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Efferent projections of the infralimbic cortex of the rat.

On the basis of stimulation studies, it has been proposed that the infralimbic cortex (ILC), Brodmann area 25, may serve as an autonomic motor cortex. To explore this hypothesis, we have combined anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde tracing with wheat germ aggutinin conjugated to horseradish peroxidase (WGA-HRP) to determine the efferent projections from the ILC. Axons exit the ILC in one of three efferent pathways. The dorsal pathway ascends through layers III and V to innervate the prelimbic and anterior cingulate cortices. The lateral pathway courses through the nucleus accumbens to innervate the insular cortex, the perirhinal cortex, and parts of the piriform cortex. In addition, some fibers from the lateral pathway enter the corticospinal tract. The ventral pathway is by far the largest and innervates the thalamus (including the paraventricular nucleus of the thalamus, the border zone between the paraventricular and medial dorsal nuclei, and the paratenial, reuniens, ventromedial, parafasicular, and subparafasicular nuclei), the hypothalamus (including the lateral hypothalamic and medial preoptic areas, and the suprachiasmatic, dorsomedial, and supramammillary nuclei), the amygdala (including the central, medial, and basomedial nuclei, and the periamygdaloid cortex) and the bed nucleus of the stria terminalis. The ventral efferent pathway also provides descending projections to autonomic cell groups of the brainstem and spinal cord including the periaqueductal gray matter, the parabrachial nucleus, the nucleus of the solitary tract, the dorsal motor vagal nucleus, the nucleus ambiguus, and the ventrolateral medulla, as well as lamina I and the intermediolateral column of the spinal cord. The ILC has extensive projections to central autonomic nuclei that may subserve a role in modulating visceral responses to emotional stimuli, such as stress.

Animals↗

Complex AV nodal dynamics during ventricular-triggered atrial pacing in humans.

In vitro experiments have shown that the complexity of atrioventricular nodal (AVN) conduction dynamics increases with heart rate. Although complex AVN dynamics (e.g., alternans) have been observed clinically, human AVN dynamics during rapid pacing have not been systematically investigated. We studied such dynamics during ventricular-triggered atrial pacing in 37 patients with normal AVN function (18 patients with dual AVN pathway physiology and 19 patients without). Alternans, which always resulted from single pathway conduction, occurred in 18 patients. In 16 patients (3 of whom also had alternans), quasisinusoidal AVN conduction oscillations occurred (mean frequency 0.02 Hz); such oscillations have not been previously reported. There were no significant differences in the dynamics for patients with or without dual AVN pathways. To illuminate the governing dynamic mechanism, a second atrial pacing trial was performed on 12 patients after autonomic blockade. Blockade facilitated alternans but inhibited oscillations. This study suggests that rapid AVN excitation in vivo can lead to autonomically mediated AVN conduction oscillations or single pathway alternans that are a function of inherent nonlinear dynamic AVN tissue properties.

Atrioventricular Node↗

Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury.

Autonomic dysreflexia is a condition that develops after spinal cord injury in which potentially life-threatening episodic hypertension is triggered by stimulation of sensory nerves in the body below the site of injury. Central sprouting of small-diameter primary afferent fibers in the dorsal horn of the spinal cord occurs concurrently with the development of this condition. We propose a model for the development of autonomic dysreflexia in which increased nerve growth factor (NGF) in the injured cord stimulates small-diameter primary afferent fiber sprouting, thereby magnifying spinal sympathetic reflexes and promoting dysreflexia. We identified this population of afferent neurons using immunocytochemistry for calcitonin gene-related peptide. Blocking intraspinal NGF with an intrathecally-delivered neutralizing antibody to NGF prevented small-diameter afferent sprouting in rats 2 weeks after a high thoracic spinal cord transection. In the same rats, this anti-NGF antibody treatment significantly decreased (by 43%) the hypertension induced by colon stimulation. The extent of small-diameter afferent sprouting after cord transection correlated significantly with the magnitude of increases in arterial pressure during the autonomic dysreflexia. Neutralizing NGF in the spinal cord is a promising strategy to minimize the life-threatening autonomic dysreflexia that develops after spinal cord injury.

Afferent Pathways↗

Electrophysiology: the Wolff-Parkinson-White syndrome.

