed increased c-Fos-positive cell counts in the NTS compared with the sham EA group (P < 0.05) in FD rats. Acute restraint stress induces gastric dysrhythmia in a rodent model of FD. EA at ST36 improves GSW under stress in FD rats mediated via the central and autonomic pathways, involving the NTS and vagal efferent pathway.

Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms.

Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited, and mechanisms are largely unknown. We investigated the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then, a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic functions were assessed by spectral analysis of heart rate variability (HRV) derived from an electrocardiogram. Serum levels of pancreatic polypeptide (PP), norepinephrine (NE), and acetylcholine (ACh) in colon were assessed. 1) Acute SNS at 5 Hz, 100 µs was found effective in enhancing rectal compliance and accelerating distal colon transit (P < 0.05 vs. sham SNS). 2) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight, and water content of fecal pellets, and accelerated the distal colon transit (29.4 ± 3.7 min with sham SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 3) SNS significantly increased vagal activity (P = 0.035) and decreased sympathetic activity (P = 0.012), assessed by spectral analysis of HRV as well as by the serum PP. 4) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. We concluded that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function.NEW & NOTEWORTHY Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, effects are limited, and mechanisms are largely unknown. This paper shows that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility mediated via the autonomic-cholinergic function.

Dependence of c-fos Expression on Amplitude of High-Frequency Spinal Cord Stimulation in a Rodent Model.

OBJECTIVES: Clinical high-frequency spinal cord stimulation (hfSCS) (>250 Hz) applied at subperception amplitudes reduces leg and low back pain. This study investigates, via labeling for c-fos-a marker of neural activation, whether 500 Hz hfSCS applied at amplitudes above and below the dorsal column (DC) compound action potential (CAP) threshold excites dorsal horn neurons. MATERIALS AND METHODS: DC CAP thresholds in rats were determined by applying single biphasic pulses of SCS to T12 -T13 segments using pulse widths of 40 or 200 µsec via a ball electrode placed over the left DC and increasing amplitude until a short latency CAP was observed on the L5 DC and sciatic nerve. The result of this comparison allowed us to substitute sciatic nerve CAP for DC CAP. SCS at T12 -T13 was applied continuously for two hours using: sham or hfSCS at 500 Hz SCS, 40 µsec pulse width, and 50, 70, 90, or 140% CAP threshold. Spinal cord slices from T11 -L1 were immunolabeled for c-fos, and the number of c-fos-positive cells was quantified. RESULTS: 500 Hz hfSCS applied at 90 and 140% CAP threshold produced substantial (≥6 c-fos + neurons on average per slice per segment) c-fos expression in more segments between T11 and L1 than did sham stimulation (p < 0.025, 90% CAP; p < 0.001, 140% CAP, Fisher's Exact Tests) and resulted in more c-fos-positive neurons on average per slice per segment ipsilateral to than contralateral to the SCS electrode at 70, 90, and 140% CAP threshold (p < 0.01, Wilcoxon Signed Rank Tests). CONCLUSIONS: The finding of enhanced c-fos expression in the ipsilateral superficial dorsal horn provides evidence for activation/modulation of neuronal circuitry associated with subperception hfSCS.

Spinal Cord Stimulation With "Conventional Clinical" and Higher Frequencies on Activity and Responses of Spinal Neurons to Noxious Stimuli: An Animal Study.

