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Modulation of the autonomic nervous system by peptides: Implication in brain-gut axis
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
18.3 Autonomic vs Myogenic Influences on Cerebral Blood Flow in Humans J.A. Taylor Department of Physical Medicine & Rehabilitation, Harvard Medical School, Cambridge MA, USA
29
inhalation challenge provides a useful method to calibrate the conventional BOLD signal, allowing quantitative assessment of oxygen metabolic change during brain activation. Conclusions: FMRI mapping of brain CBF regulation is becoming a reliable technique and has the potential for clinical diagnosis and basic science application.
doi:10.1016/j.autneu.2015.07.340 The ability of the cerebral vasculature to maintain steady blood flow in the face of changing systemic pressure, i.e., cerebral autoregulation, is critical to neurophysiologic health. Transient faster fluctuations in pressure (e.g., due to respiration) are transmitted to the cerebral circulation almost linearly, whereas slow ones that may have greater impact on neurophysiologic health (due to prolonged cerebral perfusion changes) are effectively buffered against. There has been a long_standing skepticism that the sympathetic system has a role regulating cerebral blood flow. However, ganglionic blockade reduces cerebral counter_regulation of pressure fluctuations and alpha-adrenergic blockade markedly linearizes the pressure-flow relation. Similar to the sympathetic system, cholinergic nerve fibers innervate the cerebrovascular bed but a cholinergic vasodilator reflex has been thought equivocal. However, muscarinic blockade abolishes cerebrovascular conductance increases with exercise and systemic cholinergic blockade increases the linear relation between the pressure_flow relationship within the range of active cerebrovascular regulation. Thus, in addition to sympathetic control, cholinergic control plays a clear role in cerebral autoregulation. Nonetheless, conventional wisdom suggests myogenic responses are the largest contributor to autoregulation. Our work has shown myogenic blockade alters the non_linearity between pressure and flow, particularly at the slowest fluctuations. But, it appears neurogenic control is largely responsible for responding to pressure changes within the active region of autoregulation, whereas vascular myogenic control lies mostly outside this region. This suggests that neurogenic control may be responsible for homoeostatic maintenance of cerebral blood flow, whereas myogenic control may be neuroprotective against ischemia and hemorrhage from rapid swings in pressure. doi:10.1016/j.autneu.2015.07.339
18.4 fMRI mapping of microvascular function and its implications in CBF regulation H. Lu Department of Radiology, Johns Hopkins University School of Medicine, USA Background: There has been substantial progress in the use of fMRI to map microvascular function in the brain. Several factors including better breathing apparatus design, improved analysis approaches, and newer MRI acquisition schemes have enabled individual-level and voxel-by-voxel mapping of cerebrovascular reactivity (CVR). Aim: To review recent development in MRI-based method to assessment CBF regulation and its applications. Methods: Technical advances in CVR mapping will be reviewed. The utility of these methods in better understanding CBF regulation, task-evoked neural activity, and cerebrovascular diseases will be demonstrated. Results: With the current technique, CVR can be measured on a voxel-by-voxel basis and its reliability is comparable, if not more superior, to other functional MRI measures such as neural activation, baseline perfusion, and brain metabolism. Compared to the gray matter, white matter is found to manifest a substantial delay (tens of seconds) in response onset time, which may be due to a slower rise in extravascular CO2 level. CVR appears to be a sensitive marker in detecting vascular deficits in patients with intracranial stenosis, compared to baseline CBF. FMRI using gas-
Abstract Selected for Presentation 18.5 α1-Adrenergic Blockade Modify The Regulation of Brain Blood Flow During Static Handgrip Exercise I.A. Fernandesa, J.D. Mattosa, M.O. Camposa, M.P. Rochaa, A.C. Machadoa, N.G. Rochaa, L.C. Viannab, A.C.L. Nóbregaa a Department of Physiology and Pharmacology, Fluminense Federal University b Department of Physical Education, University of Brasília, Brazil Background: Forearm exercise increases contralateral cerebral blood flow (BF) with no changes ispilaterally, reflecting activation of corresponding cortical areas whereas the existence of vascular sympathetic control is still uncertain. Aim: To determine the contribution of the sympathetic nervous system, through the selective alpha 1-adrenergic blockade (α1-block), on the isometric forearm exercise-induced changes on human brain blood flow distribution. Methods: Beat-to-beat BF of contra- and ispilateral internal carotid arteries (ICA, Doppler) and mean blood pressure (MBP, Finometer) were simultaneously determined in six healthy men (25±2 yrs) at rest and during 2-min of static handgrip exercise (IHE at 30% of maximal voluntary contraction) under control (CT) and α1-block (150 min after oral Prazosin [50μg/kg]). Intravenous phenylephrine (PE-1μg/kg) was administered before and after Prazosin to confirm α1-block. Skeletal muscle activity (surface electromyogram), beath-by-breath end-tidal carbon dioxide (rebreathing system) and respiratory rate were controlled throughout the study. Results: Contraand ispilateral ICAs BF were similar (pN0.05) at rest. During IHE, MBP increased (+33±6.5 mmHg; pb0.05); BF increased to contralateral (+70.6±22.8), but decreased to Ipsilateral ICA (−6.1±18.1 mL/min, pb0.05) corresponding to a greater decrease in vascular conductance (VC) in ispilateral ICA (pb0.05). IHE under α1-block elicited a smaller MBP response (pb0.05) and similar increases in BF of ICAs (pb0.05) and decreases in VC (pb0.05). The smaller reduction in VC in contralateral ICA (CT: −1.6±0.5 vs. α1-block: −0.1±0.2; pb0.05) indicates a diminished sympathetic restrain to flow. Conclusion: Selective alpha 1-adrenergic blockade revealed a role of the sympathetic system in regulating brain perfusion during isometric handgrip exercise.
