The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENT Following unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.

Intrinsic connections within the pedunculopontine tegmental nucleus are critical to the elaboration of post-ictal antinociception.

This study investigated the intrinsic connections of a key-structure of the endogenous pain inhibitory system, the pedunculopontine tegmental nucleus (PPTN), in post-ictal antinociceptive process through synaptic inactivation of the PPTN with cobalt chloride. Male Wistar rats (n = 6 or 7 per group), weighing 250-280 g, had the tail-flick baseline recorded and were submitted to a stereotaxic surgery for the introduction of a guide-cannula aiming at the PPTN. After 5 days of postoperative recovery, cobalt chloride (1 mM/0.2 µL) or physiological saline (0.2 µL) were microinjected into the PPTN and after 5 min, the tail-withdrawal latency was measured again at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 min after seizures evoked by intraperitoneal injection of pentylenetetrazole (64 mg/kg). The synaptic inactivation of PPTN decreased the post-ictal antinociceptive phenomenon, suggesting the involvement of PPTN intrinsic connections in the modulation of pain, during tonic-clonic seizures. These results showed that the PPTN may be crucially involved in the neural network that organizes the post-ictal analgesia.

Neuromodulation of vegetative state through spinal cord stimulation: where are we now and where are we going?

BACKGROUND: Vegetative state (VS) is a complex condition that represents a challenging frontier for medicine and neuroscience research. Nowadays there is no scientifically validated treatment for VS patients, and their chronic long-term assistance is very demanding for healthcare systems worldwide. OBJECTIVES: The present paper is a systematic review of the role of spinal cord stimulation (SCS) as a treatment of patients with VS. METHODS: Published literature on this topic was analyzed systematically. Clinical and epidemiological characteristics of VS, present therapeutic options and social costs of VS were also evaluated. RESULTS: Only 10 papers have been published since 1988, and overall 308 VS patients have been treated with SCS worldwide; 51.6% displayed a clinical improvement and an amelioration of the environmental interaction. These effects are probably mediated by the stimulation of the reticular formation-thalamus-cortex pathway and by cerebral blood flow augmentation induced by SCS. CONCLUSIONS: The experience on this topic is still very limited, and on this basis it is still hard to make any rigorous assessment. However, the most recent experiments represent significant progress in the research on this topic and display SCS as a possible therapeutic tool in the treatment of VS.

A trigeminoreticular pathway: implications in pain.

Neurons in the caudalmost ventrolateral medulla (cmVLM) respond to noxious stimulation. We previously have shown most efferent projections from this locus project to areas implicated either in the processing or modulation of pain. Here we show the cmVLM of the rat receives projections from superficial laminae of the medullary dorsal horn (MDH) and has neurons activated with capsaicin injections into the temporalis muscle. Injections of either biotinylated dextran amine (BDA) into the MDH or fluorogold (FG)/fluorescent microbeads into the cmVLM showed projections from lamina I and II of the MDH to the cmVLM. Morphometric analysis showed the retrogradely-labeled neurons were small (area 88.7 µm(2)±3.4) and mostly fusiform in shape. Injections (20-50 µl) of 0.5% capsaicin into the temporalis muscle and subsequent immunohistochemistry for c-Fos showed nuclei labeled in the dorsomedial trigeminocervical complex (TCC), the cmVLM, the lateral medulla, and the internal lateral subnucleus of the parabrachial complex (PBil). Additional labeling with c-Fos was seen in the subnucleus interpolaris of the spinal trigeminal nucleus, the rostral ventrolateral medulla, the superior salivatory nucleus, the rostral ventromedial medulla, and the A1, A5, A7 and subcoeruleus catecholamine areas. Injections of FG into the PBil produced robust label in the lateral medulla and cmVLM while injections of BDA into the lateral medulla showed projections to the PBil. Immunohistochemical experiments to antibodies against substance P, the substance P receptor (NK1), calcitonin gene regulating peptide, leucine enkephalin, VRL1 (TPRV2) receptors and neuropeptide Y showed that these peptides/receptors densely stained the cmVLM. We suggest the MDH- cmVLM projection is important for pain from head and neck areas. We offer a potential new pathway for regulating deep pain via the neurons of the TCC, the cmVLM, the lateral medulla, and the PBil and propose these areas compose a trigeminoreticular pathway, possibly the trigeminal homologue of the spinoreticulothalamic pathway.

Temporary reduction of blood pressure and sympathetic nerve activity in hypertensive patients after microvascular decompression.