OBJECTIVES: Spinal cord stimulation (SCS) at both conventional and higher frequencies may effectively reduce pain, but optimal parameters need to be established. This study investigated how SCS at different frequencies and pulse widths acutely modulates nociceptive activity of wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons in rats at a stimulus amplitude that influences both local circuits and dorsal column fibers. MATERIALS AND METHODS: L2 -L3 and L6 -S2 spinal segments were exposed for SCS and spinal neuronal recordings, respectively. Responses to pinch of a hindpaw were recorded before and after SCS (40 or 200 µsec pulse width at 50, 500, 1 kHz and 10 kHz, amplitude: 90% of motor threshold) for 5 or 20 min. Pinch responses were tested within 30 s after SCS ceased (first pinch) and at ∼4 min intervals until response recovery. RESULTS: 1) SCS for 5 min suppressed averaged first pinch responses, except for 40 µsec/50 Hz. 2) Only SCS with 40 µs/1 kHz suppressed more spinal neurons than 200 µsec/50 Hz. 3) All SCS parameters at 5 min increased pinch responses for a small population of cells, with the incidence being greater for WDR than for HT neurons. 4) SCS at 1 kHz (40 or 200 µsec) for 20 min reduced the response to the second pinch as compared with baseline responses. In addition, no neurons exhibited increased pinch responses. CONCLUSIONS: Compared with a typical low frequency SCS (200 µs/50 Hz) or high-frequency SCS at 10 kHz, at an amplitude designed to influence both local spinal circuits and dorsal column fiber tracts, 1 kHz SCS suppressed nociceptive responses of more spinal neurons and/or demonstrated longer persisting suppressive effects. SCS at 1 kHz surpassed both low-frequency (50 Hz) and high-frequency (10 kHz) SCS application in this normal animal model.

Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis.

The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1ß, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that 1) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS (P < 0.001); 2) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS (P < 0.001) and 1.29 ± 0.18 with VNS + EA (P < 0.001); 3) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS (P < 0.001) and 1.36 ± 0.20 with VNS + EA (P < 0.001); 4) the plasma levels of TNFα, IL-1ß, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and 5) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA (P < 0.001, P < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS.NEW & NOTEWORTHY This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in rats. The proposed chronic VNS + EA, VNS, and EA were shown to decrease DAI and ameliorate macroscopic and microscopic damages in rats with TNBS-induced colitis via the autonomic pathway. The addition of EA to VNS provided a significant effect on the behavioral assessment of inflammation (DAI, CMDI, and histological score) but not on cytokines or mechanistic measurements, suggesting an overall systemic effect of EA.View this article's corresponding video summary at https://youtu.be/-rEz6HMkErM.

Conventional and Novel Spinal Stimulation Algorithms: Hypothetical Mechanisms of Action and Comments on Outcomes.

OBJECTIVE: Spinal cord stimulation (SCS) emerged as a direct clinical spin-off from the Gate Control Theory from 1965. Over the last decade, several new modes of SCS have appeared. This review discusses these novel techniques and their hypothetical mechanisms of action. MATERIAL AND METHODS: A recent literature search on SCS coupled with the most recent data from poster presentations and congress lectures have been used to illustrate new hypothetical ways of modulating pain. RESULTS: Several physiological and neurochemical mechanisms for conventional paresthetic SCS have been described in detail. However, much less is known about the novel SCS modes of action. One new algorithm utilizes very high frequencies (up to 10 kHz) intended for direct stimulation of dorsal horns at the T9-T10 level to treat both low back pain and leg pain. Another technique uses bursts of impulses with a high internal frequency delivered to the dorsal spinal cord with a frequency of 40 Hz. Both of these therapies intend to be subparesthetic and effective both for neuropathic and nociceptive pain components. During the last few years, more moderate changes in SCS parameters have been tried in order to increase the amount of electric charge passed from the lead to the neural tissue. This strategy, called "high density SCS," utilizes frequencies up to 1200 Hz or long pulse widths. CONCLUSIONS: The present SCS therapies have developed beyond the Gate Control Concept. New hypotheses about mechanisms of action are presented and some improved results are discussed.

Inhibitory Effects and Mechanisms of Electroacupuncture via Chronically Implanted Electrodes on Stress-Induced Gastric Hypersensitivity in Rats With Neonatal Treatment of Iodoacetamide.