doi:10.1016/j.autneu.2015.07.341
MONDAY 28TH SEPTEMBER PLENARY LECTURE Yvette Taché Modulation of the autonomic nervous system by peptides: Implication in brain-gut axis Yvette Taché CURE: Digestive Diseases Research Center and Center for Neurovisceral Sciences & Women's Health, Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California
30
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
Several peptides in the brain have been identified to play a key role in the autonomic regulation of visceral function. In particular, medullary thyrotropin-releasing hormone (TRH) acting on TRH1 receptor in the dorsal motor nucleus of the vagus (DMN) play a physiological role in mediating the vagal activation induced by the cephalic phase, experimental hypoglycemia and acute cold exposure. The TRH-TRH1 receptor signaling in the DMN stimulates gastric vagal efferent discharges, myenteric cholinergic neurons and upregulates peripheral choline acetyl transferase expression leading to increase gastrointestinal blood flow, secretion, motility and gut hormone release. Recent evidence indicates also that TRH in the medulla induces a vagal anti-inflammatory response as shown by the suppression of abdominal surgery induced increase in the number of macrophage M1 cells, infiltration of neutrophils and upregulation interleukin -1β and tumor necrosis factor-alpha mRNA supporting an important role of this brain vagal pathway in the modulation of gut inflammation. Another peptide involved in the physiological regulation of the autonomic nervous system is corticotropin releasing factor (CRF). CRF action in the brain influences gastrointestinal motor function by inhibiting vagal activity while stimulating sacral parasympathetic outflow, colonic cholinergic myenteric neurons and catecholamine release. CRF signaling pathways acting on CRF1 receptors in the hypothalamus and CRF2 receptor in the medulla are involved in stress-related alterations of autonomic nervous system activity. These studies provide insight to specific brain peptidergic pathways namely the CRF system recruited by stressors or TRH under conditions of changes in metabolic status that impact on digestive function through autonomic-gut enteric nervous system interactions.
doi:10.1016/j.autneu.2015.07.342
Symposium 19: Interaction Between the Somatic and Autonomic Nervous System 19.1 The Impact of Somatosensory Input on Autonomic Functions Robert F. Schmidt Physiologisches Institut der Universität Würzburg, Am Röntgenring 9, 97070 Würzburg, Germany Activation of somatosensory receptors produces not only conscious sensations but also physiological responses. These bodily responses engage the skeletomotor, autonomic, endocrine and immune systems as well as other organ systems. This lecture will concentrate on the responses of visceral functions following activation of sensory receptors with fine afferent fibers entering the spinal cord via spinal nerves, and the brain stem via the trigeminal nerves. Their efferent pathways are autonomic efferent fibres, i.e. sympathetic and parasympathetic efferents. In some cases these pathways include hormones. Emphasis will be placed on the results with various types of non-painful, low-intensity stimulation of skin and muscles afferents in rats, including acupuncture-like stimulation. Such procedures produced marked reflex effects e. g. in the cardiovascular, the intestinal, the renal and urinary bladder system and in various hormonal systems. As an example the effects of acupuncture-like stimulation on the rhythmic micturition contractions of the urinary bladder are mentioned: Acupuncture-like stimulation applied to the perineal area inhibits both the rhythmic micturition contractions and the discharges of vesical pelvic efferent nerves, without any significant changes in hypogastric efferent nerve activity. In contrast, stimulation applied to the face, neck, forelimb,
chest abdomen, back and hindlimb is ineffective. These findings together with additional evidence indicate that the inhibition of rhythmic micturition contractions following acupuncture-like stimulation of the perineal area is a reflex response characterized by segmental organization. From these and other results presented it is suggested that somato-autonomic reflex responses participate in the effects produced by acupuncture.