Though tachyarrhythmias occur commonly in patients with the Wolff-Parkinson-White syndrome, many patients remain asymptomatic. Recent studies suggest that routine electrophysiologic testing in these individuals is of limited value. However, electrophysiologic testing remains very helpful in the symptomatic patient for predicting arrhythmia recurrence and for determining accessory pathway location and function. Unfortunately, noninvasive tests to predict high-risk WPW patients has not been proven helpful because of their low specificity. A number of recent studies have shown that autonomic function can markedly improve accessory pathway function and even counteract the effect of antiarrhythmic drugs. Given the frequent failure of antiarrhythmic therapy in the WPW syndrome, there has been increasing interest in nonpharmacologic therapies, including high-energy DC shock and radiofrequency catheter ablation of accessory pathways, which may prove to be more cost-effective than surgery.

Anti-Arrhythmia Agents↗

Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features.

Autonomic dysfunction may result from diseases that affect primarily either the central nervous system or the peripheral autonomic nervous system. The most common pathogenesis of disturbed autonomic function in central nervous system diseases is degeneration of the intermediolateral cell columns (progressive autonomic failure) or disease or damage to descending pathways that synapse on the intermediolateral column cells (spinal cord lesions, cerebrovascular disease, brainstem tumors, multiple sclerosis). The peripheral autonomic nervous system may be damaged in isolation in the acute and subacute autonomic neuropathies or in association with a generalized peripheral neuropathy. The peripheral neuropathies most likely to cause severe autonomic disturbance are those in which small myelinated and unmyelinated fibers are damaged in the baroreflex afferents, the vagal efferents to the heart, and the sympathetic efferent pathways to the mesenteric vascular bed. Acute demyelination of the sympathetic and parasympathetic nerves in the Guillain-Barré syndrome may also cause acute autonomic dysfunction. Although autonomic disturbances may occur in other types of peripheral neuropathy, they are rarely clinically important.

Autonomic Nervous System↗

Angiotensin II receptor binding and the baroreflex pathway.

Angiotensin II (Ang II) acts centrally to modulate autonomic activity and cardiovascular function. Using in vitro autoradiography we have determined the distribution of putative receptors for ANG II in brain regions associated with the baroreflex pathway. Ang II receptor binding sites were observed in the nucleus of the solitary tract (NTS), the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral medulla and intermediolateral cell column of the spinal cord. Receptor binding sites were also observed in the nodose ganglion and in association with nerve fibres in the heart. Nodose ganglionectomy and vagal ligation studies revealed that Ang II receptor binding sites are produced in the nodose ganglion and transported in the vagus nerve to terminals of vagal afferent neurones. In the NTS these presynaptic receptors could mediate the known baroreflex inhibitory action of Ang II by inhibition of neurotransmitter release. In the cat, Ang II receptors were sharply localized in the rostral ventrolateral medulla to the subretrofacial nucleus. Microinjection of Ang II (10-50 pmoles) into this region induced a sympathetically-mediated pressor response. Together these results demonstrate several regions within the baroreflex arc which contain Ang II receptors, at which Ang II may modulate cardiovascular control and autonomic function.

Angiotensin II↗

Synaptic contact of neuropeptide-and amine-containing axons on parasympathetic preganglionic neurons in the superior salivatory nucleus of the rat.

Parasympathetic preganglionic neurons in the superior salivatory nucleus (SSNNs) projecting to the pterygopalatine ganglion were labeled by retrograde transport of cholera toxin B subunit (CTB) in the rat. Morphological interactions between SSNNs and afferent fibers immunoreactive (IR) for neuropeptide and amine were examined with light and electron microscopes by double-immunostaining techniques. SSNNs were found in the ipsilateral ventrolateral part of the rostral medulla oblongata. Around SSNNs, substance P-, enkephalin-, neuropeptide Y-and somatostatin-IR nerve fibers were very rich and tyrosine hydroxylase (TH)-, serotonin (5-HT)-, vasoactive intestinal polypeptide- and calcitonin gene-related peptide (CGRP)-IR axons showed moderate density. Thyrotropin-releasing hormone-containing axons were scarce in this region. The electron microscopic examinations revealed that CTB-IR structures directly received synaptic input from axon varicosities IR for TH, 5-HT and all neuropeptides except for CGRP. These findings suggest that catecholamine, 5-HT and the neuropeptides directly influence the activity of SSNNs and are concerned with the autonomic regulation of nasal and palatal mucosa, lacrimal glands and cerebral blood vessels of the rat.

