Repetitive Peripheral Stimulation Research Articles

Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

BackgroundTo investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects.MethodsPurified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods.ResultsIntra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity.ConclusionsThese results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.

Reinstating the ability of the motor cortex to modulate cutaneomuscular reflexes in hemicerebellectomized rats

The pathways passing through the cerebellum calibrate cutaneomuscular responses. Indeed, the enhancement of cutaneomuscular responses associated with subthreshold high-frequency trains of stimulation applied on motor cortex following a period of peripheral repetitive stimulation (PRS) is prevented by hemicerebellectomy. We analysed the effects of low-frequency repetitive stimulation of motor cortex (LFRSM1) on interhemispheric inhibition (IHI) and on the modulation of cutaneomuscular reflexes in rats with left hemicerebellar ablation. IHI was assessed by paired-pulse method with a conditioning stimulus (CS) to M1 followed by a test stimulus (TS) to the opposite M1. LFRSM1 reduced IHI. Combination of LFRSM1 with PRS increased significantly the magnitudes of cutaneomuscular responses evoked ipsilaterally to the hemicerebellar ablation. The increase of the intensity of cutaneomuscular responses was correlated with the reduction of IHI. Excitability of anterior horn motoneurons pool, assessed by F-wave, remained unchanged. Conjunction of LFRSM1 with PRS can be used to restore the ability of the motor cortex to modulate the intensity of cutaneomuscular responses in case of extensive unilateral cerebellar lesion. This study underlines for the first time the potential role of callosal pathways in the deficits of corticomotor tuning of cutaneomuscular responses contralaterally to acute extensive cerebellar lesion.

Hemicerebellectomy impairs the modulation of cutaneomuscular reflexes by the motor cortex following repetitive somatosensory stimulation

We examined the cutaneomuscular reflex of the plantaris muscle of rats in response to cutaneous stimulation in isolation and in conjunction with subthreshold high-frequency trains of stimuli applied on the motor cortex, prior to and following repetitive peripheral stimulation. The cutaneomuscular reflex was also investigated under the same paradigm following hemicerebellectomy. The enhancement of cutaneomuscular responses associated with subthreshold high-frequency trains of stimulation following repetitive peripheral stimulation was prevented by hemicerebellectomy. Our results suggest that the pathways passing through the cerebellum are involved in the calibration of cutaneomuscular responses.

Stimulus intensity, coil characteristics and peripheral reafferent activation contribute to the suppressive effects of 1Hz rTMS on cortical excitability

Objective: Low-frequency (1Hz) repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) can suppress corticospinal excitability. Here we examined whether these inhibitory after effects depend on the stimulus intensity, the type of TMS coil and peripheral reafferent activation. Methods: In fifteen healthy volunteers, 900 biphasic pulses of 1Hz rTMS were given to the left M1 at an intensity of 90% or 115% of the individual resting motor threshold (subthreshold vs. suprathreshold intensity) using two commercially available 'figure-of-eight' shaped TMS coils (Magstim or Dantec coil) attached to the same magnetic stimulator. Before and twice after intervention we recorded motor evoked potentials (MEPs) evoked with the same set-up used for rTMS (MEPrTMS). Using a Magstim coil connected to two Magstim 200 stimulators, we also gave monophasic single and paired pulses to the M1 and assessed unconditioned MEPs (MEPtest), paired-pulse excitability and cortical silent period (cSP). In a control experiment, the same measurements were performed after 15min of 1Hz repetitive electrical nerve stimulation (rENS) of the right ulnar nerve at the wrist using a suprathreshold intensity. Results: We found that the suppressive effect on MEPrTMS depended on the intensity and the type of coil used for rTMS conditioning. The suppression of corticospinal excitability was more pronounced and lasted longer when a suprathreshold intensity and a Dantec coil was used. The intensity but not the type of coil also had an effect on time-dependent changes in intracortical facilitation and cSP. Suprathreshold 1Hz rENS also induced a short lasting inhibition of MEPrTMS. Conclusions: Both, the stimulation intensity and the type of TMS coil have an impact on the suppressive after effects of 1Hz rTMS. The stronger suppression of suprathreshold 1Hz rTMS can at least in part be attributed to repetitive peripheral stimulation caused by reafferent feedback. Significance: These data should be taken into account when rTMS is used for therapeutic means.

Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat

Repetitive peripheral stimulation is associated with an enhancement of the intensity of corticomotor responses. We analysed the effects of hemicerebellectomy on the modulation of cortical motor output associated with repetitive electrical stimulation of the sciatic nerve in the rat. Hemicerebellectomy blocked the enhancement of the corticomotor response. The cerebellum is a key player in this form of short-term plasticity.

Changes in the volume of the intercellular space of the cerebral cortex in conditions of peripheral stimulation in rats.

Changes in the volume of the intercellular space of the rat cerebral cortex in response to peripheral repetitive stimulation were studied. The volume of the intercellular space and its changes were assessed by a modification of the four-electrode impedance method. The results suggest that evoked electrical activity in the cerebral cortex was accompanied by 3-5% decreases in the volume of the intercellular space.