doi:10.1016/j.autneu.2015.07.343
19.2 Basic and clinical studies on the effects of cutaneous stimulation on urinary system Harumi Hotta Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Somatic afferent stimuli are used for treating an overactive bladder (OAB). However, clinical evidence for the treatment is insufficient because of lack of appropriate control stimuli. Recent animal studies showed that gentle stimuli applied to perineal skin with a roller could inhibit micturition contractions depending on roller’s surface material. We performed a clinical study to examine efficacy of gentle cutaneous stimuli for nocturia, while examining underling mechanisms in animal experiments. A cross-over, randomized double-blind study was conducted using two rollers with different effects on micturition contractions. Participants were elderly women with nocturia. Active (soft roller) or placebo (hard roller) stimuli were applied to perineal skin by participants for 1 min at bedtime during each 3-day period. In participants with OAB, mean frequency of nocturia during the active stimuli period was significantly lower than that during baseline and placebo stimuli periods. These results suggest that gentle cutaneous stimulation with the soft material is effective for treating OAB-associated nocturia. In anesthetized rats, inhibition of micturition contractions by the active stimulation was abolished by naloxone, intrathecally administered into lumbosacral spinal cord. The stimulation inhibited bladder contractions induced by stimulation of the pontine micturition center (PMC). It also inhibited bladder distension-induced increase in blood flow, as well as vesical afferent-evoked field potentials in the dorsal commissure, at the lumbosacral cord. These results suggest that the cutaneous stimulation activates spinal opioidergic system and inhibits both ascending and descending transmissions of micturition reflex pathway, leading to shutting down of positive feedback between bladder and the PMC.
doi:10.1016/j.autneu.2015.07.344
19.3 Mechanisms Underlying Peripheral and Central Actions of Acupuncture’s Autonomic Interactions John Longhurst Departments of Medicine, Physiology and Biophysics and Pharmacology and Susan Samueli Center for Integrative Medicine, University of CA, Irvine, USA Acupuncture is part of traditional Chinese medicine used for almost 6,000 years for a number of clinical conditions. Although most
18.3 Autonomic vs Myogenic Influences on Cerebral Blood Flow in Humans J.A. Taylor Department of Physical Medicine & Rehabilitation, Harvard Medical School, Cambridge MA, USA
29
inhalation challenge provides a useful method to calibrate the conventional BOLD signal, allowing quantitative assessment of oxygen metabolic change during brain activation. Conclusions: FMRI mapping of brain CBF regulation is becoming a reliable technique and has the potential for clinical diagnosis and basic science application.
doi:10.1016/j.autneu.2015.07.340 The ability of the cerebral vasculature to maintain steady blood flow in the face of changing systemic pressure, i.e., cerebral autoregulation, is critical to neurophysiologic health. Transient faster fluctuations in pressure (e.g., due to respiration) are transmitted to the cerebral circulation almost linearly, whereas slow ones that may have greater impact on neurophysiologic health (due to prolonged cerebral perfusion changes) are effectively buffered against. There has been a long_standing skepticism that the sympathetic system has a role regulating cerebral blood flow. However, ganglionic blockade reduces cerebral counter_regulation of pressure fluctuations and alpha-adrenergic blockade markedly linearizes the pressure-flow relation. Similar to the sympathetic system, cholinergic nerve fibers innervate the cerebrovascular bed but a cholinergic vasodilator reflex has been thought equivocal. However, muscarinic blockade abolishes cerebrovascular conductance increases with exercise and systemic cholinergic blockade increases the linear relation between the pressure_flow relationship within the range of active cerebrovascular regulation. Thus, in addition to sympathetic control, cholinergic control plays a clear role in cerebral autoregulation. Nonetheless, conventional wisdom suggests myogenic responses are the largest contributor to autoregulation. Our work has shown myogenic blockade alters the non_linearity between pressure and flow, particularly at the slowest fluctuations. But, it appears neurogenic control is largely responsible for responding to pressure changes within the active region of autoregulation, whereas vascular myogenic control lies mostly outside this region. This suggests that neurogenic control may be responsible for homoeostatic maintenance of cerebral blood flow, whereas myogenic control may be neuroprotective against ischemia and hemorrhage from rapid swings in pressure. doi:10.1016/j.autneu.2015.07.339
