Maturation of regenerating nerve assessed by evoked potential in the rat: hyperbolic time course.

Recovery of sensory fiber excitability after sciatic nerve lesion induced by freezing was assessed by the somesthesic evoked potential (SEP) in response to plantar pad electrical stimulation. SEP was recorded from the S1 area through chronically implanted cortical electrodes. The P1 wave reappeared on Day 22 or 23 postinjury, indicating that the axonal elongation rate ranged between 3.9 and 4.1 mm/day. P1 onset (P1o) latency decreased from 61.9 +/- 6.4 ms (SD) on Postoperative Day 22 to 18.8 +/- 1.13 ms on Day 50. Computation of standardized residuals showed that the best values for the regression equation as a function of time were obtained after hyperbolic transformation. Covariance analysis showed significant differences between untreated animals and after treatment with thyroxin (T4) and metformin p-chlorophenoxyacetate (MP) or after conditioning lesion (CL). This indicates that these treatments acted selectively on the components of the maturation process.

Respiratory rhythm multistability during sleep-wake states.

Respiratory period (RP) changes occurring during sleep-waking states were studied during 5- to 8-h recording sessions in chronic cats. RP distribution was clearly trimodal, the shortest mode occurring essentially during alert wakefulness, the largest mode during slow wave sleep and the intermediate mode during drowsy wakefulness. Immediate shifts were observed at instant awakening, whereas after an EEG arousal lasting a few seconds, the RP could remain short for several minutes. Results suggest that the respiratory pattern generator depends upon several attractors.

Gallamine and vagotomy enhance respiratory modulation of reticular units.

Respiration related units ( RRU ) were recorded in the brainstem of cats with spinal transection at the C7-Th 1 level and breathing N2O. The proportion of RRU in several structures was compared in control and in 3 experimental groups: (1) paralyzed with gallamine triethiodide; (2) vagotomized; and (3) both vagotomized and paralyzed. After gallamine, RRU percentage was multiplied by 3 in the bulbo-pontine reticular formation (RF) and as much as 20 in the mesencephalic RF. Vagotomy multiplied RRU proportions by 2 in the bulbo-pontine RF, by 12 in the mesencephalic RF and by 3 in the pneumotaxic complex (nucleus parabrachialis medialis ( NPBM ) and K olliker -Fuse (KF) nucleus). The effects of gallamine and vagotomy were not additive. Gallamine still increased proportion of RRU in the RF after vagotomy showing that the gallamine effect is not vagally mediated; this was in contrast to the previously reported suppression by vagotomy of phrenic discharge facilitation induced by gallamine. The total number of firing units in the RF was not modified by gallamine or vagotomy. It is concluded that the respiratory modulation of reticular neurons is selectively enhanced by gallamine and vagotomy through two independent mechanisms.

Dissociation between respiratory phase switching and phasic phrenic response on low-intensity stimulation of pneumotaxic complex and nearby structures.

Excitatory and inhibitory phasic phrenic responses (ePPR and iPPR) and inspiratory on-switch and off-switch (I-ON-S and I-OFF-S) were compared on stimulation of the pneumotaxic complex and neighboring reticular formation in cats anesthetized with nitrous oxide, curarized and spinalized at the C7 level. Stimulation consisted of a single pulse or train of 2 to 5 shocks whose intensity ranged between 100 and 300 microA. Single shock stimulation of the Kölliker-Fuse (KF) nucleus and of a region 1 mm just caudal evoked a pure iPPR during the phrenic burst. With single pulse of high intensity delivered in the second half of inspiration (I), the iPPR was associated with I-OFF-S. Single shock stimulation of a wider brain stem area including the medial part of the nucleus parabrachialis medialis (NPBM), nucleus parabrachialis lateralis and adjacent lateral and central tegmental fields evoked early iPPR combined with a later ePPR when delivered in I, and ePPR alone during expiration (E). Train stimulation of much more restricted areas could evoke I-ON-S or I-OFF-S depending on the site of stimulation and time of delivery in I or E. Definite dissociations occurred between iPPR and I-OFF-S according to the place of stimulation. A maximal iPPR, obtained from a region ventral to the NPBM, was never found to be associated with I-OFF-S. The excitability of I-ON-S, and ePPR amplitude showed opposite time-courses during E and had different latencies.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacological basis of the action of isaxonine (author's transl)]. / Bases pharmacologiques de l'action de l'isaxonine.

The author reviews previous therapeutic attempts to stimulate regeneration of peripheral nerves. Since 1971 he has been studying a synthetic compound, isaxonine, which in rats accelerates nerve regeneration and functional recovery. Stimulation of axonal regeneration and collateral sprouting has been demonstrated in tissue cultures. The therapeutic activity of the compound has been demonstrated in man in leprous neuropathy and in vincristine neuropathy. Isaxonine has specific affinity for peripheral nerves. Its acts directly on the neuron or indirectly by stimulating production of a growth factor remains unknown. In vitro and in vivo studies isaxonine have shown that isaxonine antagonizes the noxious effects of Vinca alkaloids on neurotubular structure. Research in progress suggest a possible action of this new compound in other diseases related to tubulin anomaly.

