Targeting the red nucleus for cerebellar tremor.

Deep brain stimulation of the thalamus (and especially the ventral intermediate nucleus) does not significantly improve a drug-resistant, disabling cerebellar tremor. The dentato-rubro-olivary tract (Guillain-Mollaret triangle, including the red nucleus) is a subcortical loop that is critically involved in tremor genesis. We report the case of a 48-year-old female patient presenting with generalized cerebellar tremor caused by alcohol-related cerebellar degeneration. Resistance to pharmacological treatment and the severity of the symptoms prompted us to investigate the effects of bilateral deep brain stimulation of the red nucleus. Intra-operative microrecordings of the red nucleus revealed intense, irregular, tonic background activity but no rhythmic components that were synchronous with upper limb tremor. The postural component of the cerebellar tremor disappeared during insertion of the macro-electrodes and for a few minutes after stimulation, with no changes in the intentional (kinetic) component. Stimulation per se did not reduce postural or intentional tremor and was associated with dysautonomic symptoms (the voltage threshold for which was inversed related to the stimulation frequency). Our observations suggest that the red nucleus is (1) an important centre for the genesis of cerebellar tremor and thus (2) a possible target for drug-refractory tremor. Future research must determine how neuromodulation of the red nucleus can best be implemented in patients with cerebellar degeneration.

Diencephalic and mesencephalic influences on ponto-medullary respiratory control in normoxic and hypoxic conditions: an in vitro study on central nervous system preparations from newborn rat.

We investigated the effects of the diencephalon and mesencephalon on the central respiratory drive originating from ponto-medullary regions in normoxic and hypoxic conditions, using central nervous system preparations from newborn rats. We used two approaches: 1) electrophysiological analysis of respiratory frequency and the amplitude of inspiratory C4 activity and 2) immunohistochemical detection of Fos protein, an activity-dependent neuronal marker. We found that, in normoxic conditions, the mesencephalon moderated respiratory frequency, probably by means of an inhibitory effect on ventral medullary respiratory neurons. Diencephalic inputs restored respiratory frequency. Moreover, O(2)-sensing areas in the diencephalon (caudal lateral and posterior hypothalamic areas) and mesencephalon (ventrolateral and dorsolateral periaqueductal gray) seem to increase the amplitude of respiratory bursts during adaptation of the central respiratory drive to hypoxia. In contrast, decrease in respiratory frequency during hypoxia is thought to be mediated by a cluster of ventral hypothalamic neurons.

Somatosensory evoked potentials for the diagnosis of proximal sensory median neuropathy with preserved distal sensory action potential.

A 33 year-old-man with paresthesia in first three fingers of the right hand after minor trauma of the arm was examined electrophysiologically. The proximal sensory median neuropathy was isolated which it is unusual in traumatic lesion. Motor and distal sensory conduction studies were normal but sensory evoked potentials (SEPs) were abnormal by right median nerve stimulation at the wrist level with decrease in amplitude of peripheral potential at the Erb's point, the cervical and contralateral parietal levels. This pattern, preserved distal sensory action potential and abnormal peripheral SEPs were suggesting the presence of proximal sensory block conduction without wallerian degeneration. The recovery was complete and fast in correlation with the absence of axonopathy.

Role of respiratory and non-respiratory neurones in the region of the NTS in the elaboration of the sneeze reflex in cat.

