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[A case of paraneoplastic autonomic and sensorimotor neuropathy with dysfunction in the afferent limb of baroreflex arc].

A 65-year-old man visited our hospital with complaints of tingling sensation in the distal parts of his extremities and dysuria, which first appeared 2 months before admission. He had no abnormal findings on physical examination. Neurological examination revealed sensory impairment of glove and stocking type, mild motor weakness and muscular atrophy in the proximal parts of arms and legs, and absent tendon reflexes in knees and ankles. Fasciculation was observed on his shoulders and upper extremities, and myokymia on the abdominal wall and bilateral calves. He had hyponatremia, which was proved to be caused by SIADH. Anti-acetylcholine receptor antibody, anti-GM1 ganglioside antibody and anti-galactocerebroside antibody were detected in the serum. Chest X-ray showed mass shadows in the mediastinum, which were confirmed as malignant thymoma by needle biopsy. Orthostatic hypotension, neurogenic bladder and anhidrosis were observed by the autonomic function tests. Lesions responsible for orthostatic hypotension and SIADH were suspected in the afferent fibers from baroreceptors, since an reactive increase of plasma arginine vasopressin to orthostatic hypotension was blunted and reflex hypertension in the cold pressor test was well-preserved, while overshoot in Valsalva's maneuver was absent. It is important that afferent baroreceptor dysfunction may be associated with paraneoplastic neurological syndrome, since lesions in acute autonomic neuropathy are usually in the efferent fibers.

Afferent Pathways↗

Autonomic neural regulation of immunity.

The 'cytokine theory of disease' states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the 'cholinergic anti-inflammatory pathway', efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage alpha7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This 'hard-wired' connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage alpha7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti-inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.

Autonomic Nervous System↗

A comparative scale of autonomic function with age through the tone-entropy analysis on heart period variation.

Tremendous numbers of heart rate variability studies have aimed to elucidate age-associated alterations of autonomic function in the past decades. However, the studies, far from clarifying ageing mechanisms, fell into confusion by a lack of common scales. The purpose of this study is to show a possibility to establish a comparative scale of autonomic function through a method, tone-entropy (T-E) analysis on heart period variation, whose validity has been already examined on typical physiological cases (Oida et al. in J Appl Physiol 82:1794-1801, 1997; Oida et al. in J Gerontol 54A:M219-M224, 1999a; Oida et al. in Acta Physiol Scand 165:129-134, 1999b; Oida et al. in Acta Physiol Scand 165:421-422, 1999c; Amano et al. in Eur J Appl Physiol 94:602-610, 2005). In this study, 276 subjects from teens to seventies were examined at rest by T-E analysis together with conventional time and frequency domain analyses. The tone (negativity represents vagal predominance) became significantly high [-0.174 +/- 0.026 (teens) to -0.024 +/- 0.004 (seventies), P < 0.05 for one-way ANOVA], and the entropy (total autonomic activity), significantly low [4.40 +/- 0.12 (teens) to 2.90 +/- 0.09 bit (seventies), P < 0.05] with advancing age. The result, plotted in 2-D T-E space, showed that the ageing traced a curvi-linear relation from right-bottom to left-top, and was consistent with previously studied typical physiological cases. The conventional analyses showed almost the same autonomic reduction as T-E did, but failed in detecting delicate alteration of autonomic balance. The results, showing that autonomic activity reduced in both pathways impairing vagal predominance significantly with ageing, suggested a possibility to assess autonomic function in 2-D T-E space in a comparative way.

Adolescent↗

Autonomic dysreflexia, induced by noxious or innocuous stimulation, does not depend on changes in dorsal horn substance p.

After experimental spinal cord injury (SCI) in rats, autonomic dysreflexia is commonly induced by slightly noxious cutaneous or visceral stimuli. The presence of autonomic dysreflexia is associated with an increase in the afferent fiber arbor area labeled by cholera toxin B or with an anti-CGRP antibody. Our goal was to examine further the sensory afferent input contributing to exaggerated autonomic spinal reflexes and subsequent increases in blood pressure after SCI, typical of autonomic dysreflexia. We observed that changes in blood pressure and heart rate induced by slightly noxious stimuli (2.0-mL balloon colon distension, cutaneous pinch) were increased in magnitude with time after SCI. In contrast, cardiovascular responses induced by non-noxious stimuli (1.0-mL balloon colon distension, light stroking of hair) were relatively constant. We examined substance P-immunoreactive afferent fibers to identify type C, unmyelinated afferent fibers, and A delta lightly myelinated fibers in superficial and deeper laminae of the dorsal horn, respectively. The area of substance P-immunoreactive fibers was quantified in laminae I-V of the dorsal horn. Analysis revealed no difference in substance P afferent fiber area in laminae I-II, or laminae III-V, between sham-injured and SCI rats. These data suggest that noxious, or innocuous, stimulation induces autonomic dysreflexia without expansion of the central arbors of substance P-immunoreactive sensory neurons. Furthermore, autonomic dysreflexia induced by noxious stimulation increases with time after spinal cord injury.

