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Autonomous neurobiological pathways to late-life major depressive disorder: clinical and pathophysiological implications.

The objective of our study was to elucidate distinct paths to depression in a model that incorporates age, measures of medical comorbidity, neuroanatomical compromise, and cognitive status in a sample of patients with late-life major depressive disorder (MDD) and nondepressed controls. Our study was cross-sectional in nature and utilized magnetic resonance imaging (MRI) estimates of brain and high-intensity lesion volumes together with clinical indices of cerebrovascular and nonvascular medical comorbidity. Neuroanatomic and clinical measures were incorporated into a structural covariance model in order to test pathways to MDD. Our data indicate that there are two paths to MDD; one path is represented by vascular and nonvascular medical comorbidity that contribute to high-intensity lesions that lead to depression. Smaller brain volumes represent a distinct path to the mood disorder. Age influences depression by increasing atrophy and overall medical comorbidity but has no direct impact on MDD. These findings demonstrate that there are distinct biological substrates to the neuroanatomical changes captured on MRI. These observations further suggest that neurobiological mechanisms acting in parallel may compromise brain structure/function, thereby predisposing individuals to clinical brain disorders such as depression.

Affect↗

Pelvic somato-visceral reflexes after spinal cord injury: measures of functional loss and partial preservation.

For people with spinal cord injuries, the impact of bladder, bowel and sexual problems on quality of life and lost opportunities can be devastating. Supra-sacral spinal lesions can cause incontinence by interrupting those pathways that normally coordinate the function of the bladder, bowel and sphincters. From a scientific perspective, neural control of the pelvic organs is one of the most intriguing in the body, involving both somatic and autonomic pathways participating in an exquisitely fine integration of lumbo-sacral reflexes. This chapter aims to review briefly those aspects of neural control of the pelvic organs that are amenable to neurophysiological examination in man. More specifically, it will focus in greater detail on the interactions of somatic and autonomic lumbo-sacral pathways responsible for coordinating the bladder and sphincters. Where appropriate, it will make comparisons with those controlling the bowel. It will describe how measurement of pelvic floor and sphincter reflexes can be used to assess the modulatory effects of sacral autonomic pathways on sacral somatic reflexes and vice versa including the so-called "guarding reflex" and vesical inhibitory reflexes. Aberrant activity following spinal cord injury (SCI), such as bladder hyperreflexia and sphincter dyssynergia, will be discussed in relation to these reflexes. The effects of volitional modulation of pelvic floor reflexes in people with both complete and incomplete lesions will be described. Finally, the chapter will address the possible utility of neurophysiological measures for complementing the established neurological classification and the assessment of somatic sensory-motor impairment in SCI.

Autonomic Pathways↗

Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.

OBJECTIVE: As the primary link between brain and gut, autonomic and endocrine dysfunction may play a role in the pathophysiology of the irritable bowel syndrome (IBS). The aim of this study was to assess autonomic, endocrine, and symptomatic responses to food intake in diarrhea-predominant and constipation-predominant IBS patients, compared to normals. METHODS: Twelve women with diarrhea-predominant or alternating IBS (IBS-D), 12 women with constipation predominant IBS (IBS-C), and 20 healthy women participated. GI symptoms, saliva cortisol concentration, heart rate, and heart rate variability were assessed at baseline and after a meal. Spectral analysis of heart rate variability was used as a measure of the sympathovagal regulation of the heart rate. RESULTS: Both groups of IBS patients showed a significant postprandial increase in GI symptoms. IBS-D showed a significant increase in the low frequency/high frequency band ratio and a decrease in the high frequency band power during the first postmeal period, which was significantly different, not only from controls, but also from IBS-C. IBS-D also showed a significant postprandial increase in cortisol, which was not evident in controls or IBS-C. There was a significant correlation between the vagal response and the postprandial increase in GI symptoms in IBS-D (r = 0.6, p < 0.05). CONCLUSIONS: These findings support the notion that the IBS symptom groups are characterized by different physiological responses to visceral stimuli, and point to a role of autonomic pathways in IBS symptomatology.

Adult↗

An epinephrine-containing pathway in avian spinal cord: development and localization.