Extracellular recordings were made in the dorsal respiratory group (DRG) and adjacent reticular formation following single-shock stimulation of the anterior ethmoidal nerve (AEN) and during sneeze evoked by repetitive stimulation of the AEN in nembutal-anaesthetized, curarized and ventilated cats. These neurones were characterised according to (i) their activity during the respiratory cycle (as inspiratory augmenting or decrementing (I Aug or I Dec), expiratory augmenting or decrementing (E Aug or E Dec), silent or tonic), and (ii) their axonal projection (bulbospinal or non-bulbospinal-non-vagal (BS or NBS-NV)). Following single-shock stimulation of the AEN, most of the inspiratory neurones were transiently inhibited, whereas E Aug neurones were activated and E Dec neurones were activated and then inhibited. Silent neurones responded with a multispike or a paucispike pattern. Following repetitive stimulation of the AEN and during the resulting sneeze reflex, I Aug neurones increased their activity in parallel with the phrenic activity, I Dec neurones fired at the onset and at the end of the inspiration, E Dec and some silent neurones fired either during the compressive phase or after the expulsive phase, whereas E Aug and some silent neurones fired during the expulsive phase. We conclude that sneeze involves a reconfiguration of the central respiratory drive which uses, at least partly, the respiratory network to trigger a non-ventilatory defensive motor act.

Activities of vagal receptors in the different phases of sneeze in cats.

We studied the activity of 50 slow-adapting receptors (SAR), 13 rapidly-adapting receptors (RAR) and 3 expiratory modulated receptors in the different phases of sneeze in tracheostomized and non-tracheostomized anaesthetized cats. SAR activity increased progressively during the first phase of the preparatory inspiration in parallel to integrated diaphragmatic activity. During the second phase of the preparatory inspiration, SAR increased their discharge frequency; higher threshold SAR and RAR were recruited. During the compressive phase, discharge of SAR kept stable or increased slightly in parallel to an increase in transpulmonary pressure, while expiratory modulated receptors were activated. During the expulsive phase, only RAR were activated. Increase in transpulmonary pressure at the end of the inspiration phase of sneeze shortened expiratory duration and increased the rate of rise of expiratory muscle activity. Increase in transpulmonary pressure at the end of the compressive phase further shortened expiratory duration. These results suggest: first, a facilitatory effect on the triggering of the second phase of the preparatory inspiration from SAR; second, a modulation of the early stage of expiration by SAR, RAR and expiratory modulated receptors during the compressive phase; third, a permissive effect on a rapid expulsive thrust by SAR which can be further limited by RAR; fourth, a facilitatory effect on the triggering of inspiratory activity that follows the expiratory thrust by RAR. Both SAR and RAR might participate in the occurrence of successive sneeze in an attack and in the increased frequency of sneezing. Our results suggest that complex convergent inputs from nasal and vagal receptors, which alter the respiratory rhythm and rhythmogenesis, modulate finely the sneeze reflex.

Influence of vagal afferents in the sneeze reflex in cats.

We studied the effects of bilateral vagotomy and step pulmonary inflations (5, 10, 15 mmHg, i.e., 0.66, 1.33, 2 kKPa) on sneeze reflex in ketamine-anaesthetized cats. Bilateral vagotomy lengthens the duration of preparatory inspiration and diminishes the amplitude of expiratory activities in sneeze. In contrast, 5 mmHg pulmonary inflation facilitates the sneeze. It shortens the inspiratory preparation and increases the frequency of sneeze attacks. At 10 mmHg pulmonary inflations, inspiration is inhibited and only expiratory thrust occurs. At 15 mmHg pulmonary inflations, vagal afferent stimulations inhibit the sneeze.

Nasal air puff stimulations and laryngeal, thoracic and abdominal muscle activities.

In cats, we studied the activity of laryngeal, thoracic and abdominal muscles and the variations in oesophageal pressure in response to air puff stimulations of the nasal mucosa. Following single stimulations, inspiratory and laryngeal dilator muscles were transiently inhibited. During inspiratory inhibition, expiratory muscles and laryngeal constrictor were transiently activated. Repetitive air puff stimulations, which induced sneeze, evoked a similar pattern of transient activities during the inspiratory preparation of sneeze. This resulted in transient fluctuations of the oesophageal pressure, whose mean value became more negative as the preparatory inspiration enhanced. Our results suggest that the entire pool of respiratory neurons (bulbospinal, vagal and facial) works together in the sneeze reflex. Study of transient inspiratory inhibition demonstrates two periods during the preparatory inspiration phase of sneeze. In the first period transient effects are related to each shock of the stimulation. The second period is characterized by a diminution or a lack of transient effects associated with the stimulation. At the end of the expulsive phase, the diaphragm and the glottal dilator were further activated.