Afferent Pathways↗

Role of somatic afferents in autonomic system control of the intestinal motility.

(1) In anesthetized (chloralose-urethane) rats, strong mechanical stimuli which were applied to the abdominal skin always inhibited motility of the small intestine. This reflex is referred to as an 'inhibitory cutaneo-intestinal reflex'. Similar stimuli applied to the skin of the upper chest, neck, forepaws, or hindpaws, however, evoked the opposite effect, which is referred to as a 'facilitatory cutaneo-intestinal reflex'. (2) By recording the activity of efferent sympathetic nerves to the small intestine and by transecting intestinal sympathetic or parasympathetic nerves we found that the inhibitory cutaneo-intestinal reflex was largely due to an increase in intestinal sympathetic efferent activity, and that the facilitatory cutaneo-intestinal reflex was due to decrease in the intestinal sympathetic efferent nerve activity; both changes reflexly evoked. (3) The inhibitory cutaneo-intestinal reflex was shown to be a propriospinal reflex which was caused by excitation of group IV (unmyelinated) cutaneous afferent nerve fibers. On the other hand, the facilitatory cutaneo-intestinal reflex seemed to be mediated through supraspinal pathways, and was evoked by excitation of mainly group III (A-delta group) cutaneous afferent nerve fibers. (4) Interaction between the cutaneo-intestinal reflex and intestino-intestinal reflex was demonstrated. (5) The possibility of a dorsal root reflex contribution to cutaneo-intestinal reflex was eliminated. (6) Significance of the cutaneo-intestinal reflex in neural control of the gastro-intestinal tract was discussed.

Adrenergic Fibers↗

Tumor necrosis factor-alpha in the dorsal vagal complex suppresses gastric motility.

Gastric hypomotility, loss of appetite, nausea, and vomiting frequently accompany critical infectious illness, radiation sickness, and carcinogenesis. The present studies examined the possibility that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), may be responsible for provoking some of these autonomic signs associated with illness. Gastric motility of urethane-anesthetized rats was prestimulated with intracisternal applications of thyrotropin-releasing hormone (TRH), a peptide known to activate parasympathetic vagal excitatory pathways to the stomach. Microinjection of TNF-alpha (as low as 0.02 fmol) directly into the dorsal vagal comples (DVC) suppressed TRH-stimulated gastric motility for prolonged periods of time. Duration of suppression ranged from 5 min to more than an hour, dependent on both the dose of TNF-alpha and accuracy of placement of the microinjection within the DVC. This suppression demonstrated a dose-dependent effect of TNF-alpha that required an intact vagal pathway. These studies indicate that TNF-alpha may represent a unique cytokine 'afferent' signal which directly regulates the excitability of vago-vagal reflex circuits resulting in altered gastric motility during disease states.

Afferent Pathways↗

Confocal microscopic analysis reveals sprouting of primary afferent fibres in rat dorsal horn after spinal cord injury.

Following high thoracic spinal cord transection (SCT) in rats, abnormal changes in arterial pressure in response to sensory stimulation (autonomic dysreflexia) are correlated with changes in neural circuitry in the injured spinal cord. Anterograde transport of wheat germ agglutinin conjugated to Texas Red (WGATR) and confocal microscopy were used to characterize the increased arbourization of Adelta and Abeta fibre populations in laminae III-V of the dorsal horn. In cord-injured animals, significantly greater areas of WGATR-labeled fibres were found in the deeper laminae of the dorsal horn than in control rats. This increased area likely reflects sprouting of the Adelta, Abeta, and possibly C fibre populations. The time course of sprouting matches the onset of autonomic dysreflexia, indicating a possible functional correlation between the two phenomena.

Afferent Pathways↗

The heartbeat-evoked brain potential in patients suffering from diabetic neuropathy and in healthy control persons.

OBJECTIVES: Neurotransmission from the heart to the brain results in a heartbeat evoked potential (HEP). This potential appears as a positive waveform ranging from 250 to 600 ms after the onset of ventricular contraction. Only limited information exists as to what extent the HEP is sensitive to a dysfunction in cardio-afferent pathways. Thus, the HEP was studied in patients with autonomic diabetic neuropathy. METHODS: Twenty-five patients and a healthy control group of equal size participated. The HEP was obtained as the average over 1200 EEG sweeps (18 channels) sampled contingent upon the onset of ventricular contraction. A heartbeat attention task and a distraction task were employed. Patients answered a questionnaire pertaining to the frequency of subjective symptoms related to diabetic neuropathy. RESULTS: The HEP amplitude at frontal, central and temporal locations was significantly diminished in patients in the latency range of 280-330 ms. A significant correlation was found between the questionnaire score of subjective autonomic symptoms and the reduction in the HEP. CONCLUSIONS: We conclude that the HEP is sensitive to a comparably moderate abnormality in nerve function. Furthermore, we assume that the processing of subjective symptoms of the disease and the generation of the HEP share some common neuronal pathways.