BACKGROUND: Stress is considered an independent factor causing and aggravating gastrointestinal symptoms, including visceral pain. The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on stress-induced gastric hypersensitivity in rats treated with neonatal iodoacetamide mimicking human functional dyspepsia (FD). METHODS: Neonatal rats were treated with gavage of 0.2 mL of 0.1% iodoacetamide in 2% sucrose daily for six days starting on tenth day after birth. The control group was given 0.2 mL of 2% sucrose. When the rats were eight weeks old, acute restraint stress was performed on them for 90 min. EA at ST36 (ZuSanLi) was performed during the acute stress or 30 min after the stress. Adrenoceptor blocking drugs (propranolol and phentolamine) were injected intraperitoneally 30 min before acute restraint stress to explore possible sympathetic mechanisms. Visceral-motor responses to gastric distention were assessed by electromyogram (EMG). RESULTS: 1) Stress-induced gastric hypersensitivity was significantly more severe in the FD rats, compared to the control rats. It was blocked by the adrenoceptor antagonists. 2) EA inhibited stress-induced gastric hypersensitivity; the preventive effect of EA (given during stress) was more remarkable than the curative effect (given after stress). Stress resulted in a higher sympathovagal ratio and this was suppressed by EA. CONCLUSIONS: Rats treated with neonatal iodoacetamide mimicking FD are more vulnerable to stress. Stress-induced gastric hypersensitivity can be prevented or suppressed by EA at ST36 via the restoration of sympathovagal balance.

Electrical neuromodulation at acupoint ST36 normalizes impaired colonic motility induced by rectal distension in dogs.

Electroacupuncture (EA) has been shown to improve impaired gastric motility and slow waves in both humans and animals. However, its effects on colonic motility have rarely been investigated. The aim of this study was to investigate the effects and underlying mechanisms of EA on impaired colonic motility induced by rectal distension (RD)in dogs. Colon contractions and transit were measured in various sessions with and without EA in hound dogs chronically placed with a colonic cannula. Colonic contractile activity was assessed by motility index (MI). Autonomic functions were determined by the spectral analysis of the heart rate variability derived from the electrocardiogram. It was found 1) RD suppressed colonic motility by 40.5% (10.8 ± 0.9 with RD vs. 6.4 ± 0.8 at baseline, P < 0.002). EA at ST36 normalized colonic contractions suppressed by RD (12.9 ± 2.8, P < 0.002 vs. RD and P = 0.1 vs. control). 2) Administration of atropine blocked the ameliorating effect of EA on colon motility. 3) RD also delayed colonic transit (65.0 ± 2.0% with RD vs. 86.0 ± 1.9% without RD, P < 0.001) that was restored with EA (84.0 ± 1.9%, P = 0.178 vs. control). 4) EA increased vagal activity suppressed by RD (0.37 ± 0.07 with RD + EA vs. 0.09 ± 0.03 with RD without EA, P < 0.001). In conclusion, RD inhibits colonic contractions and delays colonic transit in dogs; EA at ST36 restores the RD-induced impairment in both colonic contraction and transit by enhancing vagal activity and mediated via the cholinergic pathway.

Comparison of burst and tonic spinal cord stimulation on spinal neural processing in an animal model.

OBJECTIVES: Spinal cord stimulation (SCS) using bursts of pulses suppressed neuropathic pain as well or better than tonic stimulation and limited the incidences of parasthesias. The present translational study explored possible differences in mechanisms of burst and tonic SCS on nociceptive spinal networks and/or the gracile nucleus supraspinal relay. MATERIALS AND METHODS: Visceromotor reflexes (VMRs, a nociceptive response) or extracellular activity of either L6-S2 spinal neurons or gracile nucleus neurons were recorded during noxious somatic stimulation (pinching) and visceral stimulation (colorectal distension [CRD]) in anesthetized rats. A stimulating (unipolar, ball) electrode at L2-L3 delivered 40 Hz burst or tonic SCS at different intensities relative to motor threshold (MT). RESULTS: Average MTs for burst SCS were significantly lower than for tonic SCS. Burst SCS reduced the VMR more than tonic SCS. After high-intensity SCS (90% MT), spinal neuronal responses to CRD and pinch were reduced similarly for burst and tonic SCS. At low-intensity SCS (60% MT), only burst SCS significantly decreased the nociceptive somatic response. Tonic but not burst SCS significantly increased spontaneous activity of neurons in the gracile nucleus. CONCLUSION: Based on the clinically relevant burst versus tonic parameters used in this study, burst SCS is more efficacious than tonic SCS in attenuating visceral nociception. Burst and tonic SCS also suppress lumbosacral neuronal responses to noxious somatic and visceral stimuli; however, burst SCS has a greater inhibitory effect on the neuronal response to noxious somatic stimuli than to noxious visceral stimuli. Reduced or abolished paresthesia in patients may be due in part to burst SCS not increasing spontaneous activity of neurons in the gracile nucleus.

