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Identification of pain processing systems by electrical stimulation of the brain.

Much can be learned about the brain's function in pain processing through electrical stimulation. The spinothalamic tract which is conceived to be the chief pathway for nociceptive pain and whose interruption induces dissociated sensory loss can be recognized from the anterolateral columns of the spinal cord to the posterior thalamus by the induction of feelings of chiefly contralateral, somatotopographically organized, warm, cool, or cold sensations, less often burning and rarely pain. The spinoreticulothalamic tract, whose function in normal pain processing is controversial and whose interruption produces no clinically detectable sensory loss, is normally silent to stimulation. However, in patients with deafferentation pain, it appears to become sensitive to electrical stimulation, both in the anterolateral columns and in midbrain and medial thalamus, giving rise to chiefly contralateral, non-somatotopographically organized, burning or painful sensations which often reproduce fairly accurately the patient's pain. This phenomenon, which does not appear to occur in patients with nociceptive pain, may reflect denervation neuronal hypersensitivity which is a possible pathophysiological mechanism explaining deafferentation pain. The dorsal column/lemniscal system can be recognized by electrical stimulation from the spinal cord to the somatosensory cortex by the induction of paraesthesiae. Its chronic stimulation at the level of the dorsal column, the ventrocaudal nucleus or the internal capsule appears capable of suppressing deafferentation pain. The arc of neuronal tissue extending from the septal area through hypothalamus and periventricular grey to the periaqueductal grey, which acts as a receptor area for opiates and endorphins, thereby exerting an inhibitory effect on access to the spinothalamic tract, can also be exploited through chronic stimulation for the control of pain. Stimulation of the periventricular area gives rise to feelings of warmth, comfort and relaxation, of the hypothalamus, horror and autonomic effects while that of the periaqueductal grey induces discomfort, distress, anxiety and weeping, and of the septal area flushing, paraesthesiae, nausea, nystagmus and a feeling of warmth. Thus four brain systems involved in pain signalling can be recognized by electrical stimulation, one which conveys nociceptive pain to consciousness, another that suppresses it, one that may undergo denervation neuronal hypersensitivity and bring deafferentation pain into consciousness, possibly by establishing novel connectivity and one that is presumably capable of suppressing that hyperactivity.

Afferent Pathways↗

Electrical stimulation prolongs the survival days of leukemic mice treated with methotrexate.

To investigate effects of electrical stimulation on survival days of leukemic mice treated with methotrexate (MTX), L1210-bearing mice were treated by MTX and calcium folinate (leucovorin) rescue therapy (MTX: 400 mg/kg, followed by leucovorin at the dose of 7.5 mg/kg at 8, 15 and 24 hr after MTX) under electrical stimulation (foot shock: shock amplitude, 0.4 mA; voltage, 60-100 V/cm; shock duration, 5 sec; frequency, 0.5 Hz) of various lengths. The survival days were significantly prolonged by 6-hr electrical stimulation in combination with MTX, while plasma MTX concentrations and pharmacokinetic parameters such as the area under the curve (AUC-12 hr) and clearance (CL) were not significantly altered. Psychological stress did not alter the efficacy of MTX in the communication box paradigm. Amplified efficacy of MTX was shown in a length-dependent manner when electrical stimulation of various lengths were applied to L1210-bearing mice.

Animals↗

Sex differences in the responses of spinal wide-dynamic range neurons to subcutaneous formalin and in the effects of different frequencies of conditioning electrical stimulation.

The purpose of this study was to investigate sex-related differences in nociception elicited by s.c. injection of different concentrations (1-5%) of formalin. S.c. formalin-induced biphasic (early and late phases) persistent nociception was assessed by extracellularly recording the spontaneous activities of single spinal dorsal horn wide-dynamic range neurons in anesthetized male and female rats. The nociceptive responses of the dorsal horn wide-dynamic range neurons following s.c. injection of 5%, but not 1% and 2.5%, formalin in female rats were significantly stronger than the responses obtained in male rats. However, these concentration-dependent differences with respect to different sexes existed only in the late, but not the early, phase of formalin-induced nociception in intact, not spinal rats. The 5% formalin-induced late phase nociception in male rats was significantly depressed by 15 min of repeated conditioning electrical stimulation at a frequency of 5 Hz as well as 50 Hz during and after the period of conditioning electrical stimulation (intensity: 1 mA; pulse duration: 1 ms). In contrast, the inhibitory effect of 50 Hz conditioning electrical stimulation on the 5% formalin-elicited late phase response in female rats was markedly greater in magnitude and longer in duration than that of 5 Hz conditioning electrical stimulation. No significant depressive effects of 5 Hz conditioning electrical stimulation on formalin-induced nociception were found in female rats, indicating that the distinct effects of conditioning electrical stimulation at different frequencies are different in animals of opposite sexes. In conclusion, s.c. administration of different concentrations of formalin shows a distinct sex-related difference in its late tonic nociception of spinal nociceptive sensory neurons. Sex differences in formalin-induced tonic nociception are stimulus intensity dependent and related to the modulation from the supraspinal regions. S.c. formalin-induced late phase nociception in female rats is only sensitive to depression at a frequency of 50 Hz, but not 5 Hz, of conditioning electrical stimulation. This suggests that the involvement of the central mechanisms in the antinociceptive effects of conditioning electrical stimulation may be different at various frequencies of stimulation.

