[Physiology of the Vagus Nerve: Basic Medical Research from the Past to the Present].

The vagus nerve, which is the 10th cranial nerve, exits from the medulla and distributes widely to the visceral organs. Although it contains the motor, somatic, and sympathetic nerves, the main component is the parasympathetic nerve, which acts as the core of homeostasis. The vagal efferent regulates the cardiac muscle, striated muscle and glands, while the vagal afferent sends the information from the visceral organs to the brain. The vagus nerve is also responsible for the gut-brain axis.

Somatosensory regulation of resting muscle blood flow and physical therapy.

Somatosensory stimulation can affect skeletal muscle blood flow (MBF) at rest in anesthetized animals via pressor reflex response or antidromic and local vasodilation. Increase in MBF due to reflex pressor response occurs generally in the skeletal muscles of the entire body, while antidromic and local vasodilation are limited to the peripheral stimulation site. Since increased MBF improves several disorders (muscle stiffness, pain, etc.), it is reasonable to further explore the effective use of somatic stimulation in physical therapies, such as massage, acupuncture, anma, and shiatsu or acupressure, in treating skeletal muscle disorders.

Somatoautonomic reflexes in acupuncture therapy: A review.

Oriental therapies such as acupuncture, moxibustion, or Anma, have been used to treat visceral disorders since ancient times. In each of these therapies, stimulation of the skin or underlying muscles leads to excitation of afferent nerves. The sensory information is carried to the central nervous system, where it is transferred to autonomic efferents, thus affecting visceral functions. This neuronal pathway, known as the "somatoautonomic reflex", has been systematically studied by Sato and his colleagues for over a half century. Nearly all their studies were conducted in anesthetized animals, whereas human patients are conscious. Responses in patients or the events following therapeutic somatic stimulation may differ from those observed in anesthetized animals. In fact, it is increasingly apparent that the responses in patients and animals are not always coincident, and the differences have been difficult for clinicians to reconcile. We review the mechanism of the "somatoautonomic reflex" as described in anesthetized animals and then discuss how it can be applied clinically.

Increased blood serotonin concentrations are correlated with reduced tension/anxiety in healthy postpartum lactating women.

The serotonin (5-HT) system in the brain plays an important role in mood regulation. The postpartum period is considered a high-risk time for mood and anxiety disorders. We assessed changes in 5-HT levels in whole blood (as an indicator of brain 5-HT concentrations) and mood states before and after delivery in 28 healthy, lactating postpartum women. Mood states were evaluated using Profile of Mood States questionnaires (POMS). Measurements were done on the same day in early (first week) and late (third-fourth and sixth-seventh weeks) postpartum, and compared with those in the third trimester and in age-matched, healthy, non-pregnant women. Mean 5-HT concentrations were significantly higher and mean tension/anxiety scores of POMS were significantly lower in late (but not early) postpartum than in the third trimester or non-pregnant controls. 5-HT concentrations correlated with tension/anxiety in the third trimester and late postpartum, indicating an important role for the 5-HT system in the regulation of tension/anxiety in healthy postpartum women. The mechanism underlying the changes in the 5-HT system may be rapid inhibition induced by the marked decrease in estradiol after delivery and gradual excitation caused by lactation-induced brain oxytocin release during the postpartum period.

Activation of the anterior prefrontal cortex and serotonergic system is associated with improvements in mood and EEG changes induced by Zen meditation practice in novices.

To gain insight into the neurophysiological mechanisms involved in Zen meditation, we evaluated the effects of focused attention (FA) on breathing movements in the lower abdomen (Tanden) in novices. We investigated hemodynamic changes in the prefrontal cortex (PFC), an attention-related brain region, using 24-channel near-infrared spectroscopy during a 20-minute session of FA on Tanden breathing in 15 healthy volunteers. We found that the level of oxygenated hemoglobin in the anterior PFC was significantly increased during FA on Tanden breathing, accompanied by a reduction in feelings of negative mood compared to before the meditation session. Electroencephalography (EEG) revealed increased alpha band activity and decreased theta band activity during and after FA on Tanden breathing. EEG changes were correlated with a significant increase in whole blood serotonin (5-HT) levels. These results suggest that activation of the anterior PFC and 5-HT system may be responsible for the improvement of negative mood and EEG signal changes observed during FA on Tanden breathing.