We have studied the uptake mechanism, biochemistry and autoradiographic localization of a descending epinephrine-containing pathway in the chick spinal cord. This epinephrine (E) projection has a developmental timetable (appears at 14 days in ovo) that is different from those of the serotonin (5-HT) and norepinephrine (NE) projections which appear at 8 and 12 days respectively. E possesses its own uptake mechanism with different pharmacological specificities from those of the NE and 5-HT uptake mechanisms. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that converts NE to E, is present in the cord at 14 days in ovo which is the same time that the uptake mechanism is detectable. Transection of the spinal cord at upper thoracic levels almost completely eliminates the uptake mechanism and PNMT activity below the transection, indicating a supraspinal origin of this pathway. E can first be detected fluorimetrically at 12 days in ovo but at this age E appears not to be of supraspinal origin since transmission at 5 days in ovo does not deplete the spinal cord of E. However, transection of the spinal cord at 3 days post-hatching does markedly reduce the E content by 12 days. Autoradiographic analysis after uptake with [3H]E shows a circumscribed localization of the uptake of E to the neuropil of the preganglionic sympathetic nucleus (nucleus of Terni). These observations demonstrate the presence of a separate descending epinephrine-containing projection in the avian spinal cord which terminates predominantly on preganglionic sympathetic neurons. This pathway may be the major central autonomic pathway in the avian spinal cord.

Aging↗

Reflex bronchial vasodilation in dogs evoked by injection of a small volume of water into a bronchus.

Injection of water into a lobar bronchus stimulates airway C-fibers and rapidly adapting receptors and evokes airway defense reflexes. To determine whether this stimulus also evokes a reflex increase in bronchial blood flow (Qbr), we injected 1-2 ml of water into a lobar bronchus in anesthetized dogs. Injection decreased arterial pressure but increased Qbr from 9 +/- 1 to 21 +/- 3 ml/min. The increase had a latency of 6-8 s and reached a peak after approximately 20 s; Qbr returned to control after 60-90 s. Airway mucosal blood flow, measured by colored microspheres, increased in proportion to Qbr. In contrast, flow in an adjacent intercostal artery that did not supply the airway decreased slightly. Injection of isosmotic saline had little effect. In 13 of 16 dogs, the water-induced increase in Qbr was abolished by cutting or cooling the cervical vagus nerves and hence was entirely dependent on centrally mediated vagal pathways. When the vagus nerves were intact, about one-third of the vasodilator response remained after pharmacological blockade of muscarinic and adrenergic receptors. We conclude that in dogs the defense response to water in the lower airways includes a large increase in Qbr that is partly due to activation of nonadrenergic noncholinergic autonomic pathways.

Animals↗

Localization of NADPH diaphorase in the lumbosacral spinal cord and dorsal root ganglia of the cat.

The distribution of NADPH-d activity in the spinal cord and dorsal root ganglia of the cat was studied to evaluate the role of nitric oxide in lumbosacral afferent and spinal autonomic pathways. At all levels of the spinal cord NADPH-d staining was present in neurons and fibers in the superficial dorsal horn and in neurons around the central canal and in the dorsal commissure. In addition, the sympathetic autonomic nucleus in the rostral lumbar segments exhibited prominent NADPH-d cellular staining whereas the parasympathetic nucleus in the sacral segments was not well stained. The most prominent NADPH-d activity in the sacral segments occurred in fibers extending from Lissauer's tract through laminae I along the lateral edge of the dorsal horn to lamina V and the region of the sacral parasympathetic nucleus. These fibers were very similar to VIP-containing and pelvic nerve afferent projections in the same region. They were prominent in the S1-S3 segments but not in adjacent segments (L6-L7 and Cx1) or in thoracolumbar and cervical segments. NADPH-d activity and VIP immunoreactivity in Lissauer's tract and the lateral dorsal horn were eliminated or greatly reduced after dorsal-ventral rhizotomy (S1-S3), indicating the fibers represent primary afferent projections. A population of small diameter afferent neurons in the L7-S2 dorsal root ganglia were intensely stained for NADPH-d. The functional significance of the NADPH-d histochemical stain remains to be determined; however, if NADPH-d is nitric oxide synthase then this would suggest that nitric oxide may function as a transmitter in thoracolumbar sympathetic preganglionic efferent pathways and in sacral parasympathetic afferent pathways in the cat.

Afferent Pathways↗

It's time to flower: the genetic control of flowering time.

In plants, successful sexual reproduction and the ensuing development of seeds and fruits depend on flowering at the right time. This involves coordinating flowering with the appropriate season and with the developmental history of the plant. Genetic and molecular analysis in the small cruciform weed, Arabidopsis, has revealed distinct but linked pathways that are responsible for detecting the major seasonal cues of day length and cold temperature, as well as other local environmental and internal signals. The balance of signals from these pathways is integrated by a common set of genes to determine when flowering occurs. Excitingly, it has been discovered that many of these same genes regulate flowering in other plants, such as rice. This review focuses on recent advances in how three of the signalling pathways (the day-length, vernalisation and autonomous pathways) function to control flowering.