Neural changes in acute arthritis in monkeys. III. Changes in substance P, calcitonin gene-related peptide and glutamate in the dorsal horn of the spinal cord

The effects of an experimentally induced arthritis on immunoreactivity of putative primary afferents neurotransmitter/neuromodulators were examined. Immunoreactive staining for substance P (SP), calcitonin generelated peptide (CGRP) and glutamate (Glu) in the monkey dorsal horn was examined following inflammation of one knee joint induced by injection of 5% kaolin and 5% carrageenan. Spinal cords were examined at different time periods after induction of arthritis (2.5, 4, 6 and 8 h). Side to side differences in immunoreactivity were determined by a computer assisted quantitation system. A significant overall decrease in immunoreactivity of the lumbar versus the cervical dorsal horn was found for SP. The decrease for SP showed maximal changes of 68.3% at 4 h and 54.7% at 6 h. Immunoreactivity for CGRP was decreased 31.5% at 8 h and variable at other time points. Immunoreactivity for Glu, showed an ipsilateral increase of 31.4% at 4 h, 33.7% at 6 h, 39.9% at 8 h and a significant effect for lumbar versus cervical. Repetitive peripheral stimulation of the joint was shown to be important for changes in SP and Glu immunoreactivity. Without frequent peripheral stimulation in the early stages of the development of arthritis, SP showed no quantitative side to side differences. Increases in Glu immunoreactivity were present but not as prominent with minimal joint manipulation. These studies suggest that Glu may be involved in the aching pain of inflammation at rest whereas SP, CGRP and Glu may mediate pain induced by joint movement.

THE BIPHASIC PATTERN OF THE CONVULSIVE PROPERTY OF ENFLURANE IN CATS

The nature of the epileptoid state produced by enflurane was examined in the concentration range 2-5% in cats. A biphasic pattern in the convulsant property was revealed. The ease of induction of seizure by repetitive peripheral stimulation, the duration of seizures, and the activation of reticular neuronal firing during seizure activity showed peak values between 3 and 4%, whereas the values were significantly lower both above and below this range. The amplitudes of the somato-sensory evoked potential also showed a biphasic pattern which correlated well with the severity of the epileptoid state as judged by the aforementioned indices. These findings, when compared with evidence on the actions of other convulsant drugs, and with the known depressant actions of enflurane, suggest a combination of depressant and convulsant properties, the balance of which varies depending on the depth of anaesthesia.

Evidence for spike propagation in cortical dendrites

A study was made of some of the properties of 99 spikes recorded from neurons scattered throughout the somatosensory cortex of the rat. All of the spikes were recorded extracellularly with microelectrodes, and were evoked by electrical stimulation of the skin of the contralateral forepaw. The behavior of every spike was followed over increasing cortical depths from the depth at which it was first recorded. Particular note was made of any changes in spike amplitude, spike latency, and spike frequency-following (i.e., the ability of the spike to follow repetitive peripheral stimulation of varying frequencies) that occurred concomitant with the changes in the cortical recording depth. The changes that were seen most often when the recording depth was increased were an increase in spike amplitude, a decrease in spike latency, and an increase in spike frequency-following. All these changes did not necessarily occur in the same spike. On six occasions the direction of these changes was reversed when the recording electrode was raised after having been lowered. One possible—and, it was thought, the most likely—interpretation of the results is that the recordings made were of spikes which were being actively propagated in ascending, vertically orientated, intracortical dendrites rather than in similarly orientated intracortical axons.

Evoked single cortical unit activity in the somatic sensory areas

1. 1. Evoked activity in single cortical units was isolated in the somatosensory areas of cat and monkey under barbiturate anesthesia or chloralose anesthesia combined with d-tubocurarine or B-erythroidin. Peripheral mechanical or nerve stimulation was used. 2. 2. The spikes were predominantly initially negative when recorded with 4–12 μ electrodes. Larger positive-negative and positive spikes were recorded with 0.5–3 μ electrodes together with smaller initially negative spikes. 3. 3. The latency for the first spike of some units was variable in successive records and varied greatly between units, especially under light anesthesia. Other units showed extraordinary consistency of firing. 4. 4. Some units fired on the commencing limb of the positive primary response which was usually reversed in sign when the electrode tip was 0.5–1.0 mm. deep. The earliest evoked activity at depths of 220–350 μ occurred several milliseconds later than the earliest activity at greater depths in the cortex. 5. 5. High frequency repetitive discharges of the same cortical unit were observed following a single peripheral stimulus. However, this can occur as early in the sensory system as the cuneate nuclear relays. Because injury by the electrode can cause an increased number of spikes per discharge, multiple discharges require a careful evaluation. 6. 6. In some units, increases in strength of nerve stimulation or alterations in site of peripheral stimulation, which reduced the latency for the first spike, lead to an increase in rate of firing and number of spikes per discharge. 7. 7. Cells lying within a few micra of one another often fire with different latencies, number of spikes per high frequency discharge, interspike intervals and may be preferentially activated from different afferent sources. 8. 8. The receptive field of some somesthetic association area units included all four limbs, but the timing of unit firing may significantly differ with the site of stimulation. 9. 9. Absolute and relative unresponsive phases are distinguished in single cortical unit responses to paired shocks to the same nerve. Alteration in strength of the test shock may alter duration and degree of these phases. A later supernormal phase is also distinguished. The response to repetitive peripheral stimulation was studied. 10. 10. Forms of inhibitory and occlusive interaction are distinguished following stimuli to two nerves. Interaction may occur with nearly synchronous volleys in peripheral nerves. 11. 11. The significance of single cortical unit recording is discussed as related to spread of activity in the cortex, the mechanism of the primary response, population sampling and transmission of information in the sensory system.