The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states. Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need to provide an expert consensus that defines the appropriate use of neuromodulation technologies for appropriate patients. The Neuromodulation Appropriateness Consensus Committee (NACC) was formed to give guidance to current practice and insight into future developments. METHODS: The INS executive board selected members of the international scientific community to analyze scientific evidence for current and future innovations and to use clinical experience to fill in any gaps in information. The NACC used PubMed and Google Scholar to obtain current evidence in the field and used clinical and research experience to give a more complete picture of the innovations in the field. RESULTS: The NACC has determined that currently approved neurostimulation techniques and technologies have expanded our ability to treat patients in a more effective and specific fashion. Despite these advances, the NACC has identified several additional promising technologies and potential applications for neurostimulation that could move this field forward and expand the applicability of neuromodulation. CONCLUSIONS: The NACC concludes that the field of neurostimulation is an evolving and rapidly changing one that will lead to improved patient access, safety, and outcomes.

The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain. Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need for guidance regarding safety and risk reduction for implantable neurostimulation devices. The INS convened an international committee of experts in the field to explore the evidence and clinical experience regarding safety, risks, and steps to risk reduction to improve outcomes. METHODS: The Neuromodulation Appropriateness Consensus Committee (NACC) reviewed the world literature in English by searching MEDLINE, PubMed, and Google Scholar to evaluate the evidence for ways to reduce risks of neurostimulation therapies. This evidence, obtained from the relevant literature, and clinical experience obtained from the convened consensus panel were used to make final recommendations on improving safety and reducing risks. RESULTS: The NACC determined that the ability to reduce risk associated with the use of neurostimulation devices is a valuable goal and possible with best practice. The NACC has recommended several practice modifications that will lead to improved care. The NACC also sets out the minimum training standards necessary to become an implanting physician. CONCLUSIONS: The NACC has identified the possibility of improving patient care and safety through practice modification. We recommend that all implanting physicians review this guidance and consider adapting their practice accordingly.

Skin blood flow response to locally applied mechanical and thermal stresses in the diabetic foot.

Diabetic foot ulcers are one of the most common complications in diabetics, causing significant disabilities and decreasing the quality of life. Impaired microvascular reactivity contributes to the development of diabetic foot ulcers. However, underlying physiological mechanisms responsible for the impaired microvascular reactivity in response to extrinsic causative factors of foot ulcers such as mechanical and thermal stresses have not been well investigated. A total of 26 participants were recruited into this study, including 18 type 2 diabetics with peripheral neuropathy and 8 healthy controls. Laser Doppler flowmetry was used to measure skin blood flow at the first metatarsal head in response to a mechanical stress at 300mmHg and a fast thermal stress at 42°C. Wavelet analysis of skin blood flow oscillations was used to assess metabolic, neurogenic and myogenic controls. Our results indicated that diabetics have significantly decreased metabolic, neurogenic and myogenic responses to thermal stress, especially in the neurogenic and myogenic controls during the first vasodilatory response and in the metabolic control during the second vasodilatory response. Diabetics have a significantly decreased myogenic response to mechanical stress during reactive hyperemia. Our findings demonstrate that locally applied mechanical and thermal stresses can be used to assess microvascular reactivity and risk of diabetic foot ulcers.

Spinal neuromodulation mitigates myocardial ischemia-induced sympathoexcitation by suppressing the intermediolateral nucleus hyperactivity and spinal neural synchrony.

Introduction: Myocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known. Methods: In this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS. Results: ARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS. Discussion: These results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

Is constant current or constant voltage spinal cord stimulation superior for the suppression of nociceptive visceral and somatic stimuli? A rat model.

