Therapeutic electrical stimulation of the central nervous system

The electrical effects on the nervous system have been known for long. The excitatory effect has been used for diagnostic purposes or even for therapeutic applications, like in pain using low-frequency stimulation of the spinal cord or of the thalamus. The discovery that High-Frequency Stimulation (HFS) mimics the effect of lesioning has opened a new field of therapeutic application of electrical stimulation in all places where lesion of neuronal structures, such as nuclei of the basal ganglia, had proven some therapeutic efficiency. This was first applied to the thalamus to mimic thalamotomy for the treatment of tremor, then to the subthalamic nucleus and the pallidum to treat some advanced forms of Parkinson's disease and control not only the tremor but also akinesia, rigidity and dyskinesias. The field of application is increasingly growing, currently encompassing dystonias, epilepsy, obsessive compulsive disease, cluster headaches, and experimental approaches are being made in the field of obesity and food intake control. Although the effects of stimulation are clear-cut and the therapeutic benefit is clearly recognized, the mechanism of action of HFS is not yet understood. The similarity between HFS and the effect of lesions in several places of the brain suggests that this might induce an inhibition-like process, which is difficult to explain with the classical concept of physiology where electrical stimulation means excitation of neural elements. The current data coming from either clinical or experimental observations are providing elements to shape a beginning of an understanding. Intra-cerebral recordings in human patients with artefact suppression tend to show the arrest of electrical firing in the recorded places. Animal experiments, either in vitro or in vivo, show complex patterns mixing inhibitory effects and frequency stimulation induced bursting activity, which would suggest that the mechanism is based upon the jamming of the neuronal message, which is by this way functionally suppressed. More recent data from in vitro biological studies show that HFS profoundly affects the cellular functioning and particularly the protein synthesis, suggesting that it could alter the synaptic transmission by reducing the production of neurotransmitters. It is now clear that this method has a larger field of application than currently known and that its therapeutical applications will benefit to several diseases of the nervous system. The understanding of the mechanism has opened a new field of research, which will call for reappraisal of the basic effects of electricity on the living tissues.     

Comparison of magnetic and electrical phrenic nerve stimulation in assessment of phrenic nerve conduction time

Similowski, Thomas, Selma Mehiri, Alexandre Duguet,Valérie Attali, Christian Straus, and Jean-Philippe Derenne.Comparison of magnetic and electrical phrenic nerve stimulation inassessment of phrenic nerve conduction time. J. Appl.Physiol. 82(4): 1190-1199, 1997.Cervicalmagnetic stimulation (CMS), a nonvolitional test of diaphragm function,is an easy means for measuring the latency of the diaphragm motorresponse to phrenic nerve stimulation, namely, phrenic nerve conductiontime (PNCT). In this application, CMS has some practical advantagesover electrical stimulation of the phrenic nerve in the neck (ES).Although normal ES-PNCTs have been consistently reported between7 and 8 ms, data are less homogeneous for CMS-PNCTs, with some reportssuggesting lower values. This study systematically compares ES-and CMS-PNCTs for the same subjects. Surface recordings ofdiaphragmatic electromyographic activity were obtained for sevenhealthy volunteers during ES and CMS of varying intensities. Onaverage, ES-PNCTs amounted to 6.41 ± 0.84 ms and were littleinfluenced by stimulation intensity. With CMS, PNCTs were significantlylower (average difference 1.05 ms), showing a marked increase as CMSintensity lessened. ES and CMS values became comparable for a CMSintensity 65% of the maximal possible intensity of 2.5 Tesla. Thesefindings may be the result of phrenic nerve depolarization occurringmore distally than expected with CMS, which may have clinicalimplications regarding the diagnosis and follow-up of phrenic nervelesions.

     

Structure and developmental expression of the nerve growth factor receptor in the chicken central nervous system

Chicken nerve growth factor (NGF) receptor cDNAs have been isolated and sequenced in an effort to identify functionally important receptor domains and as an initial step in determining the functions of the NGF receptor in early embryogenesis. Comparisons of the primary amino acid sequences of the avian and mammalian NGF receptors have identified several discrete domains that differ in their degree of conservation. The highly conserved regions include an extracellular domain, likely to be involved in ligand binding, in which the positions of 24 cysteine residues and virtually all negatively charged residues are conserved; a transmembrane region, including flanking stretches of extracellular and cytoplasmic amino acids, which has properties suggesting it interacts with other proteins; and a cytoplasmic PEST sequence, which may regulate receptor turnover. Transient expression of NGF receptor mRNA has been seen in many regions of the developing CNS. Experiments suggest that both NGF and its receptor help regulate development of the retina.     

Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation

The extent to which diaphragmatic fatigue results from failure of neural drive has been investigated using twitch occlusion. Fatigue was induced by repeatedly generating transdiaphragmatic pressures (Pdi) of either 50 or 75% maximum Pdi (Pdimax) until approximately 10 min after the target Pdi could no longer be reached (Tlim). Maximal bilateral shocks delivered periodically to the phrenic nerves elicited Pdi twitches between breaths (Tr) and superimposed on the voluntary contractions (Ts). The ratio [1 - Ts/Tr], which provides an index of the degree of central nervous system muscle activation, increased as fatigue developed. However, superimposed twitches were still detectable at and beyond Tlim when all contractions involved maximal efforts. They were not seen in maximal contractions of the unfatigued muscle. Initially, the diaphragm electromyogram increased, but then declined. No impairment of neuromuscular transmission was seen. We conclude that at and beyond Tlim about one-half of the reduction in Pdimax resulted from reduced central motor drive; the remainder resulted from peripheral muscle contractile failure. No fatigue was evident during 50% Pdimax dynamic contractions.     