Afferent Pathways↗

The effect of electrical stimulation on the experimentally denervated rat muscle.

The m. quadriceps of white rats was electrically stimulated after nerve crush and after nerve section. Electrically stimulated muscles showed fewer central nuclei and a greater number of necrotic single fibres. The demonstration of motor endplates could not give a reliable indication of the onset of reinnervation. The various results show the importance of the trophic influence of the nerve and raise the suspicion that electrical stimulation has a retarding effect on the atrophy but also on regeneration of the fibres. After 7 weeks the unstimulated muscles show a greater degree of regeneration than the stimulated ones.

Animals↗

Properties and latencies of potentials evoked in postganglionic sympathetic nerves by electrical stimulation of aortic, sinus and hypoglossal nerves in cats.

The properties and latencies of potentials evoked in cardiac (CN) and renal (RN) sympathetic nerves by electrical stimulation of the sinus, aortic and hypoglossal nerves were studied in cats. Electrical stimulation of the sinus nerve evoked only excitatory responses in the sympathetic nerves. Electrical stimulation of the aortic nerve fibers evoked excitatory or inhibitory responses in sympathetic nerves. It was possible to evoke 4-5 Hz oscillations in CN and RN after electrical stimulation of the aortic and sinus nerve.-It is suggested that electrical stimulation of the baroafferents is partially responsible for "post-excitatory inhibition" in CN and RN. The central transmission time was the same for the aortic and sinus chemoreceptor reflex and for the somatosympathetic reflex. This period was shorter than the central transmission time of the aortic nerve baroreceptor reflex.

Animals↗

Sensory threshold measurements for electrical stimulation of the digits.

Repeated impedance measurements of electrical stimulation to the finger using the stimulator of an electromyograph were evaluated in seven normal subjects to determine whether reliable threshold values to perception of pain could be obtained. Stimuli were delivered through ring or disc electrodes separated by 3 cm and interfaced to the skin of the digit with EKG paste. Stimulation through these electrodes produced only relative values of threshold, expressed as a potentiometer dial setting. Such values proved to be meaningful only when repeated during a single session. A possible reason for the apparent unreliability of repeated measurements over time is discussed. When a constant current source was substituted, reliable and consistent threshold measurements were obtained. It is suggested that the clinician wishing to make accurate, repeatable and quantified measurements of patient thresholds to electrical stimulation of the finger employ a nonloading source, namely, a constant current or constant voltage stimulator.

Adult↗

The effects of a single high voltage electrical stimulation with an anticancer drug on in vivo growing malignant tumors.

Giving a high voltage electrical stimulation (5 kv/cm, 2 msec) under bleomycin administration (5 mg/body, im) resulted in a significant size decrease of subcutaneously inoculated AH-109A hepatocellular carcinomas in Donryu rats. The tumor size decreased to an average 17 per cent of the initial mass 4 days after the treatment and the average survival period was extended to almost 200 per cent of that of the control. However, neither high voltage electrical stimulation nor bleomycin administration alone demonstrated an anticancer effect. It was thus concluded that the concomitant use of a high voltage electrical stimulation and an anticancer drug has the potential to be effectively applied in cancer treatment.

Animals↗

Electrically stimulated relaxation is not mediated by GABA in cat lower esophageal sphincter muscle.