Adolescent↗

Direct reciprocal connections between the bed nucleus of the stria terminalis and dorsomedial medulla oblongata: evidence from immunohistochemical detection of tracer proteins.

Connections between the bed nucleus of the stria terminalis and the dorsomedial medulla oblongata have been examined by immunohistochemical detection of the tracer proteins horseradish peroxidase (HRP) or wheat germ agglutinin (WGA). Two sets of four rats received 0.2 or 0.4 microliter of either tracer injected into the dorsomedial medulla oblongata, were fixed by perfusion 48 hours later, and were processed for immunohistochemical detection of the tracers. Rats receiving HRP showed only a few single neurons retrogradely labelled in the ipsilateral bed nucleus, and some anterogradely labelled fibers. Rats receiving WGA showed a large number of retrogradely labelled neurons in the ipsilateral bed nucleus. Labelled neurons were most concentrated in a group in the central, dorsal, and lateral aspects of the nucleus at the level of the anterior commissure and just caudal to this. Just ventral to this group was a dense cluster of anterogradely labelled fibers. The retrogradely labelled neurons ranged from 12 to 20 microns in size and were multipolar. These findings indicate that there are direct reciprocal connections between the bed nucleus of the stria terminalis and the autonomic centers of the dorsomedial medulla oblongata and strengthen the concept that this nucleus is involved in forebrain integration of autonomic functions.

Afferent Pathways↗

Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

Apoptosis↗

[Relationships between the brain and the immune system].

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).

Animals↗

Cranial afferent glutamate heterosynaptically modulates GABA release onto second-order neurons via distinctly segregated metabotropic glutamate receptors.

The balance between excitation and inhibition dictates central integration. Glutamatergic and GABAergic neurotransmission dominate this process. Cranial primary afferents enter the brainstem to release glutamate (Glu) onto second-order neurons within the caudal nucleus tractus solitarius (NTS) to initiate autonomic reflexes. The simplest pathways for these reflexes contain as few as two central neurons, but display robust frequency-dependent behavior. Within NTS, multiple metabotropic Glu receptors (mGluRs) are present, but their roles are poorly understood. Using synaptically discriminated second-order NTS neurons in brainstem slices and mechanically dissociated NTS neurons with intact boutons, we show that Glu differentially controls GABA release via distinct presynaptic mGluRs. In second-order NTS neurons recorded in slices, activation of primary afferents at frequencies as low as 10 shocks per second released sufficient Glu to alter rates of spontaneous IPSCs (sIPSCs). In both approaches, group I mGluRs increased GABA release in some neurons, but, on different neurons, group II and group III mGluRs decreased the sIPSC rate. mGluR actions were remarkably rapid, with onset and reversal beginning within 100 msec. In all cases, mGluR actions were exclusively presynaptic, and mGluRs did not alter postsynaptic properties in second-order neurons in either slices or isolated neurons. Tests with capsaicin and alphabeta-methylene ATP suggest that myelinated and unmyelinated afferent pathways engage both mGluR-GABA mechanisms. Afferent Glu spillover provides heterosynaptic cross talk with GABAergic inhibition in NTS. This process may critically shape the dynamic character and use dependence for cranial afferent transmission at the first stage of autonomic reflexes.

Animals↗

Hypothalamo-cerebellar and cerebello-hypothalamic pathways: a review and hypothesis concerning cerebellar circuits which may influence autonomic centers affective behavior.

Experimental data which have suggested the probability of connections between the cerebellum and hypothalamus are reviewed. Early studies relied mainly on physiological methods and, in general, concluded that such connections were multisynaptic being relayed via an undetermined number of synapses in the bulbar reticular formation. Recent studies, using horseradish peroxidase techniques, have identified direct connections between cerebellar nuclei and the hypothalamus and between several regions of hypothalamus and the cerebellar cortex. It is proposed that the cerebellum, by way of direct nucleo-hypothalamic projections and the resultant descending hypothalamic projections to visceral centers, has a variety of specific circuits through which it can directly influence autonomic centers. It is further noted that autonomic centers, as exemplified by hypothalamo-cerebellar projections, may have equally specific feedback loops to cerebellar cortex. Direct cerebello-hypothalamic projections and the subsequent diffuse pathways from hypothalamus into a number of forebrain areas may represent circuits responsible for the affective responses seen as a result of cerebellar ablation and/or stimulation.