Afferent Pathways↗

Responses of rat lateral hypothalamic neuron activity to vestibular nuclei stimulation.

Effects of lateral vestibular nucleus (LVN) stimulation on neuronal activity in the rat lateral hypothalamic area (LHA), including specific glucose-sensitive neurons, were investigated by extracellular and intracellular recordings in vivo. Stimulation of the contralateral LVN evoked 3 types of response in 46% (111/240) of the neurons recorded extracellularly: long latency (38.1 +/- 23.6 ms) excitation (62/111, 56%), short latency (6.9 +/- 3.1 ms) excitation-inhibition (33/111, 30%), and inhibition with 20.1 +/- 11.1 ms latency (16/111, 14%). Glucose-sensitive neurons, which were identified by electrophoretic application of glucose, did not respond specifically to such stimulation. Neuronal activity was recorded intracellularly from 31 LHA neurons, of which 13 responded to LVN stimulation. Seven of the 13 neurons showed a long latency EPSP (10.4 +/- 5.5 ms) and the remaining 6 exhibited an EPSP-IPSP sequence with shorter latency (4.5 +/- 3.0 ms). The amplitude of these responses was graded with a change in stimulus intensity. The EPSPs of both types of response were considered to be polysynaptic because of shortening of latencies by higher current stimulation. Since the LHA is implicated in the regulation of autonomic nerve activity, the present results showing polysynaptic pathways from the LVN to the LHA suggest functional involvement of the LHA in vestibulo-autonomic responses.

Animals↗

Behavioral inhibition and prefrontal cortex in decision-making.

Every day we make innumerable decisions; some require no effort at all whereas others require considerable deliberation and weighing of various options. Despite the importance of decision-making in our lives and increased research interest, the specific neural mechanisms underlying decision-making remain unclear. We propose that the brain has at least two cortical pathways that independently generate a decision about appropriate behavior in given circumstances. These two pathways are extensions of the dorsal and ventral streams of the visual processing pathways. The parieto-premotor (extended dorsal) pathway makes decisions about motor actions in a largely autonomous and automatic fashion whereas the temporo-ventrolateral prefrontal (extended ventral) pathway is involved primarily in deliberate decisions and inhibitory control over behavior through the inhibitory function of the ventrolateral prefrontal cortex.

Animals↗

Trigeminal autonomic cephalalgias. Pathophysiology and classification.

Trigeminal Autonomic Cephalalgias (TACs) is a grouping of headache syndromes that includes cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). They are recognized clinically by their episodic, stereotypic attack profile and very often prominent cranial autonomic symptoms, such as lacrimation, conjunctival injection or rhinorrhea. They involve afferent activation of the trigeminal innervation of intracranial pain-producing structures, or the perception of that activation, and reflex activation of the facial, seventh cranial, nerve outflow pathway. This excess reflex trigeminal-autonomic activation seems to be permitted by dysfunction in the brain, specifically in the posterior hypothalamic gray matter. Understanding the anatomy and physiology of these disorders has greatly facilitated their management and the development of exciting new strategies such as neuromodulatory approaches to the management of the more intractable cases.

Cluster Headache↗

Orthostatic intolerance in Behcet's disease.

Neurological manifestations are known to occur in patients with Behcet's Disease (BD) and significantly affect the clinical course of the disease. Nevertheless, the prevalence, pattern and severity of autonomic impairment in such patients have yet to be defined. In this paper, we presented a BD patient with orthostatic tachycardia. Non-invasive standardized autonomic function tests revealed no evidence of autonomic impairment, but profound orthostatic tachycardia accompanied by abnormal catecholamine increase was observed upon standing. The diagnosis of Orthostatic Intolerance (OI) was made and initial symptomatic therapy was started. The contribution of an immunological damage to components of neural pathways in the pathogenesis of the autonomic involvement can be assumed.

Adult↗

Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems.

