Effect of dichloromethane fraction of Areca catechu nut on monoamines associated behaviors and tyramine pressor sensitivity in rodents.

The current study was aimed at investigating the effect of Areca catechu nut dichloromethane fraction (7 mg/kg) on monoamines (serotonin and dopamine) modulation (5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypes) and its interaction with tyramine (cheese effect). The dichloromethane fraction caused pronounced increase in 5-HTP-induced tremors (50%) with negligible PEA-induced stereotypes (20%). Additionally, it did not produce a significant increase in the tyramine pressor effects. These results suggest that the dichloromethane fraction of A. catechu nut primarily elevates serotonin levels (probably via monoamine oxidase A inhibition) and does not induce cheese effect.

Pathological tremor prediction using surface electromyogram and acceleration: potential use in 'ON-OFF' demand driven deep brain stimulator design.

OBJECTIVE: We present a proof of concept for a novel method of predicting the onset of pathological tremor using non-invasively measured surface electromyogram (sEMG) and acceleration from tremor-affected extremities of patients with Parkinson's disease (PD) and essential tremor (ET). APPROACH: The tremor prediction algorithm uses a set of spectral (Fourier and wavelet) and nonlinear time series (entropy and recurrence rate) parameters extracted from the non-invasively recorded sEMG and acceleration signals. MAIN RESULTS: The resulting algorithm is shown to successfully predict tremor onset for all 91 trials recorded in 4 PD patients and for all 91 trials recorded in 4 ET patients. The predictor achieves a 100% sensitivity for all trials considered, along with an overall accuracy of 85.7% for all ET trials and 80.2% for all PD trials. By using a Pearson's chi-square test, the prediction results are shown to significantly differ from a random prediction outcome. SIGNIFICANCE: The tremor prediction algorithm can be potentially used for designing the next generation of non-invasive closed-loop predictive ON-OFF controllers for deep brain stimulation (DBS), used for suppressing pathological tremor in such patients. Such a system is based on alternating ON and OFF DBS periods, an incoming tremor being predicted during the time intervals when DBS is OFF, so as to turn DBS back ON. The prediction should be a few seconds before tremor re-appears so that the patient is tremor-free for the entire DBS ON-OFF cycle and the tremor-free DBS OFF interval should be maximized in order to minimize the current injected in the brain and battery usage.

Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation.

Deep brain stimulation (DBS) provides dramatic tremor relief when delivered at high-stimulation frequencies (more than ∼100 Hz), but its mechanisms of action are not well-understood. Previous studies indicate that high-frequency stimulation is less effective when the stimulation train is temporally irregular. The purpose of this study was to determine the specific characteristics of temporally irregular stimulus trains that reduce their effectiveness: long pauses, bursts, or irregularity per se. We isolated these characteristics in stimulus trains and conducted intraoperative measurements of postural tremor in eight volunteers. Tremor varied significantly across stimulus conditions (P < 0.015), and stimulus trains with pauses were significantly less effective than stimulus trains without (P < 0.002). There were no significant differences in tremor between trains with or without bursts or between trains that were irregular or periodic. Thus the decreased effectiveness of temporally irregular DBS trains is due to long pauses in the stimulus trains, not the degree of temporal irregularity alone. We also conducted computer simulations of neuronal responses to the experimental stimulus trains using a biophysical model of the thalamic network. Trains that suppressed tremor in volunteers also suppressed fluctuations in thalamic transmembrane potential at the frequency associated with cerebellar burst-driver inputs. Clinical and computational findings indicate that DBS suppresses tremor by masking burst-driver inputs to the thalamus and that pauses in stimulation prevent such masking. Although stimulation of other anatomic targets may provide tremor suppression, we propose that the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.

Stereotactic neurosurgery for disabling tremor in multiple sclerosis: thalamotomy or deep brain stimulation?