Postnatal development of the anterior ethmoidal nerve in cats: unmyelinated and myelinated nerve fiber analysis.

This is the first quantitative electron microscopic study of anterior ethmoidal nerve in adult and newborn cats. The adult nerve comprises about 1,000 myelinated fibers including A delta (65%) and A beta (35%) fibers and 6,000 unmyelinated fibers. At birth, only 27% of the adult myelinated fibers complement is already present. The immaturity of the nerve is discussed in relation to that of the sneeze reflex.

The sneeze: maturation of the reflex in kittens.

This is the first study to compare the influence of nasal afferent stimulation on inspiratory and expiratory muscle activity during sneezing, in kittens and adult cats. In kittens, we demonstrate that nasal afferent stimulation does not reinforce inspiratory activity prior to the expiratory thrust as it normally does in adult cats. These stimulations evoke an active expiration similar to but weaker than the expiratory thrusts observed under the same conditions during sneezing in adult cats. Sneezing can be elicited from three weeks of life. Among the different hypotheses discussed, the most likely explanation appears to be the immaturity of medullary respiratory connections.

Influence of trigeminal nasal afferents on bulbar respiratory neuronal activity.

This study examined the influence of nasal trigeminal afferents, the anterior ethmoidal nerve (AEN) and posterior nasal nerves (PNN) on the spike discharges of respiratory-related neurons recorded in the ventral respiratory group (VRG) (2.6-3.5 mm lateral to the midline, from 1 mm rostral to 3 mm caudal to the obex and at depth of 2-4 mm below the dorsal surface). Electrical stimulations to the AEN and PNN were administered to 10 pentobarbital anaesthetized cats and to 8 ketamine anaesthetized, vagotomized, curarized and ventilated cats. Single shock stimulations of either nerve evoked transient and total inhibition of inspiratory activities. Expiratory-related neurons of the VRG presented three patterns of activity in response to stimulation:excitation, inhibition or inhibition followed by excitation. More generally, expiratory units are activated with a short latency. In the course of repetitive stimulation of the AEN and PNN we observed a prolongation of the spontaneous inspiratory discharge which presented transient, short inhibition in response to each shock. Most expiratory units presented a short activation which was synchronous with the transient inhibition of inspiratory activities. When repetitive stimulation provoked a sneeze-like response, we observed a progressive increase in the duration of transient inspiratory inhibition first, associated with a progressive reinforcement of transient expiratory activation. Secondarily, just before the expiratory thrust, we noted a stronger inhibition of the inspiratory activity which preceded a high-frequency (400 Hz) expiratory discharge. Nasal afferents exert a forceful excitatory effect on bulbospinal (BS) and non-bulbospinal-non-vagal (NBS-NV) expiratory cells of the VRG. The effects due to vagotomy and curarization are discussed.

Trigeminal nasal receptors related to respiration and to various stimuli in cats.

In twenty adult cats of either sex under nembutal anaesthesia, we aimed at delineating the sensitive territory of trigeminal nerves innervating the nasal mucosa. The different trigeminal nerves (anterior ethmoidal, posterior nasal and infraorbital nerves) were dissected in the orbit. Activity of these nerves was recorded during spontaneous nasal and tracheal breathing and in response to various stimuli: mechanical (manual probing and air jets) and irritants (ammonia vapours). Multiple and unitary activity recorded in nerve filaments enabled a classification of the receptors on the basis of their discharge pattern as rapidly-, intermediately- or slowly adapting receptors, and as drive or non-drive nasal receptors depending on whether or not the respiratory modulation was preserved during tracheal breathing.