Affect↗

Central noradrenergic neurons: the autonomic connection.

Most CNS noradrenergic (NE) cell groups reside in portions of the medulla oblongata primarily involved in autonomic control (A1, A2, A5) and even the pontine locus coeruleus (A6) receives a major innervation from these medullary areas. This review examines the neuroanatomical and neurophysiological literature relevant to the issue of the role of CNS NE neurons in central autonomic control (with emphasis on cardiovascular control). It is concluded that NE cells, with the possible exception of certain A5 and A1 neurons, have relatively weak or no inputs from visceral cardiovascular afferents but provide a complex "open loop" control over non-aminergic circuits which are more specialized in the processing of cardiovascular and other autonomic reflexes. The question of whether the C1 "adrenergic" cells of the rostral medulla oblongata actually use noradrenaline as a neurotransmitter is also briefly addressed.

Adrenergic Fibers↗

A specific role of phosphatidylinositol 3-kinase gamma. A regulation of autonomic Ca(2)+ oscillations in cardiac cells.

Purinergic stimulation of cardiomyocytes turns on a Src family tyrosine kinase-dependent pathway that stimulates PLCgamma and generates IP(3), a breakdown product of phosphatidylinositol 4,5-bisphosphate (PIP2). This signaling pathway closely regulates cardiac cell autonomic activity (i.e., spontaneous cell Ca(2+) spiking). PIP2 is phosphorylated on 3' by phosphoinositide 3-kinases (PI3Ks) that belong to a broad family of kinase isoforms. The product of PI3K, phosphatidylinositol 3,4,5-trisphosphate, regulates activity of PLCgamma. PI3Ks have emerged as crucial regulators of many cell functions including cell division, cell migration, cell secretion, and, via PLCgamma, Ca(2+) homeostasis. However, although PI3Kalpha and -beta have been shown to mediate specific cell functions in nonhematopoietic cells, such a role has not been found yet for PI3Kgamma. We report that neonatal rat cardiac cells in culture express PI3Kalpha, -beta, and -gamma. The purinergic agonist predominantly activates PI3Kgamma. Both wortmannin and LY294002 prevent tyrosine phosphorylation, and membrane translocation of PLCgamma as well as IP(3) generation in ATP-stimulated cells. Furthermore, an anti-PI3Kgamma, but not an anti-PI3Kbeta, injected in the cells prevents the effect of ATP on cell Ca(2+) spiking. A dominant negative mutant of PI3Kgamma transfected in the cells also exerts the same action. The effect of ATP was observed on spontaneous Ca(2+) spiking of wild-type but not of PI3Kgamma(2/2) embryonic stem cell-derived cardiomyocytes. ATP activates the Btk tyrosine kinase, Tec, and induces its association with PLCgamma. A dominant negative mutant of Tec blocks the purinergic effect on cell Ca(2+) spiking. Tec is translocated to the T-tubes upon ATP stimulation of cardiac cells. Both an anti-PI3Kgamma antibody and a dominant negative mutant of PI3Kgamma injected or transfected into cells prevent the latter event. We conclude that PI3Kgamma activation is a crucial step in the purinergic regulation of cardiac cell spontaneous Ca(2+) spiking. Our data further suggest that Tec works in concert with a Src family kinase and PI3Kgamma to fully activate PLCgamma in ATP-stimulated cardiac cells. This cluster of kinases provides the cardiomyocyte with a tight regulation of IP(3) generation and thus cardiac autonomic activity.

Adenosine Triphosphate↗

Suppresion of autonomic postganglionic discharges by pentobarbital in dogs, with or without endotoxemia.

Initial effects of pentobarbital (8 mg/kg) on autonomic efferent and afferent discharge rates were studied in 26 dogs under morphine-chloralose anesthesia. Half of the dogs were given endotoxin E. coli (1 mg/kg) before pentobarbital. The postganglionic cervical vagal efferentation of all the dogs decreased as did the postganglionic cardiac sympathetic efferentation. The heart rate of the dogs given endotoxin decreased, while an increase in heart rate with abolition of respiratory arrhythmia, was observed in dogs without endotoxin. The aortic pressure of the former dogs dropped while it fell only slightly in the latter ones. The aortic arch baroreceptor activity decreased while the changes of left atrial B-type receptor activity were not significant. The changes of the left atrial and central venous pressures were slight but those of the pulmonary arterial pressure generally paralleled the changes in the aortic pressure. Pentobarbital, accordingly, seems to exert both sympatholytic and vagolytic effects. These explain the heart rate changes, as well as the impaired cardiac contractility it evokes. The obvious impairment of cardiovascular control mechanisms by pentobarbital should be seriously considered in investigations into the cardiovascular control.

Action Potentials↗