Disabling tremor is common in multiple sclerosis and up to 75% of patients experience tremor at some point during their disease. The treatment of this tremor, however, remains challenging. Pharmacotherapy in general has been disappointing and stereotactic neurosurgery is becoming increasingly popular. However, the results of stereotactic treatments reported are variable and no systematic review has been performed. The aim of this study was to assess the role of thalamotomy and deep brain stimulation in the treatment of tremor in multiple sclerosis, and to compare the differences in efficacy and safety between the two techniques. We identified the relevant published studies and cases by searching the MEDLINE, EMBASS and the references lists of related articles, and performed a systematic review and assessment of the full texts of all articles selected. Initial tremor suppression was seen in 93.8% of patients who had thalamotomy and 96% in those who had deep brain stimulation. A total of 63.5% of patients had persistent tremor suppression at 12 months or more after thalamotomy. Twelve results for deep brain stimulation were not available in the reviewed literature. Functional improvement was seen only in 47.8% of those who underwent thalamotomy as opposed to 85.2% of those who had deep brain stimulation. While three of the four reported deaths were in patients who underwent thalamotomy, three of the four procedure-related haemorrhages followed DBS. Other common adverse effects like hemiparesis, dysarthria, swallowing difficulties, balance disorder, etc., was reported in both procedures. Numerous studies have attempted to assess the efficacy and safety of thalamotomy and DBS in the treatment of MS tremor, but no standardized outcome measures were used. Nonetheless, the data suggest that both thalamotomy and thalamic DBS are comparable procedures for tremor suppression and that adverse effects can occur with both procedures.

Amplitude- and frequency-dependent changes in neuronal regularity parallel changes in tremor With thalamic deep brain stimulation.

The mechanisms by which deep brain stimulation (DBS) alleviates tremor remain unclear, but successful treatment can be achieved with properly selected frequency and amplitude. The clinical tremor response to thalamic DBS for essential tremor is dependent on the stimulation frequency and amplitude, and for high frequencies (> or = 90 Hz), increasing amplitude suppressed tremor, whereas for low frequencies (< 60 Hz), increasing amplitude aggravated tremor. We studied the effects of stimulation frequency and amplitude on the output of a population of intrinsically active model neurons to test the hypothesis that regularization of neuronal firing patterns is responsible for the clinical effectiveness of DBS. The firing patterns of model thalamocortical neurons were dependent on stimulation frequency and amplitude in a manner similar to the clinical tremor response. Above a critical frequency, increasing amplitude reduced the coefficient of variation (CV) of the neuronal firing pattern, whereas for low frequencies, increasing the amplitude increased the CV of neuronal activity. The correlation between the changes in tremor and the changes in the CV of neuronal firing supports the hypothesis that regularization of neuronal firing pattern during DBS is one of the mechanisms underlying the suppression of tremor.

Inhibitory role of Acorus calamus in ferric chloride-induced epileptogenesis in rat.

The roots and rhizomes of Acorus calamus (Family: Araceae) have been used in the ancient systems of medicine for the treatment of various neurological disorders. Of the various methods used for inducing experimental epileptic models, the intracortical administration of ferric chloride (FeCl(3)) into sensorimotor cortex induces recurrent seizures and epileptic discharge similar to human post-traumatic epilepsy through the generation of free radicals. The present study focuses on the effect of Acorus calamus on the behavioral, electroencephalographic, and antioxidant changes in FeCl(3)-induced rat epileptogenesis. Topical administration of FeCl(3) (5 microL; 100 mM) into the sensorimotor cortex of rats showed an increase in the wet dog shake behavior, spike wave discharges together with an significant increase in antioxidant enzyme activity, such as superoxide dismutase and catalase, resulting in an increase in the level of lipid peroxidation in cerebral cortex. Pretreatment with Acorus calamus (200 mg/kg b.w., p.o. for 14 days) and also diazepam (DZ, 20 mg/kg b.w., i.p.) decreased the WDS behavior, spike wave discharges with single isolated positive waves, and a significant decrease in activity of superoxide dismutase and level of lipid peroxidation was observed in cerebral cortex with respect to those observed in FeCl(3)-induced epileptic group. Data presented in this study clearly show that Acorus calamus possesses the ability for preventing the development of FeCl(3)-induced epileptogenesis by modulating antioxidant enzymes, which in turn exhibit the potentiality of Acorus calamus to be developed as an effective anti-epileptic drug.