[Acceleration by isaxonine of muscle reinnervation. Electrophysiological demonstration in leprotic neuropathy (author's transl)]. / Accélération de la réinnervation musculaire par l'isaxonine. Mise en évidence électrophysiologique au cours des neuropathies hanséniennes.

On a model of compressive human neuropathy--leprous neuropathy occuring below an osteoligamentary canal following a process of sclerosis--a double-blind survey of isaxonine versus a placebo was undertaken after matching of patients to obtain similar pairs. After four months of treatment with isaxonine, the electrophysiological tests (EMG of the anterior tibialis and of the abductor digiti minimi muscle) showed a very significant improvement in the graphs of patients receiving the active agent, as compared to a lack of improvement, even an aggravation for those patients receiving the placebo. It may thus be concluded that muscular reinnervation has occurred, either by sprouting of the remaining healthy fibers or by regeneration of the damaged axons, or by both phenomena simultaneously.

[Neurotoxic substances as a tool to understand some mechanisms of peripheral neuropathies (author's transl)]. / Apport des neurotoxiques a la compréhension des mécanismes des neuropathies périphériques.

The study of toxic experimental models of neuropathies has been a decisive step to understand some cellular mechanisms of human neuropathies. The progressive development of toxic neuropathies allow to the possibility of isolating their initial mechanism. Dying back axonopathies are the commonest neuropathies as observed in clinical practice, and their experimental models had been extensively studied. Acrylamide and n-hexane intoxications have shown the following results : 1) The onset of the neuropathy is located at the most distal node of the longest and largest fibres. Sensory fibres are impaired before the motor ones. 2) Fast axoplasmic transport stops distally. 3) Impaired enzymes of the energetic cycle were observed distally. Proximal axonopathies as those resulting from IDPN intoxication are a possible model to clear up the cellular mechanisms of the lateral amyotrophic sclerosis. Human toxic neuronopathies and myelinopathies are uncommon. Such experimental models are described in relation to other human neuropathies.

Apneusis and apnea after parabrachial or Kölliker-Fuse N. lesion; influence of wakefulness.

Comparisons were made between the effects of bilateral lesions of either the nucleus parabrachialis medialis (NPBM) or the Kölliker-Fuse (KF) nuclei in bivagotomized, spinalized and immobilized cats. In a first group animals were electrolytically decerebrated; in a second group animals were locally anaesthetized and atraumatically restrained (semi-chronic encéphale isolé preparation). Lesions resulted in: (1) a marked increase in TI (apneusis); (2) 50--80% decrease in amplitude of the integrated phrenic discharge (IPD); (3) variable lengthening, of TE. Following KF lesion, effects were significantly larger on TE in the decerebrate group, and on TI in the encéphale isolé group. In the encéphale isolé group awakening reduced TE and TI and brought them close to their prelesion values following both NPBM and KF lesion; on the other hand light sleep induced by pentobarbital led to expiratory apnea after KF lesion and reduced IPD amplitude to zero after NPBM lesion. It is proposed that the onset, tonic drive and cut off of the I discharge are normally controlled by three differently weighted influences originating from NPBM, KF and reticular formation respectively.

Nerve-growth promoting action of isaxonine in rat.

After sciatic nerve lesion by freezing, the length of the most rapidly regenerating fibres was significantly increased by i.p. injection of isaxonine (N-isopropyl-amino-2-pyrimidine orthophosphate) in the rat. A dose-effect relationship was demonstrated. Both sensory and motor function returned earlier in treated animals.

Pentobarbitone effects on respiration related units; selective depression of bulbopontine reticular neurones.

Respiration related units (RRUs) were recorded in cats, locally anesthetized, vagotomized and immobilized, under two different experimental conditions: (1) receiving pentobarbitone intravenously at a dose inducing slight but highly significant changes in phrenic discharge; (2) unanesthetized, with a spinal section at C6. RRU characteristics were analysed in unitary volumes constituted by cubes of a matrix including the brain stem. Four parameters of RRU discharges were compared in cubes = RRU density (RRUD), RRU proportion and two indices of respiratory modulation. Cubes were sampled in: (1) dorsal and ventral bulbar respiratory nuclei, (2) pneumotaxic centre (PC), and (3) seven fields of the bulbopontine and mesencephalic reticular formation. Using the paired sample method for comparing data cube by cube in the two conditions it was shown that under pentobarbitone, RRU activity was profoundly depressed in the reticular formation surrounding dorsal and ventral bulbar respiratory nuclei, in the region bridging the gap between these and the pneumotaxic centre and extending from the pneumotaxic level to the decussation of the brachium conjunctivum. In contrast RRU activity was unchanged at the level of dorsal and ventral bulbar respiratory nuclei and in the nucleus parabrachiallis medialis (NPBM) and was increased in the Kölliker-Fuse nucleus (KF). In the mesencephalic reticular formation, increased activity was observed for non-modulated units and to a larger extent for units driven by the bulbopontine respiratory system.