Diaphragm metabolism during supramaximal phrenic nerve stimulation

The metabolic changes accompanying diaphragm fatigue caused by supramaximal stimulation of the phrenic nerves are incompletely described. In particular, we wished to determine whether the occurrence of anaerobic metabolism correlated with fatigue as defined by decline in force generation. In 10 anesthetized mechanically ventilated mongrel dogs we measured arterial pressure, transdiaphragmatic pressure (Pdi), phrenic arterial flow (Qdi-Doppler flow probe), arterial and phrenic venous blood gases, and lactate levels. From these we derived indexes of diaphragm O2 consumption (VO2) and lactate production. Bilateral phrenic nerve pacing was carried out (50 Hz, duty cycle 0.4, 24 contractions/min) for two 15-min pacing periods separated by a 45-min rest period. Over each pacing period Pdi decreased from approximately 16 to approximately 10 cmH2O (P less than 0.01, no significant difference between periods). Initially, during pacing, Qdi and VO2 each increased fivefold over prepacing base line. Qdi remained elevated at this level whereas VO2 decreased over the pacing period by approximately 25%. Hence, the change in VO2 over the pacing period was due primarily to changes in O2 extraction. During the first pacing period lactate production was observed early and declined throughout the pacing period. No lactate production was observed during the second pacing period, although Pdi, VO2, and Qdi responses were the same for both pacing periods. Phrenic venous PO2 remained greater than 30 Torr throughout both pacing periods.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diaphragmatic pressures: transvenous vs. direct phrenic nerve stimulation

Diaphragmatic force, determined by stimulating the phrenic nerve while simultaneously measuring the pressures in a closed respiratory system, was assessed in five anesthetized dogs over a 5-h period to evaluate the inherent variability of this technique. Transdiaphragmatic pressure (Pdi) was measured at functional residual capacity during stimulation (120 Hz, 0.2-ms duration) of one phrenic nerve by either direct phrenic nerve stimulation (DPNS) or transvenous phrenic nerve stimulation (TPNS). An analysis of variance showed no significant (P greater than 0.50) change during the 5-h period. There was a significant correlation (r = 0.94, P less than 0.001) between Pdi obtained by TPNS and that obtained by DPNS. It is concluded that either DPNS or TPNS can be used to evaluate diaphragmatic strength over a 5-h period and that TPNS can be used in lieu of DPNS.     

Secretion of nerve growth factor by central nervous system glioma cells in culture

Bacteriophage immunoassays, radioimmunoassays, and biological assays have been used to measure levels of NGF in media conditioned by rat C-6 glioma cells in culture. By all three criteria, these cells secrete a macromolecule which is indistinguishable from mouse submandibular gland NGF.     

Mechanisms of magnetic stimulation of central nervous system neurons

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fiber's diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.     

Diaphragm EMG measured by cervical magnetic and electrical phrenic nerve stimulation

The purpose of the study was to compareelectrical stimulation (ES) and cervical magnetic stimulation (CMS) ofthe phrenic nerves for the measurement of the diaphragm compound muscleaction potential (CMAP) and phrenic nerve conduction time. A specially designed esophageal catheter with three pairs of electrodes was used,with control of electrode positioning in 10 normal subjects. Pair A and pairB were close to the diaphragm (pairA lower than pairB); pair C waspositioned 10 cm above the diaphragm to detect the electromyogram fromextradiaphragmatic muscles. Electromyograms were also recorded fromupper and lower chest wall surface electrodes. The shape of the CMAPmeasured with CMS (CMS-CMAP) usually differed from that of the CMAPmeasured with ES (ES-CMAP). Moreover, the latency of theCMS-CMAP from pair B (5.3 ± 0.4 ms) was significantly shorter than that from pairA (7.1 ± 0.7 ms). The amplitude of the CMS-CMAP(1.00 ± 0.15 mV) was much higher than that of ES-CMAP (0.26 ± 0.15 mV) when recorded from pair C.Good-quality CMS-CMAPs could be recorded in some subjects from anelectrode positioned very low in the esophagus. The differences betweenES-CMAP and CMS-CMAP recorded either from esophageal or chest wallelectrodes make CMS unreliable for the measurement of phrenic nerveconduction time.

     

Distribution and developmental expression of lamin-like immunoreactivity in the central nervous system.

Lamins are the major proteic constituents of the nuclear lamina, the innermost layer of the nuclear membrane. The immunolocalization of lamins in the rat central nervous system was studied using polyclonal antibodies. Besides an ubiquitarious localization in the nuclear membranes of neurons and glial cells, an intense lamin-like immunoreactivity was found in the soma and dendrites of cerebellar Purkinje cells. The same specific reaction was also observed in the human cerebellum. Experiments performed in newborn animals demonstrated that the cytoplasmic expression of lamins in Purkinje cells begins during postnatal development.