Arabidopsis↗

The pha-4 gene is required to generate the pharyngeal primordium of Caenorhabditis elegans.

In the 4-cell Caenorhabditis elegans embryo, two blastomeres are destined to generate pharyngeal cells, each by a distinct developmental strategy: one pathway is inductive, while the other is autonomous. Here, we identify the pha-4 locus. In animals lacking pha-4 activity, an early step in pharyngeal organogenesis is blocked: no pharyngeal primordium is formed and differentiated pharyngeal cells are absent. Most other tissues are generated normally in pha-4 mutants, including cells related to pharyngeal cells by cell lineage and position. Thus, pha-4 activity is required to form the pharyngeal primordium. We propose that pha-4 marks a convergence of the inductive and autonomous pathways of pharyngeal development and suggest that establishment of pharyngeal organ identity is a crucial step for pharyngeal organogenesis.

Animals↗

Neurophysiological evaluation of sexual dysfunction in familial amyloidotic polyneuropathy--Portuguese type.

Familial amyloidotic polyneuropathy (FAP)--Portuguese type, is an autosomal dominant polyneuropathy related with an abnormal transthyrretin (TTR Met 30). In males, the first complaint can be sexual dysfunction. Fifteen FAP patients, mean age 37 +/- 7.7 years, mean disease duration 5.2 +/- 2.2 years, all males, complaining of sexual dysfunction were studied with pudendal evoked potentials (PEP), bulbocavernous reflex (BCR) and sympathetic skin response (SSR). PEP and BCR reflect the central somatosensory pathways and sacral arch functioning; SSR relates with autonomic pathways. The aims of this study were: to correlate clinical and EMG scores with somatic and autonomic fibres involvement; to evaluate the timing of somatic and autonomic nerves lesion in disease evolution. Results showed: that PEP and BCR abnormalities have a statistically significant correlation with clinical and EMG scores; abnormal SSR in the plant precede other clinical or EMG abnormalities in the present study.

Adult↗

Receptor-receptor interactions in central cardiovascular regulation. Focus on neuropeptide/alpha(2)-adrenoreceptor interactions in the nucleus tractus solitarius.

The nucleus tractus solitarii (NTS) is a key nucleus in central cardiovascular control. In this mechanism it is well known the role of the alpha(2)-adrenoreceptors for the modulation of the autonomic pathways. Moreover a number of neuropeptides described in the NTS, including Neuropeptide Y (NPY), Galanin (GAL) and Angiotensin II (Ang II), have different roles in regulating the cardiovascular function within this nucleus. We show in this review several data which help to understand how these neuropeptides (NPY, GAL and Ang II) could modulate the cardiovascular responses mediated through alpha(2)-adrenoreceptors in the NTS. Also we show for the first time the interactions between neuropeptides in the brain, specifically the interactions between NPY, GAL, and Ang II, and its functional relevance for central cardiovascular regulation. These data strength the role of neuropeptides on central autonomic control and provide some evidences to understand the neurochemical mechanisms involved in the cardiovascular responses from the NTS.

Angiotensin II↗

Autonomic stimulation.

Therapeutic stimulation of the autonomic nervous system has been limited by lack of qualitative or quantitative evaluation of autonomic mechanisms. This article provides an historical review of knowledge about autonomic pathways and critical evaluation of available tests of autonomic function. Recent developments in evaluation of autonomic dysfunction and improvement in techniques of neurostimulation have facilitated the development of a number of clinically useful treatments for bladder control, sexual problems, peripheral vascular disease, angina pectoris, and seizure disorders. Future therapeutic measures may allow specific control of hypertension, pain, cardiac arrhythmias, trophic disorders and balance.

Autonomic Nervous System↗

Autonomic dysreflexia: pharmacological management of hypertensive crises in spinal cord injured patients.

Interruption of autonomic pathways by spinal cord injury (SCI) causes dysfunctional autonomic dysreflexia (AD), which was first described in 1917, still remains unrecognized by those in the medical profession not involved in SCI care. Autonomic dysreflexia is a syndrome generally manifest by cardiovascular symptoms and characterized by paroxysmal hypertension. These symptoms appear in patients with spinal cord injury above the sympathetic outflow from the spinal cord (T6). Since patients with high level SCI are usually hypotensive, the high blood pressures that develop during AD represent pressure changes of a magnitude that can cause cerebrovascular accidents and death of the subject. We discuss the therapeutic interventions that abate and curtail the symptoms and prevent the catastrophic sequelae of autonomic dysreflexia.