OBJECTIVES: This study compares the effects of constant current (CC) and constant voltage (CV) spinal cord stimulation (SCS) at various frequencies and intensities on standard nociceptive measurements in rats, the visceromotor reflex (VMR) and neuronal activity, during noxious visceral and somatic stimuli. MATERIALS AND METHODS: Abdominal muscle electromyographic activity changes were measured to indicate VMR, and extracellular activity of L6-S2 spinal neurons was recorded during somatic (pinching) and noxious visceral stimulation (colorectal distension [CRD], 60 mmHg) in anesthetized rats. A stimulating (unipolar ball) electrode at L2-L3 delivered CC- or CV-SCS at varied frequencies and intensities. RESULTS: CC-SCS reduced VMR evoked by CRD significantly more than CV-SCS (p < 0.05). For neuronal activity, high-frequency CC-SCS (40 and 100 Hz) and CV-SCS (100 Hz) effectively reduced intraspinal somatic nociceptive transmission more than low-frequency SCS (2 Hz). No significant differences were observed between the effects of CC- and CV-SCS on spontaneous activity and nociceptive responses of spinal neurons to noxious CRD following short- (five to ten minutes) or long-term (20-30 min) SCS. CONCLUSIONS: Although high-frequency CC- and CV-SCS may be more useful for the management of somatic pain, CC-SCS may be more effective for treating complex pain systems like visceral hypersensitivity.

Cross-organ sensitization of thoracic spinal neurons receiving noxious cardiac input in rats with gastroesophageal reflux.

Gastroesophageal reflux (GER) frequently triggers or worsens cardiac pain or symptoms in patients with coronary heart disease. This study aimed to determine whether GER enhances the activity of upper thoracic spinal neurons receiving noxious cardiac input. Gastric fundus and pyloric ligations as well as a longitudinal myelotomy at the gastroesophageal junction induced acute GER in pentobarbital-anesthetized, paralyzed, and ventilated male Sprague-Dawley rats. Manual manipulations of the stomach and lower esophagus were used as surgical controls in another group. At 4-9 h after GER surgery, extracellular potentials of single neurons were recorded from the T3 spinal segment. Intrapericardial bradykinin (IB) (10 microg/ml, 0.2 ml, 1 min) injections were used to activate cardiac nociceptors, and esophageal distensions were used to activate esophageal afferent fibers. Significantly more spinal neurons in the GER group responded to IB compared with the control group (69.1 vs. 38%, P < 0.01). The proportion of IB-responsive neurons in the superficial laminae of GER animals was significantly different from those in deeper layers (1/8 vs. 46/60, P < 0.01); no difference was found in control animals (7/25 vs. 20/46, P > 0.05). Excitatory responses of spinal neurons to IB in the GER group were greater than in the control group [32.4 +/- 3.5 impulses (imp)/s vs. 13.3 +/- 2.3 imp/s, P < 0.01]. Forty-five of 47 (95.7%) neurons responded to cardiac input and ED, which was higher than the control group (61.5%, P < 0.01). These results indicate that acute GER enhanced the excitatory responses of thoracic spinal neurons in deeper laminae of the dorsal horn to noxious cardiac stimulus.

Effect of wheelchair tilt-in-space and recline angles on skin perfusion over the ischial tuberosity in people with spinal cord injury.