18.4 fMRI mapping of microvascular function and its implications in CBF regulation H. Lu Department of Radiology, Johns Hopkins University School of Medicine, USA Background: There has been substantial progress in the use of fMRI to map microvascular function in the brain. Several factors including better breathing apparatus design, improved analysis approaches, and newer MRI acquisition schemes have enabled individual-level and voxel-by-voxel mapping of cerebrovascular reactivity (CVR). Aim: To review recent development in MRI-based method to assessment CBF regulation and its applications. Methods: Technical advances in CVR mapping will be reviewed. The utility of these methods in better understanding CBF regulation, task-evoked neural activity, and cerebrovascular diseases will be demonstrated. Results: With the current technique, CVR can be measured on a voxel-by-voxel basis and its reliability is comparable, if not more superior, to other functional MRI measures such as neural activation, baseline perfusion, and brain metabolism. Compared to the gray matter, white matter is found to manifest a substantial delay (tens of seconds) in response onset time, which may be due to a slower rise in extravascular CO2 level. CVR appears to be a sensitive marker in detecting vascular deficits in patients with intracranial stenosis, compared to baseline CBF. FMRI using gas-
Abstract Selected for Presentation 18.5 α1-Adrenergic Blockade Modify The Regulation of Brain Blood Flow During Static Handgrip Exercise I.A. Fernandesa, J.D. Mattosa, M.O. Camposa, M.P. Rochaa, A.C. Machadoa, N.G. Rochaa, L.C. Viannab, A.C.L. Nóbregaa a Department of Physiology and Pharmacology, Fluminense Federal University b Department of Physical Education, University of Brasília, Brazil Background: Forearm exercise increases contralateral cerebral blood flow (BF) with no changes ispilaterally, reflecting activation of corresponding cortical areas whereas the existence of vascular sympathetic control is still uncertain. Aim: To determine the contribution of the sympathetic nervous system, through the selective alpha 1-adrenergic blockade (α1-block), on the isometric forearm exercise-induced changes on human brain blood flow distribution. Methods: Beat-to-beat BF of contra- and ispilateral internal carotid arteries (ICA, Doppler) and mean blood pressure (MBP, Finometer) were simultaneously determined in six healthy men (25±2 yrs) at rest and during 2-min of static handgrip exercise (IHE at 30% of maximal voluntary contraction) under control (CT) and α1-block (150 min after oral Prazosin [50μg/kg]). Intravenous phenylephrine (PE-1μg/kg) was administered before and after Prazosin to confirm α1-block. Skeletal muscle activity (surface electromyogram), beath-by-breath end-tidal carbon dioxide (rebreathing system) and respiratory rate were controlled throughout the study. Results: Contraand ispilateral ICAs BF were similar (pN0.05) at rest. During IHE, MBP increased (+33±6.5 mmHg; pb0.05); BF increased to contralateral (+70.6±22.8), but decreased to Ipsilateral ICA (−6.1±18.1 mL/min, pb0.05) corresponding to a greater decrease in vascular conductance (VC) in ispilateral ICA (pb0.05). IHE under α1-block elicited a smaller MBP response (pb0.05) and similar increases in BF of ICAs (pb0.05) and decreases in VC (pb0.05). The smaller reduction in VC in contralateral ICA (CT: −1.6±0.5 vs. α1-block: −0.1±0.2; pb0.05) indicates a diminished sympathetic restrain to flow. Conclusion: Selective alpha 1-adrenergic blockade revealed a role of the sympathetic system in regulating brain perfusion during isometric handgrip exercise.
doi:10.1016/j.autneu.2015.07.341
MONDAY 28TH SEPTEMBER PLENARY LECTURE Yvette Taché Modulation of the autonomic nervous system by peptides: Implication in brain-gut axis Yvette Taché CURE: Digestive Diseases Research Center and Center for Neurovisceral Sciences & Women's Health, Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California
30
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
Several peptides in the brain have been identified to play a key role in the autonomic regulation of visceral function. In particular, medullary thyrotropin-releasing hormone (TRH) acting on TRH1 receptor in the dorsal motor nucleus of the vagus (DMN) play a physiological role in mediating the vagal activation induced by the cephalic phase, experimental hypoglycemia and acute cold exposure. The TRH-TRH1 receptor signaling in the DMN stimulates gastric vagal efferent discharges, myenteric cholinergic neurons and upregulates peripheral choline acetyl transferase expression leading to increase gastrointestinal blood flow, secretion, motility and gut hormone release. Recent evidence indicates also that TRH in the medulla induces a vagal anti-inflammatory response as shown by the suppression of abdominal surgery induced increase in the number of macrophage M1 cells, infiltration of neutrophils and upregulation interleukin -1β and tumor necrosis factor-alpha mRNA supporting an important role of this brain vagal pathway in the modulation of gut inflammation. Another peptide involved in the physiological regulation of the autonomic nervous system is corticotropin releasing factor (CRF). CRF action in the brain influences gastrointestinal motor function by inhibiting vagal activity while stimulating sacral parasympathetic outflow, colonic cholinergic myenteric neurons and catecholamine release. CRF signaling pathways acting on CRF1 receptors in the hypothalamus and CRF2 receptor in the medulla are involved in stress-related alterations of autonomic nervous system activity. These studies provide insight to specific brain peptidergic pathways namely the CRF system recruited by stressors or TRH under conditions of changes in metabolic status that impact on digestive function through autonomic-gut enteric nervous system interactions.