Ventral prefrontal cortex and serotonergic system activation during pedaling exercise induces negative mood improvement and increased alpha band in EEG.

This study evaluates a possible involvement of the prefrontal cortex (PFC) and serotonergic (5-HT) system in psychiatric and electroencephalography (EEG) changes during and after pedaling exercise (PE). The subjects performed PE for 15 min using a cycle ergometer. PE rate was kept at 60 rpm, and the work load (93+/-5.4 W) was decided for each subject before the experiment based on a Rating of Perceived Exertion of 12-13 for self-selected exercise intensity. Cerebral oxygenation in the PFC was assessed by concentration changes in oxygenated hemoglobin (oxyHb) using 24-channel near-infrared spectroscopy. We found that PE evoked a significant increase in oxyHb levels in the ventral PFC during PE as compared with that in the dorsal PFC. Subjects had a feeling of reduced negative mood accompanied by a tendency of increased vigor-activity after PE, as assessed by the Profile of Mood States (POMS) questionnaire. Because the ventral PFC is associated with mood state, we hypothesized that the observed mood changes may have been induced by the activation of the ventral PFC. As for EEG changes during and after PE, we found a significant increase in the relative powers of high-frequency alpha bands (10-13 Hz) during and after PE. A significant increase in whole blood 5-HT level was obtained after PE. Because cortical attenuation would be caused by the 5-HT-induced inhibition of the basal forebrain, we hypothesized that the observed EEG changes are linked with the increased blood 5-HT level or an augmentation of the 5-HT system in the brainstem.

Decreased blood serotonin in the premenstrual phase enhances negative mood in healthy women.

The purpose of this study was to evaluate mechanisms underlying the action of selective serotonin reuptake inhibitors on the improvement of negative mood symptoms in premenstrual syndrome. We assessed relationships between serotonin (5-HT) levels in the brain (estimated from 5-HT concentrations in whole blood) and negative mood states during the premenstrual phase in 13 healthy women. Mood states were evaluated using the Profile of Mood States questionnaire. We also evaluated relationships between 5-HT and ovarian hormones (oestradiol and progesterone). A significant negative correlation was seen between 5-HT concentrations in whole blood and negative mood scores (tension-anxiety and fatigue) observed in the premenstrual phase. A significant positive correlation was observed between 5-HT and oestradiol in the premenstrual phase, but not in the follicular phase. These results suggest that healthy women with lower whole blood 5-HT concentrations in the premenstrual phase exhibit enhanced negative mood due to lower 5-HT concentrations at brain synapses, which may be caused in part by lower oestrogen concentration.

Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat.

The present study re-evaluated an existing notion that serotonin (5-hydroxytryptamine; 5-HT) could not cross the brain to the circulating blood via the blood-brain barrier (BBB). To elevate brain 5-HT alone, 5-hydroxytryptophan (5-HTP; 30-75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5-HT after 5-HTP administration). A microdialysis method and HPLC system were used to determine the brain 5-HT levels in samples collected from the frontal cortex. Blood 5-HT levels were determined from whole blood, not platelet-poor plasma, collected from the central vein. We found that blood 5-HT levels showed a significant augmentation whenever brain 5-HT levels were significantly elevated after the administration of 5-HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5-HT levels remained augmented. These results indicate that augmented brain 5-HT can cross the BBB through the 5-HT transporter from the brain to the circulating blood.

Corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus are involved in arousal/yawning response of rats.