Ascending projection from the respiratory centre to mesencephalon and diencephalon.

The brainstem reticular formation, subthalamus and thalamus were explored in a search for units modulated by the respiratory centre. Experiments were performed on cats under local anesthesia, in which respiratory center oscillation was independent of movement of the lungs and thorax. A large proportion of units firing tonically showed an increasing frequency, phase related to phrenic nerve activity. Respiration related units (RRUs) rostral to the pneumotaxic centre were concentrated in definite areas of the brainstem reticular formation, subthalamus and thalamus. Respiratory modulation disappeared rostral to a section performed at the ponto-mesencephalic junction.

[Acceleration of the speed of neuronal growth by a new neurotropic substance: N-isopropyl-amino-2-pyrimidine].

16 hrs. after per os administration of 14C N-isopropyl-amino-2-pyrimidine (IAP) in the Rat, radioactivity of the sciatic nerve is significantly higher than in plasma and other organs. In vitro IAP (base, orthophosphate or dichloracetate) accelerates neurite outgrowth of explained spinal ganglion after 48 hrs. of incubation in nutritive medium. Results suggest that IAP incorporated in nerve cell acts on cellular mechanisms controlling nerve growth.

Discharge patterns of bulbo-pontine respiratory unit populations in cat.

Respiration related units (RRU) were recorded during a stratigraphic exploration of medulla and pons from the cervical junction to the caudal part of the pneumotaxic system in the semi-chronic locally anesthetized 'isolated respiratory centre' of the cat. Metal 'low impedance, capacitance compensated' microelectrodes recorded multi-unit signals from which unitary discharges were discriminated and processed by computer; it is suggested that using these techniques, the sample was a good representation of the total unit population. The phase relation to phrenic discharge was determined on cycle triggered time histograms. Of 23,000 units, 28% had a definite respiratory modulation. Examined individually, each RRU showed a stable discharge pattern corresponding to one of various respiratory types, the majority of which have been described previously. Both temporal and spatial distributions of RRU discharges were analyzed. Temporal distribution of peak firing frequencies (PFF) of 5,000 RRU sampled anatomically at random showed two main populations whose modes were observed during inspiration (I) or expiration (E). Troughs were observed in the histogram at the transition from I to E and E to I, thus indicating low probability for finding phase spanning RRU in the medulla and pons up to the pneumotaxic level. These statistical results turned out to be identical to those obtained with an a priori classification method comparable to that used in most of the previous works. In addition, the PFF distribution suggested that the E population could be further divided into 3 sub-populations whose modes fall in early, mid, and late expiration respectively. Comparison of RRU temporal distribution in two regions, one rostral, another caudal to a frontal Horsley-Clarke plane situated 3 mm in front of the obex, showed that, in the caudal region, 70% of the RRU were I units, while, in the rostral medulla and pons, equal proportions of I and E neurons were found. Temporal distribution of RRU peak frequencies was studied separately in anatomical structures where the probability of finding RRU was high. No clear correspondence between RRU types and anatomy could be found, but marked differences between structures were observed, thus suggesting nevertheless a different spatial distribution for I and E populations.

Three dimensional representation of bulbo-pontine respiratory networks architecture from unit density maps.

Results of the preceding paper32 suggest that bulbo-pontine respiration related units (RRU) could be classed into 4 populations according to the relation of their peak firing frequency to the respiratory cycle: one inspiratory (I) and 3 expiratory (E) (early, mid and late). A further study of their spatial distribution is reported. Recorded units totalling 26,520 were distributed through a matrix of unitary cubes of which about 2,000 were found within the limits of the medulla and pons. Both percentage and density of respiratory and non-respiratory units were estimated in each cube. Statistical analysis of unit distribution showed a high probability of finding RRU in certain regions. The probability of finding I and E units in separate cubes was high, whereas there was no probability better than chance for recording one of the 3 E types separately from the 2 others. Therefore, only two populations, I and E, could be considered for spatial analysis. A thresholding technique applied to I and E unit density figures in unitary cubes demonstrated a definite limit for I and E populations. A computerized, three-dimensional (3-D) reconstruction of the outer surfaces of the I and E networks showed that half a medullary system consisted of 2 contiguous and uninterrupted columns extending from the cervical junction up to the pneumotaxic system. The main body of the I population was found in the caudal third and dorsolateral part of the bulbopontine region, while the main body of the E population was in the middle third in a ventromedial position. Both have caudal and rostral extensions that run parallel to the main axis of the brainstem and give rise to several lateral branches; these lie in close contact and interdigitate extensively, especially in the rostral third of the bulbopontine region. From the outer limits of I and E networks, a progressive increase of unit density levels was observed towards the core; it showed that inside both I and E populations, RRU aggregate into high density foci (HDF). Large HDF were found in the main body of each population. Smaller HDF were observed scattered throughout the medulla; I, and to a lesser extent E, HDF invade and surround sensory and motor nuclei and roots of the branchial nerves.