Trigeminal afferences implied in the triggering or inhibition of sneezing in cats.

The aim of this study was to precise the role of the different trigeminal nerve branches involved in innervation of the nostril in triggering the sneeze reflex. Electrical stimulation of the anterior ethmoidal, posterior nasal and infraorbital nerves was performed in anaesthetized cats. Stimulation of these 3 nerves produced sneezing identical to that induced by mechanical stimulation. Our results emphasize inhibition of the sneeze reflex related to stimulation of the anterior ethmoidal or the posterior nasal nerves by stimulation of the infraorbital nerve.

Phrenic-to-phrenic inhibition and excitation in spinal cats.

In decerebrate, C2-spinalized cats, stimulation of the C6-phrenic root produces a weak activation of phrenic motoneurons in the adjacent C5 segment in a few animals (23%). When phrenic motoneurons are electrically excited by testing stimulation applied to the spinal cord or internal intercostal nerve, the evoked responses recorded in a cervical phrenic root are partly inhibited by conditioning stimulation applied to another ipsilateral or contralateral cervical phrenic root. We therefore conclude that phrenic fibers exert both inhibitory and excitatory effects on adjacent phrenic motoneurons in the cervical spinal cord.

Effects of ipsilateral and contralateral cervical phrenic afferents stimulation on phrenic motor unit activity in the cat.

The phrenic-to-phrenic inhibitory reflex has been analyzed using recordings of activity of single C5-phrenic motor units (PMUs). After ipsilateral or contralateral stimulation of the C6-phrenic root, early and late PMUs exhibit a similar inhibition. After contralateral stimulation, the duration of the inhibition is smaller and the threshold stimulus is higher than the corresponding values observed after ipsilateral stimulation. The latency of the inhibition is similar for both stimulations. Hemispinalization, contralateral to the recording site, affects weakly the phrenic-to-phrenic reflex. We conclude that early and late PMUs receive a similar inhibitory input from phrenic afferents and that the inhibition observed after cervical phrenic nerve stimulation may involve spinal cord circuits.

Inhibitory and excitatory effects on respiration by phrenic nerve afferent stimulation in cats.

Respiratory effects of electrical stimulation of phrenic nerve afferents were studied in anesthetized cats, either spontaneously breathing or paralyzed and ventilated. The type of phrenic afferent fibers activated was controlled by recording the evoked action potentials from dorsal root fibers. In both preparations, stimulation at a strength sufficient to activate small diameter myelinated phrenic nerve afferents induced a biphasic response. The first phase lasted a few respiratory cycles and was inhibitory and consisted of a decrease in tidal volume (VT) or phrenic activity (NA), inspiratory time (TI), respiratory duty cycle (TI/Ttot) and instantaneous ventilation (VE) or minute phrenic activity (NMA). Expiratory time (TE) increased and breathing frequency (f) and mean inspiratory flow (VT/TI) or mean inspiratory neural activity (NA/TI) did not change. This short-term response was suppressed in animals pretreated with bicuculline. The second phase was a long-term excitation in which VT or NA, f, VE or NMA and VT/TI increased whereas both TI and TI/Ttot decreased and TE did not change. Unlike published data, our results suggest that small-diameter myelinated phrenic nerve afferents are involved in these responses. These phrenic fibers, like afferents from other muscles, affect respiratory output and may play a role in the control of breathing.

Effects of stimulation of phrenic afferent fibers on medullary respiratory neurons in cat.

The effects of electrical stimulation of both cervical branches (C5 and C6) of the right phrenic nerve on medullary respiratory neuron activity were studied in anesthetized, spontaneously breathing cats. In 14 cats, the stimulation of the thin phrenic afferents had no effect on the inspiratory duration and evoked excitatory or inhibitory responses in only 3/86 inspiratory neurons tested. In 3 cats, the stimulation decreased the inspiratory duration and 26/26 inspiratory neurons showed a shortened discharge without modification of their discharge frequency. Although the effects of the stimulation were not analysed by averaging techniques, it is concluded that phrenic afferents do not exert an important control on the medullary respiratory neuron discharge.