During systemic infections, the immune system can signal the brain and act on different neuronal circuits via soluble molecules, such as proinflammatory cytokines, that act on the cells forming the blood-brain barrier and the circumventricular organs. These activated cells release prostaglandin of the E(2) type (PGE(2)), which is the endogenous ligand that triggers the pathways involved in the control of autonomic functions necessary to restore homeostasis and provide inhibitory feedback to innate immunity. Among these neurophysiological functions, activation of the circuits that control the plasma release of glucocorticoids is probably the most critical to the survival of the host in the presence of pathogens. This review revisits this issue and describes in depth the molecular details (including the emerging role of Toll-like receptors during inflammation) underlying the influence of circulating inflammatory molecules on the cerebral tissue, focusing on their contribution in the synthesis and action PGE(2) in the brain. We also provide an innovative view supporting the concept of "fast and delayed response" involving the same ligands but different groups of cells, signal transduction pathways, and target genes.

Animals↗

Effect of bombesin on thermoregulation of the rabbit.

Injections of bombesin (BOM, 125, 250 and 500 ng) into the preoptic/anterior hypothalamus caused dose-related decreases of threshold temperatures for metabolic cold defence, cutaneous vasomotor tone and respiratory rate, combined with a reduced sensitivity of these thermoregulatory effectors in response to core temperature changes induced at thermoneutral or warm ambient conditions. Intracisternal (i.c.) injections of BOM (250 ng) produced qualitatively identical thermoregulatory effector changes in response to core temperature changes. Injections of BOM into the posterior hypothalamus did not affect body temperature control. Increased locomotor behavior, licking and grooming was elicited, however, from all injection sites. The results explain the prevailing hypothermic effect of BOM as the consequence of the concerted decrease in threshold temperatures and "gains" of all autonomic thermoregulatory effectors and suggest the activation of warm inputs, relative to cold inputs, at the hypothalamic level as the underlying mechanism. Direct or indirect inhibition of the intrinsic hypothalamic system involving thyrotropin-releasing hormone (TRH) and consequent deactivation of central noradrenergic pathways known to generate the entire autonomic pattern of cold defence might be involved in the neuro-humoral changes resulting in hypothermic effects of centrally applicated BOM.

Animals↗

Electro-acupuncture stimulation to muscle afferents in anesthetized rats modulates the blood flow to the knee joint through autonomic reflexes and nitric oxide.

Recent reports have focused on the mechanisms of the action of electro-acupuncture stimulation (EAS) in the regulation of blood flow to different tissues. In the knee joint, blood flow is known to be modulated mainly by sympathetic postganglionic fibers, but recently the release or induction of nitric oxide (NO) synthesis in response to electrical stimulation has also been suggested. Therefore, a direct observation of the microcirculation is needed to further understand the mechanism by which blood flow is regulated by somatic afferent stimulation. In the present study, the effects of EAS to the vastus medialis muscle on systemic hemodynamics and the knee joint microcirculation were observed in vivo using a real-time confocal laser-scanning microscope system (CLMS). Electrical stimulation (5 mA, 0.5 ms, 5 Hz) was applied for 30 min using a pair of acupuncture needles introduced into the vastus medialis muscle. To clarify a plausible involvement of NO in the responses to EAS, the stimulus was applied either in the presence or absence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Stimulation to either the muscle or the skin of the thigh after blockade of neuromuscular transmission was performed to determine the involvement of muscle contraction during EAS treatment. The changes in mean arterial pressure (MAP) and diameter of the arterioles supplying the knee joint were monitored continuously until 60 min poststimulus. Significant and persistent increases in arteriolar diameter by 26 +/- 6% and MAP by 17 +/- 2%, respectively, were observed after EAS to the muscle. Electro-acupuncture to the vastus medialis in the presence of L-NAME produced a strong decrease in diameter of the knee joint arterioles by -38 +/- 14% under the baseline with a simultaneous increase of 35 +/- 5% in MAP. EAS to the skin did not produce changes in arteriolar diameter while a slight increase in MAP by 12 +/- 6% over the baseline occurred after the stimulus. EAS to the muscle after neuromuscular blockade did not produce significant changes in diameter, while an increase in MAP by 24 +/- 8% was still observed, which facts suggest that the muscle contraction is required to produce vasodilatation. These responses suggest that a dynamic balance between the autonomic nervous system and the release of NO is the primary mechanism mediating the EAS effects on knee joint microcirculation.

Afferent Pathways↗

Role of catecholamines in the frontal cortex in the modulation of basal and stress-induced autonomic output in rats.