Nicotinic mechanisms contribute to soman-induced symptoms and lethality.

The symptoms and lethality of intoxication with the acetylcholinesterase inactivator soman are attributed primarily to excessive activation of muscarinic acetylcholine receptors; nicotinic activation is considered of less importance, a notion that may rely on studies that have used nicotinic antagonists at low doses. In this study pretreatment with the centrally acting nicotinic antagonist mecamylamine, 20mg/kg, but not 2mg/kg, prolonged survival in mice exposed to soman, 250 microg/kg (1.5 LD(50)), from 14+/-3 to 135+/-38 min (mean+/-S.E.M.; surviving animals were killed 240 min after soman administration). Pretreatment with the muscarinic blocker scopolamine, 2 or 20mg/kg (but not 0.5mg/kg) prolonged survival significantly (mean for both groups: 91 min), but the animals responded to soman with immobility, irregular respiration, fasciculation, and short episodes of convulsive crawling. These symptoms were absent in animals pretreated with scopolamine plus mecamylamine, both drugs 20mg/kg, a suggestion that they were caused by activation of nicotinic receptors. All animals pretreated with scopolamine and mecamylamine (both drugs 20 mg/kg) survived the full 240 min observation period. Administration of mecamylamine, 5 mg/kg, 5 min after soman exposure to scopolamine-pretreated animals reduced fasciculation and respiratory irregularity and prolonged survival compared to scopolamine alone, but mecamylamine, 20 mg/kg, given 10 min after soman exposure shortened survival (18+/-1 min). These results suggest that nicotinic activation plays an important part in soman-induced symptomatology and lethality but also that nicotinic antagonists given in large doses after soman exposure may have untoward effects.

Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.

INTRODUCTION: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). METHODS: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. RESULTS: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. DISCUSSION: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.

[Value of magnesium sulfate and/or valium in preventing local anesthetic toxicity of sacral block].

OBJECTIVE: To study the effects of magnesium sulfate and/or valium in preventing local anesthetic toxicity induced by sacral block. METHODS: A total of 240 adult patients scheduled for sacral block were randomized equally into four groups matched for sex, age and body weight. Ten minutes before sacral block, the patients in group B received valium (0.1 mg/kg), group C received magnesium sulfate (50 mg/kg), group D received both valium (0.1 mg/kg) and magnesium sulfate (50 mg/kg). The control (group A) received neither valium nor magnesium sulfate. Local anesthetic toxicity was observed and recorded in all the groups. RESULTS: Local anesthetic toxicity was significantly decreased in group B and group C compared with group A (P<0.05), and the toxicity was even more significantly decreased in group D(P<0.01 vs group A). CONCLUSION: Local anesthetic toxicity of sacral block can be significantly decreased by intravenous injection of valium or magnesium sulfate, and their combination produces stronger effects.

Costs of thalamic deep brain stimulation for movement disorders in patients with multiple sclerosis.

Several studies have shown that thalamic deep brain stimulation (DBS) reduces tremor and improves hand performance in patients with multiple sclerosis (MS). The purpose of this paper is to describe the cost implications of DBS in MS patients and to highlight postoperative medical requirements that can be associated with this therapy. In a prospective study of thalamic DBS in MS patients the mean equipment costs were pounds 4769 (median pounds 7010, Medtronic, 1998 prices); mean neurosurgical inpatient costs per operated patient (n = 15) were pounds 4848 (range pounds 1982-8920, median pounds 5110); and mean in-patient postoperative rehabilitation cost pounds 4602 (range pounds 0-32,225, median pounds 1783). In addition there were transport and follow up costs. Mean neurosurgical inpatient stay following stereotactic DBS implantation was 15 days (median 12 days); and mean inpatient, postoperative rehabilitation stay 54 days (median 25 days). Although there were significant improvements in hand function and tremor reduction at 12 months postoperation, the level of patient performance in activities of daily living, their perception of their handicap and ipse facto the amount of home support required were unchanged from preoperative levels. This study has highlighted significant unforeseen medical requirements and costs that can occur in MS patients who have thalamic DBS surgery.