Phrenic afferent input to the lateral medullary reticular formation of the cat.

The afferent inputs from phrenic nerve stimulation to the lateral reticular formation of the lower brain stem were studied in anesthetized spontaneously breathing cats. The activity of reticular neurons was recorded by means of extracellular tungsten microelectrodes. Electrical stimulation of the central end of the right phrenic nerve evoked excitatory or inhibitory responses in the lateral reticular nucleus (LRN), in the nucleus ambiguus (AMB) and in a region dorsal to the AMB of ipsi- and contralateral sides. Phrenic afferents belonging to the flexor reflex afferent group were involved in these responses. The discharge pattern of the respiratory related units (RRU) of the AMB were exceptionally affected by phrenic nerve stimulations. It is concluded that high threshold phrenic afferents relay in the LRN before projecting to the cerebellar cortex. The overlapping of respiratory and non-respiratory afferents in the reticular formation may participate to the adaptations of respiratory and somatomotor functions during specific behaviors.

Projection of phrenic afferents to the external cuneate nucleus in the cat.

The present study, performed on anesthetized, spontaneously breathing cats, deals with the projection of group I and II muscle afferents of the phrenic nerve (PN) to the external cuneate nucleus (ECN). Stimulation of the central end of the PN evoked a complex response in the ipsilateral ECN. Two principal components could be distinguished in this potential from the respective absolute refractory periods (ARP) and from the effect of antidromic stimulation in the ECN. Thus, the early group of waves may correspond to recordings of direct fibers and the later group to postsynaptic activations within the ECN. Similar to the forelimb nerves and intercostal nerves of the upper intercostal spaces, the larger muscle afferents of the PN project to the ECN.

Projections of phrenic afferences to the cat cerebellar cortex.

Evoked phrenic potentials were recorded on the cerebellar cortex of anesthetized adult cats after electrical stimulation of both cervical branches (C5 and C6) of the right phrenic nerve. In this case phrenic stimulation evoked a surface positive response with a mean amplitude (+/- S.D.) of 13.4 +/- 5.2 microV. The mean latency and the mean duration of this phase were, respectively, 9.5 +/- 1.2 ms and 19.4 +/- 2.1 ms. This response was found only in the ipsilateral intermediate cortex and in the ipsilateral and, to a less extent, in the contralateral vermis of the posterior part of the anterior lobe (Larsell's lobule V); these areas corresponding to the forelimb projection zones. The phrenic afferences projecting to the cerebellar cortex were essentially conducted in the contralateral ventro-lateral spinal tracts.

[Disorders of folate metabolism in the Kearns-Sayre syndrome]. / Troubles du métabolisme des folates au cours d'un syndrome de Kearns et Sayre.

In 1958, Kearns and Sayre described a syndrome characterized by external ophthalmoplegia, pigmentary retinopathy and cardiac conduction disorders. Subsequent publications have reported the presence of morphologic anomalies of muscle mitochondria and a spongiform encephalopathy. The study of folate metabolism in the present case demonstrated a marked drop in cerebrospinal fluid folate levels contrasting with normal plasma levels. The origin of this anomaly could be a disturbance in the active transport system of 5-methyl tetrahydrofolate (5 CH3 THF) in the choroidal plexuses. This compound is involved in brain metabolism at different levels: synthesis of purine and pyrimidine bases, serotonin metabolism, synthesis and methylation of membrane phospholipids. Therefore a deficit in brain 5 CH3 THF levels could be implicated in the pathophysiology of the spongiform encephalopathy. In the current state of knowledge a relation between folate transfer disorders and mitochondrial anomalies is difficult to establish.