Vagus nerve stimulation for epilepsy: is output current correlated with acute response?

OBJECTIVES: Vagus nerve stimulation (VNS) is an effective treatment for intractable epilepsy. It is unknown whether acute response is correlated with the amplitude of output current. The purpose of this study was to determine if the output current of VNS is correlated with percent reductions in seizure frequency and response. MATERIALS AND METHODS: Retrospective analysis of a multicenter randomized trial of three unique paradigms of VNS was carried out in patients with intractable partial onset epilepsy. Output current at 1 and 3 months was correlated with percent reduction in seizure frequency and response rates. RESULTS: Sixty-one subjects were enrolled and completed the study. Output current, ranging from 0.25 to 1.5 mA, was not correlated with reductions in seizure frequency, or with > or = 50% reduction in seizures. Six of seven initial non-responders did experience > or = 50% reductions in seizures after current was increased. CONCLUSIONS: The output current is not a major determinant of acute response to VNS for epilepsy. Many patients respond to low current (<1 mA). Some (20%) initial non-responders may respond to an increase in output current.

Subthalamic nucleus stimulation for primary dystonia and tardive dystonia.

With the renaissance of stereotactic pallidotomy for Parkinson's disease in 1990s, pallidotomy has become increasingly used as an effective treatment for various manifestations of medically refractory dystonia. More recently, deep brain stimulation of globus pallidus internus (GPi) has been replacing pallidotomy. Although GPi DBS has great promise for treating dystonia, there are some disadvantages. We introduce our experiences in subthalamic nucleus (STN) DBS for primary dystonia and tardive dystonia in this chapter. We propose that STN DBS has the following advantages over GPi DBS: (1) symptomatic improvement is seen immediately after stimulation, allowing us to quickly select the most suitable stimulation parameters; (2) the stimulation parameters for the STN are lower than those used for the GPi, resulting in longer battery life; and (3) STN DBS results in better symptomatic control than GPi DBS in dystonia patients when our STN data is compared to that obtained by others with using the GPi as the target. We suggest that STN DBS may be the most appropriate surgical technique for dystonia.

Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats.

PURPOSE: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats. METHODS: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin- and vehicle-treated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured. RESULTS: VNS effectively reduced seizure severity in both capsaicin- and vehicle-treated rats as compared with their non-VNS baselines. CONCLUSIONS: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression.

Suppression of harmaline-induced tremor in rats by vagus nerve stimulation.

We studied whether vagus nerve stimulation could suppress tremor in the harmaline tremor model in the rat. Animals were chronically implanted with helical leads around the left vagus nerve and a disk-shaped electrode positioned subcutaneously in the dorsal neck. Harmaline-induced tremor was recorded on a physiograph while each animal received a sequence of five 20-minute trials. Each trial consisted of five minutes of pre-stimulation baseline, five minutes of vagus nerve stimulation, and ten minutes of post-stimulation. Vagus nerve stimulation significantly suppressed harmaline-induced tremor. The suppressive effect was present within the first minute of stimulation and was reproducible across the five trials of the study. The results of this study suggest that the central generator or expression of tremor in the harmaline animal model can be suppressed by vagus nerve stimulation.

Seizure suppression by systemic epinephrine is mediated by the vagus nerve.

The present study investigated the seizure-suppressing effects of systemic epinephrine. Rats were injected with epinephrine, and seizures induced with pentylenetetrazol. Seizure severities were significantly reduced 15 min after 1 mg/kg of epinephrine. Severing the subdiaphragmatic vagus nerves abolished this effect, demonstrating that epinephrine-induced seizure suppression is mediated by subdiaphragmatic vagal afferents. The development of novel anti-epileptic drugs that exploit this peripheral pathway may yield new seizure treatments.

Electrophysiology of hippocampal CA1 neurons after prenatal ethanol exposure.

In the present study, we examined the longitudinal effects of prenatal ethanol exposure on the electrophysiological characteristics of CA1 neurons in hippocampal slices. Hippocampal slices were obtained from young (25-32-day old) and adult (63-77-day old) male offspring of rats given one of four treatments during gestation. Three groups of pregnant rats were orally intubated with 0, 4, or 6 g/kg ethanol on gestational days 8-20. Caloric intake for the 0- (nutritional control) and 4-g/kg groups was yoked to that of the 6 g/kg group. A fourth group (untreated control) was not intubated, and was given ad lib access to food. Long-term potentiation and paired-pulse inhibition were unaffected by prenatal ethanol exposure in young and adult rats; however, slices taken from the young 6 g/kg ethanol group displayed a significantly lower maximal CA1 population spike amplitude evoked by Schaffer collateral stimulation as compared to young controls. This difference was not observed in adult animals. These data suggest that some aspects of hippocampal physiology are negatively affected in young rats as a result of prenatal ethanol exposure, but this effect reverses as the animal matures.

Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation.

PURPOSE: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. METHODS: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. RESULTS: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated. CONCLUSIONS: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.

Evidence for physiologically active axonal adenosine receptors in the rat corpus callosum.

Several neurotransmitter receptors have been identified on axons, and emerging evidence suggests that central axonal conduction may be modulated by neurotransmitters. We have recently demonstrated the presence of extra-synaptic adenosine Al receptors along rat hippocampal axons. We now present immunocytochemical evidence for Al receptors on rat corpus callosum axons and show that these receptors actively modulate axon physiology. Using rat brain coronal slices, we stimulated the corpus callosum and recorded the evoked extracellular compound action potential. The lipid-soluble, Al-specific adenosine receptor agonist cyclopentyladenosine, dose-dependently decreased the compound action potential amplitude, an effect reversed by the specific Al antagonist 8-cyclopentyl-1, 3-dipropylxanthine. These data provide the first direct evidence that axonal Al adenosine receptors modulate axon physiology in the adult mammalian brain. Influencing axonal transmission is a potentially powerful mechanism of altering information processing in the nervous system.

Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery.

Radiosurgery may provide an alternative therapy for intractable epilepsy by eliminating or modifying abnormally active pacemaker neurons in epileptic foci. In the present study, the effect of radiosurgery on rat hippocampal kindling was examined. Rats received daily hippocampal stimulus trains until they were fully kindled. They then underwent radiosurgery of the kindled focus, receiving a single-dose of 0-, 10-, or 40-Gy. The 40-Gy group demonstrated an acute decrease in seizure threshold (3-5 days). Three months after radiosurgery, the threshold for seizures increased and the duration of afterdischarges decreased in the 40-Gy radiosurgery group compared to controls. The changes to both seizure threshold and afterdischarge duration were not significant in the 10-Gy group. These data suggest that radiosurgery is an effective means of reducing the epileptogenic activity of seizure foci.

Effects of prenatal ethanol exposure on hippocampal theta activity in the rat.

This study examined the effects of prenatal ethanol exposure on hippocampal theta activity in adult rats. Subjects were randomly selected from four prenatal treatment conditions: untreated, 0, 3, or 5 g/kg/day ethanol. At approximately 90 days of age, all subjects were surgically implanted with a bipolar electrode in the CA1 region of the hippocampus. Four epochs of hippocampal theta rhythm activity were recorded while the subjects were moving and four more while still, and a normalized theta score was computed and compared among groups. The 5 g/kg male group demonstrated a significantly higher theta score than controls, indicating either an increase in type I (movement-associated) theta and/or a decrease in type II (information-processing) theta activity. These results are consistent with prior reports that prenatal ethanol exposure alters hippocampal function and support clinical indications that monitoring the EEG of children may prove to be useful in the diagnosis of fetal alcohol syndrome and/or the detection of alcohol-related birth defects.

Effects of in vivo perforant path kindling on 0-Mg(2+)-induced CA1 burst activity in rat hippocampal slices.

Previous studies have reported persistent alterations in the electrophysiological characteristics of the CA1 region of the hippocampus after kindling. The present study examined the effects of perforant path kindling on 0-Mg(2+)-induced epileptiform bursting in the CA1 region of hippocampal slices. The duration of evoked bursting was significantly longer in slices taken from kindled animals as compared to those taken from implanted, non-stimulated controls. No significant differences were found in spontaneous burst frequency between slices taken from kindled and control animals. These data suggest that perforant path kindling causes a persistent increase in hyperexcitability in the CA1 region of the hippocampus leading to a facilitation of evoked burst activity perhaps through an enhancement in NMDA-related excitatory neurotransmission.

Post-training unilateral vagal stimulation enhances retention performance in the rat.

Many peripherally administered substances which modulate memory do not freely enter the brain. Such compounds may act through peripheral receptors that send messages centrally through vagal afferents. To explore this hypothesis, rats were chronically implanted with cuff electrodes on the left cervical vagus nerve. Each animal was trained 48 h after surgery on a one-trial inhibitory-avoidance task with a 0.75-mA, 1.0-s footshock. Immediately following training, each animal received either no stimulation or vagal stimulation (0.5-ms biphasic pulses; 20 Hz, 30 s) at one of three intensities (0.2, 0.4, 0.8 mA; eight animals per group). Retention was tested 24 h later. Neither the 0.2-in or 0.8-mA groups (22.1-s; 53.7-s median latency) showed altered retention performances, whereas the 0.4-mA group showed significantly improved retention (881.0 s) compared to unstimulated controls (21.1 s; U = 6, p < .01). This inverted-U shaped function indicates that vagal activation during memory consolidation modulates retention for memory tasks.

Rapid cessation of focally induced generalized seizures in rats through microinfusion of lidocaine hydrochloride into the focus.

An experimental animal model of complex partial seizures which become secondarily generalized is produced by microinfusion of the GABA antagonist bicuculline (BIC) into the deep prepiriform cortex (DPC) of rats. In the present study, we investigated the effects of microinfusion of the local anesthetic, lidocaine hydrochloride, directly into the BIC focus in the DPC and demonstrated that direct inactivation of the focus arrested a focal seizure that was in progress. A measure of the integrated amplitude of the electrocorticogram (ECoG) and behavioral seizure scores from unanesthetized and freely moving rats were used to address this question quantitatively. Microinfusion of 2% lidocaine hydrochloride into the BIC focus significantly reduced the integrated amplitude of the ECoG to levels that did not differ from baseline in either hemisphere (mean = 112% ipsilateral, 99% contralateral), whereas saline microinfusion had no effect (mean = 175% ipsilateral, 125% contralateral). Moreover, ECoG reductions after lidocaine were present as soon as the microinfusion was complete. Behaviorally, clonic seizure severity was assessed on a rating scale of 0-5. Lidocaine microinfusion significantly reduced the seizure scores to values not different from baseline during the first postinfusion measurement period (i.e., 30 s). Microinfusion of saline alone also significantly reduced behavioral seizure severity, although to a lesser degree and not as rapidly as lidocaine. This effect suggests the need for caution in interpretation and design of studies investigating the anticonvulsant effects of various pharmacologic agents when microinfusions are used.