BACKGROUND AND PURPOSE: Experimental studies suggested neurovascular compression of the brain stem as a cause of hypertension. The aim of our prospective study was to investigate the effect of microvascular decompression in patients with severe hypertension with neurovascular compression on blood pressure and central sympathetic nerve activity in the long-term. METHODS: Fourteen patients (4 males; mean age, 46+/-8 years) with essential hypertension underwent microvascular decompression of the brain stem. Vasoconstrictor muscle sympathetic nerve activity (recorded by microneurography: burst frequency, bursts/min) and blood pressure (24-hour profiles) were investigated before surgery and 7 days, 3 months, and every 6 months postoperatively. RESULTS: Muscle sympathetic nerve activity was preoperatively elevated and decreased significantly postoperatively (35+/-13 bursts/min vs 20+/-9 bursts/min; P<0.01). Sympathetic activity remained reduced 3 months (19+/-8 bursts/min; P<0.01), 6 months (19+/-7 bursts/min; P<0.01), and 12 months (23+/-9 bursts/min; P<0.01) postoperatively. However, in the long-term, sympathetic nerve activity increased again (18 months after surgery: 28+/-10 bursts, not significant; 24 months postoperatively: 34+/-12 bursts/min, not significant). Systolic and diastolic blood pressure decreased from 162+/-6/98+/-5 mm Hg preoperatively to 133+/-6/85+/-4 mm Hg (7 days postoperatively; P<0.01); 136+/-5/86+/-4 mm Hg (3 months postoperatively; P<0.01); 132+/-4/85+/-4 mm Hg (6 months postoperatively; P<0.01); 132+/-3/85+/-5 mm Hg (12 months postoperatively; P<0.01); 132+/-5/84+/-5 mm Hg; P<0.01). Twenty-four months after microvascular decompression, blood pressure increased again up to 158+/-7/96+/-6 mm Hg, corresponding to the sympathetic nerve activity course. CONCLUSIONS: Sympathetic nerve activity and blood pressure are temporary reduced by microvascular decompression in patients with severe hypertension with neurovascular compression. The data are a hint for sympathetic overactivity as a pathomechanism in this subgroup of patients.

Role of reactive oxygen species in brainstem in neural mechanisms of hypertension.

The involvement of reactive oxygen species such as superoxide is implicated in the pathogenesis of hypertension. The brain contains a high concentration of polyunsaturated fatty acids in its cell membranes. These fatty acids are targets of oxygen-derived free radicals. Thiobarbituric acid-reactive substances (TBARS), an indirect marker of oxidative stress, are increased in the brainstem of stroke-prone spontaneously hypertensive rats (SHRSP) compared with those of Wistar-Kyoto rats (WKY). In addition, the intensity of electron spin resonance signals taken from the rostral ventrolateral medulla (RVLM), a cardiovascular center, decreases more rapidly in SHRSP than in WKY. To confirm the role of reactive oxygen species in the RVLM or the nucleus tractus solitarius (NTS) in SHRSP, we transfected adenovirus vectors encoding the manganese superoxide dismutase (MnSOD) gene (AdMnSOD) or Cu/Zn-SOD gene (AdCu/ZnSOD) bilaterally into the RVLM or the NTS. After the gene transfer, blood pressure and heart rate of SHRSP, monitored by radio-telemetry system, were significantly decreased compared with non-treated SHRSP, but not WKY. Urinary norepinephrine excretion was significantly decreased in AdMnSOD- or AdCu/ZnSOD-transfected SHRSP, but not in WKY. Furthermore, we found that activation of NAD(P)H oxidase via Rac1 is a source of reactive oxygen species generation in the brain of hypertensive rats. Taken together, these results suggest that the increased oxidative stress in the RVLM and the NTS contribute to the central nervous system mechanisms underlying hypertension in SHRSP. We also found that atorvastatin has actions of reducing oxidative stress in the brain associated with sympatho-inhibitory effects.

Connectivity of an effective hypothalamic surgical target for cluster headache.

The purpose of this study was to look at the connectivity of the posterior inferior hypothalamus in a patient implanted with a deep brain stimulating electrode using probabilistic tractography in conjunction with postoperative MRI scans. In a patient with chronic cluster headache we implanted a deep brain stimulating electrode into the ipsilateral postero-medial hypothalamus to successfully control his pain. To explore the connectivity, we used the surgical target from the postoperative MRI scan as a seed for probabilistic tractography, which was then linked to diffusion weighted imaging data acquired in a group of healthy control subjects. We found highly consistent connections with the reticular nucleus and cerebellum. In some subjects, connections were also seen with the parietal cortices, and the inferior medial frontal gyrus. Our results illustrate important anatomical connections that may explain the functional changes associated with cluster headaches and elucidate possible mechanisms responsible for triggering attacks.

Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome.

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

Pontine tuberculoma presenting with horizontal gaze palsy.

A 38-year-old immunocompetent man presented with a horizontal supranuclear gaze palsy as the only neurologic manifestation of a pontine tuberculoma. Although a biopsy of the brain lesion was not performed, it was attributed to tuberculosis because of chest x-ray evidence. The patient was given empirical anti-tuberculous therapy. After one month, the gaze palsy had fully recovered and repeat MRI showed a decrease in the size of the lesion. This is the first reported case of supranuclear gaze palsy without diplopia as a manifestation of a tuberculous brain stem lesion.

Generalized seizures induced by an epileptic focus in the mesencephalic reticular formation: impact on the understanding of the generalizing mechanism.

The mode of seizure propagation was studied using a generalized seizure model induced by microinjection of kainic acid (KA) into a unilateral mesencephalic reticular formation (MRF) in cats and rats. Stereotactic surgery was performed under pentobarbital anesthesia; an injection cannula was placed into a unilateral MRF, and bipolar electrodes were implanted into the MRF and the thalamus. Microinjection of KA induced generalized seizures. Focal electrical seizures were elicited in the injected site of the MRF starting 30 min after the injection. The initial clinical change during each seizure was behavioral arrest. These seizures immediately developed to generalized seizures, which were characterized by generalized tonic convulsions with short-term clonic convulsions. On EEG, each generalized seizure started at the same time in all the sites of the brain recorded. Autoradiographic study using a rat model demonstrated high glucose utilization in the MRF, bilateral thalamus, forebrain and bilateral cerebral cortices. The results demonstrated an active participation of MRF in the mechanism of generalized seizures.

Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation.

Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freund's adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending pathways. The imbalance of these modulating systems may be one mechanism underlying variability in acute and chronic pain conditions.

[Ictal syncopes. Cardiac sympathetic innervation disorder as the etiology?]. / Iktuale Synkopen. Kardiale sympathische Innervationsstörung als Ursache?

We report 3 cases of an ictal sinus arrest. All patients suffered from temporal lobe epilepsy (TLE). Seizures were monitored with simultaneous video-eeg during preoperative epilepsy diagnosis. One patient with cortical dysplasia, who frequently suffered from long lasting syncopes, had a nearly completely missing cardiac sympathetic innervation in MIBG-SPECT (=Meta-Iodide-Benzyle-Guanidine-single-photon-emission tomography). Cardiac investigation including long-term ECG and echocardiography had shown normal findings. After epilepsy surgery the syncopal events in all patients disappeared. A dominant parasympathetic ictal stimulus following excitation of the reticular formation might cause the ictal bradycardia and sinus arrest. A missing sympathetic innervation, possibly occurring as fehlbildung together with cortical dysplasia, which makes autoregulation impossible, might then be the explanation for sudden cardiac ictal death.

Supraspinal inhibition of nociceptive dorsal horn neurones in the anaesthetized rat: tonic or dynamic?

1. Tonic inhibition of sensory spinal neurones is well known to descend from the rostroventral medulla. It is not clear if this inhibition is dynamically activated by peripheral noxious stimuli. 2. Transection of the ipsilateral dorsolateral funiculus (DLF) removed a descending inhibition of multireceptive spinal neurones and disproportionally prolonged the after-discharge component of their response to a noxious cutaneous stimulus. 3. Microinjection of GABA or tetracaine into the medullary nucleus gigantocellularis pars alpha (GiA) similarly prolonged the after-discharge in response to noxious stimuli. 4. Recordings of GiA cells, initially using minimal surgery, revealed that many had low levels of spontaneous activity and responded vigorously to noxious stimuli applied to any part of the body surface. One hour after the surgery necessary to expose the spinal cord, GiA cells had a high firing rate but responded weakly to noxious stimuli. 5. The response of GiA cells to noxious stimuli was abolished by transection of only the DLF contralateral to the stimulus. 6. It is concluded that the inhibition of multireceptive dorsal horn neurones from GiA is dynamically activated by noxious cutaneous stimuli via a projection in the contralateral DLF. Surgical exposure of the spinal cord tonically activates this inhibition and masks the dynamic component.