Tremor suppression through impedance control.

This paper presents a method for designing tremor suppression systems that achieve a specified reduction in pathological tremor power through controlling the impedance of the human-machine interface. Position, rate, and acceleration feedback are examined and two techniques for the selection of feedback coefficients are discussed. Both techniques seek a desired closed-loop human-machine frequency response and require the development of open-loop human-machine models through system identification. The design techniques were used to develop a tremor suppression system that was subsequently evaluated using human subjects. It is concluded that nonadaptive tremor suppression systems that utilize impedance control to achieve a specified reduction in tremor power can be successfully designed when accurate open-loop human-machine models are available.

[The selectivity of the action of muscarinic agonists in vivo]. / Izbiratel'nost' deistviia muskarinovykh agonistov in vivo.

The experiments to inhibit a tremor reaction induced by various cholinomimetics have established that DED50 of atropine and amedine is significantly indifferent when tremor is caused by pilocarpine, oxotremorine, and aceclidine while the activity of amedine is lower than that of atropine when ezerine, arecoline and galantamine are applied. The comparison of the findings with the data on the selectivity of the above M-cholinolytics leads to the conclusion that in in vivo experiments, the muscarinic agonists are able to show their selectivity against various subtypes of M-cholinoreceptors. The results of in vivo experiments are found to differ from the data on the in vitro selectivity of M-cholinomimetics in some cases.

Inhibition of experimental seizures in canines by repetitive vagal stimulation.

Repetitive electrical stimulation of the canine cervical vagus nerve interrupts or abolishes motor seizures induced by strychnine and tremors induced by pentylenetetrazol (PTZ). Tremors were defined as rhythmic alternating contractions of opposing muscle groups, exerting much less force than seizure contractions. Seizures were induced by injection boluses of strychnine or PTZ at 1- to 4-min intervals until sustained muscle activity was observed electromyographically (EMG). Vagal stimulation terminated seizures in 0.5-5 s. There were prolonged periods with no spontaneous EMG activity after stimulation. The period of protection was approximately four times the stimulation period. The antiseizure actions of vagal stimulation were not altered by transection of the vagus distal to the stimulating electrode. Optimal stimulus parameters were estimated: strength, approximately 20 V (electrode resistance 1-5 omega); frequency 20-30 Hz; duration, approximately 0.2 ms. These data suggest that the antiseizure effects derive from stimulation of small-diameter afferent unmyelinated fibers in the vagus nerve. These results may form the basis of a new therapeutic approach to epilepsy.

Interaction of ethanol and the high pressure nervous syndrome in rats.

The aim of this study was to determine whether administration of ethanol protects rats against the preconvulsive symptoms of high pressure nervous syndrome (HPNS). Male Sprague-Dawley rats were given either saline or 0.5, 1.5 or 2.5 g/kg ethanol i.p. After injection, the animals were individually exposed to helium-oxygen at 60 atmospheres absolute (atm abs) pressure. The chamber temperature was adjusted to counteract ethanol- and helium-induced hypothermia. Several behavioral parameters were scored continuously during the first 64 min after injection. The time spent in tremor at high pressure was significantly less in the 1.5 and 2.5 g/kg ethanol-treated groups. The number of jerks was significantly lower in the 2.5 g/kg ethanol-treated group. The two highest doses of ethanol induced a characteristic pattern of unsteady locomotion, which was returned to normal in the 1.5 g/kg group at 60 atm abs. Other behavioral effects of ethanol, such as depression of total motor activity, were also reduced. These results indicate that ethanol can significantly ameliorate some of the adverse symptoms of HPNS in freely moving rats.