Jay D. Glass

Role of inhibitory mechanisms in trigeminal neuralgia

Segmental inhibition was elicited in the spinal trigeminal nucleus of cats by delivering a conditioning stimulus to the maxillary nerve 100 msec before the test stimulus. Carbamazepine, baclofen, and phenytoin markedly facilitated this segmental inhibition, as well as depressing the response to an unconditioned maxillary nerve stimulus. Phenobarbital, on the other hand, usually depressed the segmental inhibition. These results suggest that drugs that relieve trigeminal neuralgia both facilitate inhibitory mechanisms and depress excitatory mechanisms in the spinal trigeminal nucleus. The facilitation of inhibitory mechanisms appears to be at least as important as the depression of excitatory mechanisms and suggests that a failure of inhibitory mechanisms may play a significant role in the pathogenesis of trigeminal neuralgia.

Imipramine in absence and myoclonic‐astatic seizures

A double-blind crossover study with imipramine was conducted in 10 patients with absence and myoclonic-astatic seizures who had not responded to conventional medications. Imipramine produced a significant initial decrease in seizure frequency in 5 of the 10 patients, and in 2 patients the beneficial effect was maintained for more than 1 year. An open trial of imipramine in another 16 patients showed an initial reduction in seizure frequency in 10 patients (63 percent), and this decrease persisted for more than 1 year in 4 patients (25 percent). The effect of imipramine on the EEG did not always correlate with the clinical response. Serum content of imipramine in the patients who showed a long-term response was 40 to 120 ng per milliliter, on a total daily dose of 0.7 to 3.5 mg per kilogram. These results suggest that imipramine is a valuable addition to the treatment of seizures.

Effect of Anticonvulsant Drugs on Inhibitory and Excitatory Pathways

Summary: A conditioning stimulus to the periventricular gray matter inhibits the response of spinal trigeminal neurons to maxillary nerve stimulation. Sodium valproate and ethosuximide decrease the periventricular inhibition without significantly affecting the response of these neurons to the unconditioned maxillary nerve stimulus. We have now found that carbamazepine and phenytoin decrease the response to the unconditioned maxillary nerve stimulus, and only depress the periventricular inhibition secondarily. These results further support the hypothesis that the ability to depress selectively inhibitory pathways in the CNS is an important characteristic of antiabsence drugs, and that absence seizures may represent paroxysmal discharges in inhibitory pathways.

Antiabsence drugs and inhibitory pathways

Conditioning stimuli to the coronal gyrus or periventricular gray matter inhibit the activity of spinal trigeminal neurons. Valproate decreased the corticofugal inhibition of the spinal trigeminal nucleus, as did ethosuximide, trimethadione, and imipramine. Valproate and ethosuximide also decreased the periventricular inhibition of the spinal trigeminal nucleus, indicating that antiabsence drugs depress subcortical inhibitory pathways as well as pathways of cortical origin. These results support the hypothesis that ability to depress inhibitory pathways is an important characteristic of antiabsence drugs. The effect of valproate and ethosuximide on periventricular inhibition also suggests that these anticonvulsants may act by preventing the spread of seizure activity through subcortical pathways.

Do phenytoin and carbamazepine depress excitation and/or facilitate inhibition?

The effect of phenytoin and carbamazepine on the segmental and the periventricular inhibition was investigated in interneurons of the spinal trigeminal nucleus oralis of cats. The segmental inhibition was elicited by delivering a conditioning stimulus to the maxillary nerve 100 ms prior to the test stimulus to the maxillary nerve, and the periventricular inhibition was elicited by delivering a conditioning stimulus to the periventricular gray matter. Therapeutic serum levels of phenytoin and carbamazepine facilitated the segmental inhibition, but depressed the periventricular inhibition, while also depressing the response of trigeminal nucleus neurons to an unconditioned maxillary nerve stimulus. These results indicate that the depression of neural activity by phenytoin and carbamazepine is selective, leaving some inhibitory pathways relatively untouched and thus greatly enhancing their effectiveness. It is suggested that the anticonvulsant properties of phenytoin and carbamazepine are due to their ability to produce a relative facilitation of inhibitory feedback mechanisms.

Chloralose induced alteration of visually evoked response from specific and non-specific regions of cat neocortex

Visually evoked response (VER) and EEG from the motor cortex (precruciate gyrus) and the visual cortex (marginal gyrus) of cats were recorded from 4 to 7 h after the injection of anesthetic doses of alpha-chloralose. During the recording period the VER from the precruciat gyrus showed a 200-300% increase in amplitude while the VER from the marginal gyrus rarely varied more than 50% in amplitude, and did so independent of the changes in the VER from the precruciate gyrus. The number of large amplitude spikes in the EEG from the precruciate gyrus also increased dramatically during the recording period, but no definite correlation between changes in VER amplitude and in the number of spikes in the EEG could be demonstrated. These observations suggest a functional separation between specific and nonspecific sensory pathways, with the latter showing a considerably greater sensitivity to level of anesthesia.