Exposure of animals to noxious or stressful stimuli increases heart rate (HR) and blood pressure through activation of the autonomic nervous system (ANS) and elicits the release of the catecholamines noradrenaline (NA) and dopamine (DA) in the frontal cortex. Subregions of the frontal cortex, such as the medial frontal cortex (MFC) and agranular insular cortex (AIC) project directly to brainstem nuclei involved in autonomic control. It may be hypothesized that catecholamines in the frontal cortex could influence autonomic output through actions on these descending pathways. To evaluate this hypothesis, the effects of intracortical microinjections of drugs acting at NAergic and DAergic receptors were assessed on an autonomically mediated response, the increase in HR induced by tail pinch, in rats anesthetized with urethane. Intra-MFC or AIC injections of an antagonist of beta-adrenoceptors reduced the magnitude of the HR response to pinch. Injections of an agonist of beta-adrenoceptors into these regions increased basal HR but did not affect the pinch response. Injections of drugs acting at alpha-adrenoceptors were without effect. When injected alone, drugs acting at DAergic receptors did not effect basal HR or the response to pinch, but intra-AIC injections of a combination of a D2 antagonist and an agonist of beta-adrenoceptors increased the magnitude of the pinch response. These results suggest that catecholamines, especially NA, released in the frontal cortex are important modulators of the basal and stress-induced output of the ANS.

Anesthesia, General↗

Brainstem substrates of sympatho-motor circuitry identified using trans-synaptic tracing with pseudorabies virus recombinants.

Previous physiological investigations have suggested the existence of a neural circuit that coordinates activation of motor and autonomic efferents before or at the onset of exercise. Traditionally these circuits have been postulated to involve forebrain areas. However, overlapping populations of medullary reticular formation neurons that participate in motor or autonomic control have been described previously, suggesting that individual pontomedullary reticular formation neurons may coordinate both motor and autonomic responses. We tested this hypothesis by conducting transneuronal retrograde tracing of motor and sympathetic nervous system pathways in rats using recombinant strains of pseudorabies virus (PRV). A PRV strain expressing the green fluorescent protein (PRV-152) was injected into the left gastrocnemius muscle, which was surgically sympathectomized, whereas another recombinant (PRV-BaBlu) was injected into the left adrenal gland. Immunofluorescence methods using monospecific antisera and distinct fluorophores identified neurons infected with one or both of the recombinants. Brainstem neurons coinfected with both PRV recombinants, which presumably had collateralized projections to both adrenal sympathetic preganglionic neurons and gastrocnemius motoneurons, were observed in several areas of the pontomedullary reticular formation. The largest number of such neurons was located in the rostral ventromedial medulla within the ventral gigantocellular nucleus, gigantocellular nucleus pars alpha, raphe obscurus, and raphe magnus. These neurons are candidates for relaying central command signals to the spinal cord.

Adrenal Glands↗

Neurobiology of Acupuncture: Toward CAM.

It has long been accepted that acupuncture, puncturing and scraping needles at certain points on the body, can have analgesic and anesthetic effects, as well as therapeutic effects in the treatment of various diseases. This therapy, including acupuncture anesthesia, has drawn the attention of many investigators and become a research subject of international interest around the world. Numerous studies have demonstrated that the nervous system, neurotransmitters, endogenous substances and Jingluo (meridians) may respond to needling stimulation and electrical acupuncture. An abundance of information has now accumulated concerning the neurobiological mechanisms of acupuncture, in relation to both neural pathways and neurotransmitters/hormonal factors that mediate autonomic regulation, pain relief and other therapeutics. Early studies demonstrated that the analgesic effects of electroacupuncture (EA) are mediated by opioid peptides in the periaqueductal gray. Recent evidence shows that nitric oxide plays an important role in mediating the cardiovascular responses to EA stimulation through the gracile nucleus-thalamic pathway. Other substances, including serotonin, catecholamines, inorganic chemicals and amino acids such as glutamate and alpha-aminobutyric acid (GABA), are proposed to mediate certain cardiovascular and analgesic effects of acupuncture, but at present their role is poorly understood. The increased interest in acupuncture health care has led to an ever-growing number of investigators pursuing research in the processes of the sense of needling touch, transduction of needling stimulation signals, stimulation parameters and placebos. In this Review, the evidence and understanding of the neurobiological processes of acupuncture research have been summarized with an emphasis on recent developments of nitric oxide mediating acupuncture signals through the dorsal medulla-thalamic pathways.

Journal Article↗