This study examined the effect of Gamma-Amino butyric acid (GABA) and selective GABA receptor related drugs on the electrically stimulated relaxation in the lower esophageal sphincter muscle (LES) of a cat. Tetrodotoxin (10(-6) M) suppressed the electrically stimulated (0.5-5 Hz) relaxation of the LES. However, guanethidine (10(-6) M) and atropine (10(-6) M) had no effect indicating that the relaxations were neurally mediated via the nonadrenergic and noncholinergic (NANC) pathways. NG-nitro-L-arginine methyl ester (10(-4) M, L-NAME) also inhibited the relaxant response but did not completely abolish the electrically stimulated relaxation with 60 % inhibition, which suggests the involvement of nitric oxide as an inhibitory transmitter. This study examined the role of GABA, an inhibitory neurotransmitter, on neurally mediated LES relaxation. GABA (10(-3)-10(-5) M, non selective receptor agonist), muscimol (10(-3)-10(-5) M, GABA-A agonist), and baclofen (10(-3)-10(-5) M, GABA-B agonist) had no significant effect on the electrically stimulated relaxation. Moreover, bicuculline (10(-5) M, GABA-A antagonist) and phaclofen (10(-5) M, GABA-B antagonist) had no inhibitory effect on the electrically stimulated relaxation. This suggests that GABA and the GABA receptor are not involved in the electrically stimulated NANC relaxation in the cat LES.

Animals↗

Use of a continent colonic conduit for treatment of refractory evacuatory disorder following construction of an electrically stimulated gracilis neoanal sphincter.

BACKGROUND: This study reports the outcome from the addition of a continent colonic conduit (CCC) to an electrically stimulated gracilis neoanal sphincter in patients with severe evacuatory disorder following formation of a neosphincter for end-stage faecal incontinence. METHODS: One hundred and twenty patients had an electrically stimulated gracilis neoanal sphincter constructed for end-stage faecal incontinence. Seven patients developed severe evacuatory disorders; construction of a CCC was required in six patients and an antegrade continence enema procedure in one. RESULTS: Median follow-up of the seven patients was 77 (range 6-96) months. Six patients with evacuatory disorders had a successful outcome, defined as continence to solid and liquid stool as well as correction of the evacuatory disorder. A stoma was formed in one patient. Patients who had previously undergone anorectal reconstructive surgery were more likely to develop an evacuatory disorder following construction of an electrically stimulated gracilis neoanal sphincter than patients operated on for other reasons (chi2 = 28.13, 1 d.f., P < 0.001). CONCLUSION: Construction of a CCC is a useful technique for the majority of patients with severe evacuatory disorders following the formation of an electrically stimulated gracilis neoanal sphincter, for whom the only alternative would be an end stoma. A CCC may be incorporated with construction of an electrically stimulated gracilis neoanal sphincter in patients at significant risk of postoperative severe evacuatory disorders.

Adult↗

Respiratory responses to electrical stimulation of the basal ganglia in cats.

The aim of the present study was to investigate the involvement of basal ganglia in altering respiration. The experiments were carried out on cats using the electrical stimulation techniques. The electrical stimulation of the basal ganglia caused locus-dependent changes both in the tidal volume and the rate of respiration. The most frequent effect of stimulation was hyperpnea and decrease in the tidal volume in awake, freely moving cats. An increase in the tidal volume appeared only as rebound-like aftereffect. The stimulation that caused hyperpnea in awake cats elicited smaller changes under chloralose or ketamine-induced anaesthesia, and, in certain cases, the stimulation produced apnea. After locally applied neurotoxic damage, the electrical stimulation failed to induce significant respiratory changes. It is suggested that the fast, small amplitude ventilation is, probably, produced by high excitation that shifts the respiratory rhythm generator towards the upper limits of its regulatory range. The slowing of ventilation might be produced by an inhibitory mechanism, which is able to cause even apnea under anaesthesia.

Anesthesia↗

Luteinizing hormone releasing factor in rat hypophysial portal blood collected during electrical stimulation of the hypothalamus.

1. Ovulation was induced in Nembutal-blocked pro-oestrous rats by electrical stimulation of the hypothalamus.2. The same type of electrical stimulation was applied during the collection of hypophysial portal blood.3. Pooled hypophysial portal plasma from donors in pro-oestrus, oestrus and met-oestrus was assayed for ovarian ascorbic acid depleting (OAAD) activity.4. Electrical stimulation of the hypothalamus increased the OAAD activity, believed to be due to luteinizing hormone releasing factor (LRF), in pro-oestrus and met-oestrus, but not in oestrus.5. It is concluded that the hypothalamic nerve fibres responsible for releasing LRF into the hypophysial portal vessels are depleted of their store of this releasing factor, or are refractory to electrical stimulation, during oestrus.

Animals↗

[Suppression of tinnitus by electric stimulation in cochlear implant patients].