doi:10.1016/j.autneu.2015.07.342
Symposium 19: Interaction Between the Somatic and Autonomic Nervous System 19.1 The Impact of Somatosensory Input on Autonomic Functions Robert F. Schmidt Physiologisches Institut der Universität Würzburg, Am Röntgenring 9, 97070 Würzburg, Germany Activation of somatosensory receptors produces not only conscious sensations but also physiological responses. These bodily responses engage the skeletomotor, autonomic, endocrine and immune systems as well as other organ systems. This lecture will concentrate on the responses of visceral functions following activation of sensory receptors with fine afferent fibers entering the spinal cord via spinal nerves, and the brain stem via the trigeminal nerves. Their efferent pathways are autonomic efferent fibres, i.e. sympathetic and parasympathetic efferents. In some cases these pathways include hormones. Emphasis will be placed on the results with various types of non-painful, low-intensity stimulation of skin and muscles afferents in rats, including acupuncture-like stimulation. Such procedures produced marked reflex effects e. g. in the cardiovascular, the intestinal, the renal and urinary bladder system and in various hormonal systems. As an example the effects of acupuncture-like stimulation on the rhythmic micturition contractions of the urinary bladder are mentioned: Acupuncture-like stimulation applied to the perineal area inhibits both the rhythmic micturition contractions and the discharges of vesical pelvic efferent nerves, without any significant changes in hypogastric efferent nerve activity. In contrast, stimulation applied to the face, neck, forelimb,
chest abdomen, back and hindlimb is ineffective. These findings together with additional evidence indicate that the inhibition of rhythmic micturition contractions following acupuncture-like stimulation of the perineal area is a reflex response characterized by segmental organization. From these and other results presented it is suggested that somato-autonomic reflex responses participate in the effects produced by acupuncture.
doi:10.1016/j.autneu.2015.07.343
19.2 Basic and clinical studies on the effects of cutaneous stimulation on urinary system Harumi Hotta Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Somatic afferent stimuli are used for treating an overactive bladder (OAB). However, clinical evidence for the treatment is insufficient because of lack of appropriate control stimuli. Recent animal studies showed that gentle stimuli applied to perineal skin with a roller could inhibit micturition contractions depending on roller’s surface material. We performed a clinical study to examine efficacy of gentle cutaneous stimuli for nocturia, while examining underling mechanisms in animal experiments. A cross-over, randomized double-blind study was conducted using two rollers with different effects on micturition contractions. Participants were elderly women with nocturia. Active (soft roller) or placebo (hard roller) stimuli were applied to perineal skin by participants for 1 min at bedtime during each 3-day period. In participants with OAB, mean frequency of nocturia during the active stimuli period was significantly lower than that during baseline and placebo stimuli periods. These results suggest that gentle cutaneous stimulation with the soft material is effective for treating OAB-associated nocturia. In anesthetized rats, inhibition of micturition contractions by the active stimulation was abolished by naloxone, intrathecally administered into lumbosacral spinal cord. The stimulation inhibited bladder contractions induced by stimulation of the pontine micturition center (PMC). It also inhibited bladder distension-induced increase in blood flow, as well as vesical afferent-evoked field potentials in the dorsal commissure, at the lumbosacral cord. These results suggest that the cutaneous stimulation activates spinal opioidergic system and inhibits both ascending and descending transmissions of micturition reflex pathway, leading to shutting down of positive feedback between bladder and the PMC.
doi:10.1016/j.autneu.2015.07.344
19.3 Mechanisms Underlying Peripheral and Central Actions of Acupuncture’s Autonomic Interactions John Longhurst Departments of Medicine, Physiology and Biophysics and Pharmacology and Susan Samueli Center for Integrative Medicine, University of CA, Irvine, USA Acupuncture is part of traditional Chinese medicine used for almost 6,000 years for a number of clinical conditions. Although most