Photic evoked activity in the visual cortex of monocularly deprived cats.

Abstract Monocular eyelid closure during the first 2 months of life has previously been shown to cause a dramatic reduction in the number of neurons that can be activated by photic stimulation of the deprived eye. Those studies recorded single neuron responses to stimulation with discrete forms. In contrast, the author has previously shown that the initial components of the slow-wave response from one region of the cortex evoked by diffuse stimulation of the deprived eye are actually similar to these components when evoked from the nondeprived eye. The disparity in these findings may be due to the fact that the slow-wave data were recorded from only one region of the visual cortex and in response to diffuse photic stimulation. To resolve these differences the slow-wave response from areas 17, 18, and 19 and single-unit activity in response to diffuse photic stimulation were studied. The response evoked from the deprived eye was found to be reduced in area 17 but was sometimes actually larger in areas 18 and 19 than the response evoked from the good eye. Of 45 single units tested, 36 could be driven by stimulation of either eye. Evidently, photic stimulation of the deprived eye is capable of evoking neuronal discharge within the visual cortex. Indeed, the ability of neuronal transmission from the deprived eye to activate neurons within the visual cortex is in keeping with the evidence on behavioral recovery from monocular eyelid closure.

Visually evoked potentials from occipital and precentral cortex in visually deprived humans.

The visually evoked potential (VEP) was recorded from the scalp overlying precentral and occipital cortex in three monocularly deprived humans. The subjects had defects of the globe from birth that effectively created a condition of diffuse light rearing in one eye. In subject, BER, a 19-year-old with a recently removed congenital cataract, the occipital response evoked from the deprived eye was reduced by 53% compared with the response evoked from the good eye. In subject GUZ, age 20 with a congenital cataract, the occipital response evoked from the deprived eye was actually larger by 20% than was the response evoked from the good eye. For UTZ, age 5 with whitish cellular debri in the anterior vitreous of the eye, the occipital response evoked from the deprived eye was only 4% smaller than the response evoked from his good eye. In all three subjects, the precentral response evoked from the deprived eye was reduced in amplitude compared with the precentral response evoked from the good eye. In terms of relative effect of the deprivation upon the VEP from the two recording sites, the precentral VEP was altered to a greater extent than was the occipital VEP. These findings indicate that diffuse light rearing can affect the pathways projecting to precentral cortex independently of the specific visual pathways.

The effect of tricyclic antidepressants on corticofugal inhibition of the spinal trigeminal nucleus

Abstract A conditioning stimulus to the contralateral coronal gyrus of cats inhibits the response of certain neurons in the spinal trigeminal nucleus to maxillary nerve stimulation. This corticofugal inhibition was reduced by imipramine, and also by clomipramine, but not by desipramine or by amitriptyline. Although these drugs are all chemically related, clomipramine has a stronger serotonergic effect than imipramine, while desipramine has more of an adrenergic and less of a serotonergic and anticholinergic effect, and amitriptyline has a relatively stronger anticholinergic effect. We also found that the administration of the central anticholinergic drug procyclidine did not decrease the cortical inhibition of the trigeminal nucleus. Brompheniramine, which has a strong adrenergic and serotonergic effect, also failed to depress this corticofugal inhibition. On the other hand, the combination of an anticholinergic and an adrenergic agent (procyclidine and desipramine or procyclidine and brompheniramine) did depress this corticofugal inhibition. Our results, therefore, support the hypothesis that the cortical inhibition of the spinal trigeminal nucleus is depressed by drugs that combine anticholinergic and adrenergic properties. These observations are discussed in relation to the mechanisms that may be involved in the production and control of petit mal epilepsy, since we had previously found that anti-petit mal drugs depress the corticofugal inhibition of the trigeminal nucleus while anti-grand mal drugs do not.

Pattern processing and slow-wave activity in visual cortex of cat

Animal models play a significant role in research on human disorders. In vision research, the recording of single-neuron activity from animals has been of great value to our understanding of pattern processing mechanisms. In humans, investigations of visual function have typically utilized slow-wave activity. We have studied in cats the relationship between pattern processing and the slow-wave evoked response recorded from cortical areas 17, 18, 19 and 4 in the awake cat. We have found that within a restricted latency range the response in 17, 18 and 19 reflects the processing of the patterness of a visual stimulus. A comparison of response components occurring prior to 50 msec poststimulus showed few significant differences (P less than 0.05) between peak amplitudes evoked by a diffuse and a checkerboard pattern stimulus. A much higher proportion of response components occurring after 50 msec but prior to 300 msec poststimulus were significantly different (P less than 0.05). The response recorded from area 4 (motor cortex) did not show significant differences as a function of the diffuse and patterned stimuli. Our findings show that the slow wave recorded from cat visual cortex can reflect the pattern processing mechanisms of visual cortex. Since slow waves are used in the study of visual functions in humans, the slow wave may have an important role to play in animal models of visual disorders in humans.