Autonomic Nervous System Diseases↗

Right ventricular infarction causes heterogeneous autonomic denervation of the viable peri-infarct area.

BACKGROUND: Because efferent autonomic pathways to the right ventricle (RV) differ from the efferent autonomic projections to the left ventricle (LV), we assessed the effects of RV infarction on this innervation. METHODS AND RESULTS: We measured the ventricular effective refractory period (ERP) shortening in response to bilateral ansae subclaviae stimulation and ERP lengthening induced by bilateral vagal stimulation as markers of autonomic innervation before and after RV myocardial infarction (RVMI) produced by coronary ligation (n=28 dogs) or intracoronary latex injection (n=18 dogs) into a marginal branch of the right coronary artery in open-chest anesthetized dogs. In each dog, ERPs measured in viable peri-infarct area at two RV outflow tract (RVOT) sites and two septal and four lateral sites at the RV free wall after RVMI showed reduced or absent ERP shortening during bilateral ansae subclaviae stimulation laterally, septally, and at RVOT sites 3 hours after RVMI. ERP shortening in response to infused norepinephrine was still present. Bilateral vagal stimulation during background norepinephrine infusion (0.10 to 0.25 microg/kg per minute) lengthened the ERP at all test sites before latex injection. After transmural RVMI, vagally induced ERP prolongation was attenuated or lost at lateral, septal, and RVOT test sites. CONCLUSIONS: RVMI causes sympathetic and vagal denervation at viable sites at the RVOT, lateral, and, to a lesser extent, septal sides of the viable peri-infarct area. Autonomic denervation in the RVOT might contribute to the development of ventricular tachyarrhythmias after the acute stage of myocardial infarction involving the RV.

Animals↗

Electromyography of cavernous smooth muscle during flaccidity: evaluation of technique and normal values.

Objective evaluation of the penile innervation in impotent patients is mostly restricted to examination of the somatic pudendal pathways. These tests provide little information on the pelvic-cavernous autonomic innervation of the corporeal bodies. Electromyography of the flaccid penile smooth muscle is a reproducible and non-invasive method of evaluating these autonomic pathways and the status of intrinsic smooth muscle. Examination techniques and normal values have been studied in 15 young and potent volunteers. Recordings in 13 patients with neuropathology and 57 impotent patients are discussed.

Adult↗

Cardiovascular responses and postexercise hypotension after arm cycling exercise in subjects with spinal cord injury.

OBJECTIVE: To examine postexercise hypotension and contributing factors in subjects with spinal cord injury (SCI). DESIGN: Prospective clinical research study. SETTING: Rehabilitation center. PARTICIPANTS: Subjects with chronic cervical-level (n=19) and thoracic-level (n=8) SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subjects underwent graded arm-cycling with electrocardiogram and oxygen uptake monitoring to exhaustion. Heart rates and blood pressures were measured before and after exercising. Injury to motor and sensory pathways was determined by American Spinal Injury Association grade, and to autonomic pathways by sympathetic skin responses (SSRs) (n=16). RESULTS: Resting blood pressures and heart rates were lower in cervical than thoracic SCI (mean arterial pressure [MAP]: cervical, 76.6+/-2 mmHg; thoracic, 93.5+/-3 mmHg; P<.001). Following exercise, heart rate responses were greater in thoracic than cervical SCI; MAP increased in thoracic SCI (8.4+/-5 mmHg) and markedly decreased in cervical SCI (-9.3+/-2 mmHg) (P<.001). No subject had significant electrocardiographic abnormalities at rest or during exercise. There were correlations between SSR and heart rate and blood pressure responses to exercise; the correlation between the SSR and blood pressure response was due to an interaction between the heart rate and blood pressure responses. CONCLUSIONS: Abnormal cardiovascular responses to exercise and transient postexercise hypotension were common in cervical, but not thoracic SCI. This may be partly related to loss of descending sympathetic nervous control of the heart and vasculature following high SCI.

Adult↗

Conservation and divergence of FCA function between Arabidopsis and rice.