Hematoma tegmento-mesencefálico espontâneo: aspectos neurocomportamentais do terço rostral do tronco encefálico humano / Spontaneous tegment-mesencephalic hematoma: neurobehavioral aspects of the rostral third of the human brainstem

O tegmento do mesencéfalo e área complexa, dada a quantidade de fibras que o atravessam, provenientes de circuitos locais, de sistemas ativadores e de feixes descendentes dos hemisférios cerebrais. No presente artigo, relatamos o caso de um senhor de 67 anos, que sofreu hemorragia mesencefálica de localizaçao tegmental, vindo a falecer 1 mês depois. Inicialmente, foi julgado em coma, por apresentar ptose bilateral, ausência de fala e de movimentos espontâneos. Por volta da segunda semana, descobriu-se que podia cumprir comandos verbais, sentar, sustentar-se de pé e andar. O caso demonstra o quanto o diagnóstico do coma em bases clínicas pode ser enganoso em pacientes como esse, no qual a aparente irresponsividade de olhos fechados se deve à combinaçao inesperada de abulia e oftalmoplegia.

Abnormal cortical unit activity of the reticular formation.

Many neurological disorders are accompanied by abnormal nerve activity. However, the exact causes of this abnormal nervous activity has never been determined. Based upon my research, I propose a theory that the underlying cause of many types of neurological disorders such as minor epilepsy and narcolepsy is an abnormally functioning Na+/K+ ATPase pump at the molecular framework of the brain, notably the brainstem reticular formation (locus coerulus) and cerebellum in this particular case. The excessive and repetitive nerve activity within localized areas of the brain caused by abnormally functioning molecular Na+/K+ ATPase ion pumps may be the primary and true causes of many different types of neurological disorders since constant depolarizations of the cell membrane causes abnormally excessive amounts of certain neurotransmitters to be released. The type of neurological disorder may be a function of the abnormally occurring Na+/K+ ATPase molecular ion pump's localization within the neurological framework of the brain. To focus on my theory of repetitive nervous activity from abnormal inhibitive or defective Na+/K+ ATPase pumps, I have chosen to analyze minor epilepsy and narcolepsy intentionally. What is found is that the abnormal release of neurotransmitters during epileptic seizures or narcoleptic sleep episodes is secondary to the abnormal neuronal systematic framework underlying Na+/K+ membrane potentials since an abnormally inhibited or defective Na+/K+ ATPase pump has a direct electrogenic effect on the membrane potential.

Antiemetics in children receiving cancer chemotherapy.

Nausea and vomiting are debilitating side effects that often accompany the administration of chemotherapy and may lead to adverse physiological and psychological effects. Chemotherapy agents usually stimulate the chemoreceptor trigger zone, which then sends signals to the vomiting center in the medullary lateral reticular formation. The neurochemistry of vomiting involves serotonin and serotonin S3 receptors. Nausea and vomiting are difficult to treat once they have occurred, and prior poor antiemetic control may lead to future anticipatory nausea and vomiting. Thus, good antiemetic regimens must be prophylactic, scheduled, and individualized. Specific regimens must be adjusted to account for the emetogenic potential of the chemotherapy drug(s) being administered and the individual patient's preferences. The major classes of antiemetics include serotonin S3 receptor antagonists, phenothiazines and metoclopramide. Steroids are ineffective antiemetics alone but good potentiators of other antiemetics. We usually recommend a serotonin S3 receptor antagonist alone for less emetogenic regimens or in conjunction with dexamethasone for more emetogenic regimens. For breakthrough vomiting, we usually add lorazepam and/or scopolamine.

Reflex reticular myoclonus: relationship to some brainstem pathophysiological mechanisms.

Two patients with reflex reticular myoclonus [RRM] were tested electrophysiologically and pharmacologically. In one of the cases the underlying disease was chronic Lyme borreliosis. In the other, the RRM attacks may have been associated with procarbazine therapy applied for Hodgkin's disease. No cortical lesion could be demonstrated either clinically or electrophysiologically [EEG, averaged EEg preceeding the jerks, SSEP]. An EMG analysis of the jerks revealed the shortest latency in the muscles innervated by the accessory nerve. The latencies became longer in a more rostral muscle [masseter], as well as in a more caudal one, the muscles innervated by the facial nerve were spared. it is presumed that the complete movement pattern of the myoclonus residues in the jerk generating structure. RRM in the described cases differs from the startle by sparing the facial nerve and from the Papio papio baboon non-epileptic myoclonus by the activating effect of physostigmine. A partial therapeutic effect was achieved with a serotonine precursor, but a GABAergic therapy proved to be the most effective.