The use of electrical stimulation for the treatment of tinnitus was evaluated on 38 cochlear implant patients suffering from chronic tinnitus. In answer to a questionnaire 29 (76%) of the subjects reported a reduction of the tinnitus while using their speech processor; 15 even noted complete suppression. Sixteen patients used a processor delivering subthreshold current for 2 weeks. A placebo trial followed. Reduction of tinnitus was found in only 3 (19%) of the patients; however, 13 (81%) mentioned a substantial decrease of tinnitus when using their own device with above-threshold stimulation. The fact that tinnitus was also reduced on the contralateral side suggests that the acoustic masking effect must be the main determining factor rather than electrical stimulation. Therefore, the best therapy for the deaf seems to be the improvement of their hearing ability.

Adult↗

Charge density and charge per phase as cofactors in neural injury induced by electrical stimulation.

The possibility of neural injury during prolonged electrical stimulation of the brain imposes some constraints on the use of this technique for therapeutic and experimental applications. Stimulating electrodes of various sizes were used to investigate the interactions of two stimulus parameters, charge density and charge per phase, in determining the threshold of neural injury induced by electrical stimulation. Platinum electrodes ranging in size from 0.002 to 0.5 cm2 were implanted over the parietal cortex of adult cats. Penetrating microelectrodes fabricated from iridium, with surface areas of 65 +/- 3 x 10(-6) cm2 were inserted into the parietal cortex. Ten days after implantation, the electrodes were pulsed continuously for 7h using charge balanced, current regulated, symmetric pulse pairs, 400 microseconds per phase in duration, at a repetition rate of 50 Hz. The animals were perfused immediately after the stimulation for histologic evaluation of the brain tissue subjacent to the electrode sites. The results show that charge density (as measured at the surface of the stimulating electrode), and charge per phase, interact in a synergistic manner to determine the threshold of stimulation-induced neural injury. This interaction occurs over a wide range of both parameters; for charge density from at least 10 to 800 microC/cm2 and, for charge per phase, from at least 0.05 to 5.0 microC per phase. The significance of these findings in elucidating the mechanisms underlying stimulation-induced injury is discussed.

Animals↗

Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells.

Electropermeabilization, or electroporation, has been used to deliver genes or drugs into the cytoplasm through micropores in the cell membrane caused by electric stimulation. The cytotoxic effect of a combination of anticancer agents with electric stimulation on rat C6 and human T98G glioma cells was examined in vitro. Electric pulses of 100 microsec square waves (eight cycles at 1 Hz) at various electric fields were delivered to C6 or T98G glioma cell suspensions in combination with several anticancer agents. Cell growth was evaluated 48-72 h after treatment. Measurement of cell lysis by electric stimulation was used to assess the optimum field strength for electroporation. Electric stimulation enhanced significantly the cytotoxicity of bleomycin to both C6 and T98G cells by more than 1000-fold using an electric field of 1750 V/cm for C6 cells and 1000 V/cm for T98G cells. The enhancement disappeared when bleomycin concentration was reduced to 100 pg/ml. The cytotoxicity of carboplatin was weakly but significantly enhanced by electric stimulation when a high dose of carboplatin was used. However, there was no enhancement of the cytotoxicity of nimustine hydrochloride (ACNU), etoposide, and vincristine. These results indicate that the combination of bleomycin and electroporation is the most potent candidate for electrochemotherapy in vivo.

Animals↗

Electrical stimulation in the treatment of pain.

PURPOSE: To review the published literature concerning the treatment of painful conditions using devices that deliver electrical stimulation to nervous structures. The review briefly surveys the results obtained using surface electrodes ("TENS") as well as implanted devices. METHOD: The method used is a critical review of the important published literature up to mid-1999. References were obtained using Medline and the keywords "pain", together with "electrical", "stimulation", "neurostimulation" or "TENS". RESULTS: Electrical stimulation has been found to be of potential benefit in the management of a range of painful conditions. Adequately controlled trials of electrical stimulation are often difficult to achieve. Implanted devices tend to be used in the more severe intractable pain conditions. It is likely that there is more than one mechanism of action. The mechanisms of action are however still often poorly understood, even though historically theoretical and experimental advances in the understanding of pain mechanisms prompted the development of clinical systems and the institution of clinical studies. CONCLUSIONS: TENS has proved to be remarkably safe, and provides significant analgesia in about half of patients experiencing moderate predictable pain. Implanted devices can be more effective, but they carry a risk of device failure, implant infection or surgical complication, and are reserved for the more severe intractable chronic pains. The main implanted devices used clinically are the spinal cord stimulator and the deep brain stimulator.

Angina Pectoris↗