Although several genes have been identified in rice which are functionally equivalent to the flowering time genes in Arabidopsis, primarily genes involved in the photoperiod pathway, little data is available regarding the genes that function in the autonomous pathway in rice. In order to acquire further insight into the control of heading dates in rice, we isolated and conducted an expression analysis on OsFCA, which exhibited 38% sequence homology with Arabidopsis FCA. The N-terminal region of the OsFCA protein appears to be unusually rich in glycine-residues, unlike the N-terminal region found in FCA. However, the genetic structure of OsFCA is, in general, similar to that of FCA. RT-PCR and in silico analyses also showed that alternative splicing and polyadenylation at intron3 were conserved in the genetic expression of OsFCA. We were able to detect alpha, beta, and gamma transcripts, but not the delta transcript, of the OsFCA gene. The beta and gamma transcripts of the OsFCA gene were detected via Northern analysis in the leaves, roots, and flowers of the plant. Flowers in younger stages exhibited higher transcript levels. These data suggest that intron3 may constitute a primary control point in the OsFCA pre-mRNA processing of rice. The overexpression of OsFCA cDNA, driven by the 35S promoter, was shown to partially rescue the late flowering phenotype of the fca mutant, suggesting that the functions of the OsFCA and the FCA are partially overlapped, despite the lack of an apparent FLC homologue in the rice genome. The constitutive expression of OsFCA resulted in no downregulation of FLC, but did result in the weak upregulation of SOC1 in the transgenic Arabidopsis. OsFCA overexpression did not result in a reduction of the gamma transcript levels of FCA in the transgenic Arabidopsis either, thereby suggesting that OsFCA had no effects on the autoregulation of Arabidopsis FCA. All of these results imply conservation and divergence in the functions of FCA between rice and Arabidopsis.

Alternative Splicing↗

Central neural regulation of penile erection.

Penile erection is caused by a change of the activity of efferent autonomic pathways to the erectile tissues and of somatic pathways to the perineal striated muscles. The spinal cord contains the cell bodies of autonomic and somatic motoneurons that innervate the peripheral targets. The sympathetic outflow is mainly antierectile, the sacral parasympathetic outflow is proerectile, and the pudendal outflow, through contraction of the perineal striated muscles, enhances an erection already present. The shift from flaccidity to erection suggests relations among these neuronal populations in response to a variety of informations. Spinal neurons controlling erection are activated by information from peripheral and supraspinal origin. Both peripheral and supraspinal information is capable of eliciting erection, or modulating or inhibiting an erection already present. One can hypothesize a spinal network consisting of primary afferents from the genitals, spinal interneurons and sympathetic, parasympathetic and somatic nuclei. This system is capable of integrating information from the periphery and eliciting reflexive erections. The same spinal network, eventually including different populations of spinal interneurons, would be the recipient of supraspinal information. Premotor neurons that project directly onto spinal sympathetic, parasympathetic or somatic motoneurons, are present in the medulla, pons and diencephalon. Several of these premotor neurons may in turn be activated by sensory information from the genitals. Aminergic and peptidergic descending pathways in the vicinity of spinal neurons, exert complex effects on the spinal network that control penile erection. This is caused by the potential interaction of a great variety of receptors and receptor subtypes present in the spinal cord. Brainstem and hypothalamic nuclei (among the latter, the paraventricular nucleus and the medial preoptic area) may not necessarily reach spinal neurons directly. However they are prone to regulate penile erection in more integrated and coordinated responses of the body, such as those occurring during sexual behavior. Finally, the central and spinal role of regulatory peptides (oxytocin, melanocortins, endorphins) has only recently been elucidated.

Animals↗

Alterations in neural pathways to the urinary bladder of the rat in response to streptozotocin-induced diabetes.

Voiding dysfunction in diabetics has been attributed to a variety of causes including an axonopathy in autonomic pathways to the urinary bladder. The present study was undertaken to determine whether changes occurred in afferent and efferent neurons supplying bladders of streptozotocin (STZ)-induced diabetic rats. Nine weeks after STZ treatment, the mean cross-sectional area for retrogradely labeled (Fluoro-Gold) bladder neurons in the major pelvic ganglion (MPG) was greater in diabetics (364 microns 2) than controls (300 microns 2). The number of labeled neurons was similar in these groups. In contrast, mean cross-sectional areas of bladder afferent neurons labeled with WGA-HRP in the L6 and S1 dorsal root ganglia (DRG) were smaller (393 microns 2) in diabetics than in normal rats (528 microns 2). In addition, very few DRG neurons were labeled in STZ-treated rats and transganglionic labeling of bladder afferent projections in the L6 and S1 spinal cord with WGA-HRP was sparse. Radioimmunoassay studies revealed that substance P was reduced by 70% in the MPG and by 40% in L6 DRG, yet this peptide was unchanged in the bladders of diabetic rats. The amounts of VIP in the MPG and DRG of diabetics and controls were similar, while VIP in the bladder was increased in diabetics. These observations indicate that both afferent and efferent neurons innervating the urinary bladder are altered in the STZ-induced diabetic rat. In addition, axonal transport in visceral afferent pathways may be disrupted.

Afferent Pathways↗