OBJECTIVE: To investigate the efficacy of wheelchair tilt-in-space and recline on enhancing skin perfusion over the ischial tuberosity in wheelchair users with spinal cord injury (SCI). DESIGN: Repeated-measures, intervention, and outcomes-measure design. SETTING: A university research laboratory. PARTICIPANTS: Wheelchair users with SCI (N=11; 9 men, 2 women; mean ± SD age, 37.7±14.2y; body mass index, 24.7±2.6kg/m(2); duration of injury, 8.1±7.5y). INTERVENTIONS: Protocols (N=6) of various wheelchair tilt-in-space and recline angles were randomly assigned to participants. Each protocol consisted of a 5-minute sitting-induced ischemic period and a 5-minute wheelchair tilt-in-space and recline pressure-relieving period. Participants sat in a position without tilt or recline for 5 minutes and then sat in 1 of 6 wheelchair tilted and reclined positions, including (1) 15° tilt-in-space and 100° recline, (2) 25° tilt-in-space and 100° recline, (3) 35° tilt-in-space and 100° recline, (4) 15° tilt-in-space and 120° recline, (5) 25° tilt-in-space and 120° recline, and (6) 35° tilt-in-space and 120° recline. A 5-minute washout period (at 35° tilt-in-space and 120° recline) was allowed between protocols. MAIN OUTCOME MEASURES: Laser Doppler flowmetry was used to measure skin perfusion over the ischial tuberosity in response to changes in body positions caused by performing wheelchair tilt-in-space and recline. Skin perfusion response to wheelchair tilt-in-space and recline was normalized to skin perfusion of the upright seated position (no tilt/recline). RESULTS: Combined with 100° recline, wheelchair tilt-in-space at 35° resulted in a significant increase in skin perfusion compared with the upright seated position (no tilt/recline; P<.05), whereas there was no significant increase in skin perfusion at 15° and 25° tilt-in-space (not significant). Combined with 120° recline, wheelchair tilt-in-space at 15°, 25°, and 35° showed a significant increase in skin perfusion compared with the upright seated position (P<.05). CONCLUSIONS: Our results indicate that wheelchair tilt-in-space should be at least 35° for enhancing skin perfusion over the ischial tuberosity when combined with recline at 100° and should be at least 25° when combined with recline at 120°. Although smaller angles of wheelchair tilt-in-space and recline are preferred by wheelchair users for functional purposes, wheelchair tilt-in-space less than 25° and recline less than 100° may not be sufficient for effective pressure reduction for enhancing skin perfusion over the ischial tuberosity in people with SCI.

Somatic afferent modulation of thoracic (T9-T10) spinal neurons receiving gastric mechanical input in rats.

OBJECTIVES: The aim was to determine whether somatic afferent fiber stimulation influences thoracic spinal neuronal activity responding to gastric distensions. MATERIALS AND METHODS: Extracellular potentials of single T9-T10 spinal neurons were recorded in anesthetized male rats. Ipsilateral median and peroneal nerve afferent stimulation (MNAS, PNAS) was delivered by electrodes. Inflation of a latex balloon was used to produce gastric distension. RESULTS: MNAS and PNAS (1.5 mA, 50 Hz, 10 sec) altered activity of 63% and 66% of the spinal neurons excited or inhibited by gastric distension, respectively. MNAS more frequently reduced spinal neuronal activity with excitatory responses to gastric distension than did PNAS (p < 0.05). PNAS more likely increased neuronal activity with low-threshold excitatory responses to gastric distension than MNAS (p < 0.05). CONCLUSIONS: Peripheral somatic afferent information utilizes central pathways to modulate gastric afferent processing in T9-T10 spinal neurons. Thus, somatic afferent stimulation might be used to treat gastric pain and/or hypersensitivity.

Mineralocorticoid and glucocorticoid receptors in the amygdala regulate distinct responses to colorectal distension.

Previously we found that exposure of the amygdala to elevated levels of corticosterone (CORT) induces anxiety-like behavior coupled to colonic hypersensitivity to distension, however, the specific corticoid receptor mediating the CORT responses remains controversial. In this study we investigated, through the use of selective antagonists, the relative role of amygdaloid mineralocorticoid (MR) versus glucocorticoid receptors (GR) in CORT-mediated spinal and cardiovascular pseudoaffective reflex responses to colorectal distension (CRD). Micropellets containing, CORT and a selective MR antagonist (spironolactone) or GR antagonist (mifepristone) were implanted stereotaxically onto the dorsal margin of the amygdala in rats. On day 7 post-implantation in response to graded CRD we measured: (i) changes in the electrical activity of dorsal horn neurons in the L6-S1 spinal cord and (ii) the cardiovascular depressor responses. Exposure of the amygdala to CORT-releasing micropellets increased the proportion of spinal neurons showing high-threshold and/or long-lasting responses and potentiated the magnitude of excitation. Elevated levels of amygdala CORT also increased the magnitude of the cardiovascular depressor response to CRD. MR but not GR antagonism prevented the increase in spinal cord neuronal excitation, whereas either the MR or GR antagonist decreased the magnitude of the depressor cardiovascular response to CRD. We conclude that MR in the amygdala trigger descending pathways facilitating viscero-nociceptive processing in the spinal cord, whereas MR and GR have a non-redundant role in CORT-induced potentiation of the autonomic pseudoaffective responses to colorectal stimuli.