Our previous studies have suggested that activation of the hypothalamic paraventricular (PVN) descending oxytocinergic projections is involved in the induction of yawning accompanied by an arousal response, but the possibility that neural systems other than the oxytocinergic system in the PVN also mediate the arousal/yawning response cannot be ruled out. We assessed the activity of corticotropin-releasing factor (CRF) neurons during yawning induced by the PVN stimulation in anesthetized, spontaneously breathing rats using double-staining for c-Fos and CRF. Yawning response was evaluated by monitoring an intercostals electromyogram as an index of inspiratory activity and a digastric electromyogram as an indicator of mouth opening. We also recorded the electrocorticogram (ECoG) to determine the arousal response during yawning. Microinjection of l-glutamate (2-5 nmol) into the PVN produced a frequent yawning accompanied by an arousal shift in the ECoG, and these behavioral effects were associated with a significant increase of c-Fos positive CRF neurons in the medial parvocellular subdivision of the PVN. In addition, a marked enhancement in the c-Fos expression was found in the both locus coeruleus (LC) and global area in the cortex when the frequency of yawning response was increased by the PVN stimulation, suggesting that the arousal response during yawning might be mediated by the activation of LC neurons. The present study suggests that an activation of CRF neurons in the PVN is responsible for the arousal response accompanied by yawning behavior.

Prolonged rhythmic gum chewing suppresses nociceptive response via serotonergic descending inhibitory pathway in humans.

Serotonergic (5-HT) neurons are implicated in modulating nociceptive transmission. It is established that 5-HT neuronal activity is enhanced by rhythmic behaviors such as chewing and locomotion in animals. We thus hypothesized that 5-HT descending inhibitory pathways may be enhanced by rhythmic behavior of gum chewing in humans. To evaluate this idea, we examined nociceptive flexion reflex (NFR), while a subject chewed gum rhythmically for 20 min. NFR was elicited by electrical stimulation of the sural nerve, and the evoked potential was recorded from the biceps femoris muscle. Visual analogue scale (VAS) was also obtained. To assess 5-HT activity, we determined 5-HT levels quantitatively in platelet poor plasma (PPP) and whole blood (WB) using HPLC system. Both NFR area and VAS were significantly decreased at 5 min after the onset of chewing and these reductions persisted until cessation of chewing. There were no significant changes in NFR and VAS while resting without chewing. The PPP 5-HT level increased significantly just after cessation of chewing and had returned to the pre-chewing level by 30 min after cessation of chewing. The WB 5-HT level obtained 30 min after cessation of chewing was significantly greater than the pre-chewing level. Serotonin transporters have recently been discovered at the blood-brain barrier, suggesting that the rise in blood 5-HT may possibly reflect an increase in 5-HT level within the brain. The present results support our hypothesis that the rhythmic behavior of chewing suppresses nociceptive responses via the 5-HT descending inhibitory pathway.

Appearance of high-frequency alpha band with disappearance of low-frequency alpha band in EEG is produced during voluntary abdominal breathing in an eyes-closed condition.

This study examined the effects of voluntary abdominal breathing (VAB) on the electroencephalogram (EEG) in 22 healthy subjects. VAB was characterized by prolonged rhythmic contraction of abdominal muscles for 20 min in an eyes-closed condition. The breathing rate was instructed to be very slow, i.e., 3-4 breaths/min (inspiratory time for 6-8s and expiratory time for 9-12s). A low-frequency alpha band appeared immediately after eye closing, but it later disappeared and was replaced by a new development of a high-frequency alpha band 4-5 min after the onset of VAB. The subjects had a feeling of vigor-activity with a tendency of reduced anxiety during and/or after VAB, as assessed by POMS and STAI questionnaire scores. On the other hand, during resting in the eye-closed condition, the disappearance of the low-frequency alpha band was replaced by the occurrence of a theta/delta band. The subjects became drowsy in this condition. We therefore conclude that the increase in high-frequency alpha activity is linked to the state of vigor-activity with a tendency of reduced anxiety. Since the urinary serotonergic level significantly increased after the VAB, we suggest that the serotonergic neurons within the brain may produce the changes in the EEG patterns.

Light induces cortical activation and yawning in rats.

We examined the effects of light stimulation on cortical activation and yawning response in anesthetized, spontaneously breathing rats. Cortical activation was assessed by means of an electrocorticogram (ECoG) and yawning response was evaluated by monitoring an intercostal electromyogram as an index of inspiratory activity and a digastric electromyogram as an indicator of mouth opening. Light stimulation elicited an arousal shift in the ECoG to faster rhythms. This arousal response was followed by a single large inspiration with mouth opening, i.e. a yawning response. Higher light intensity significantly reduced the onset latency of the arousal/yawning response. Pretreatment with pyrilamine, an H1-histamine receptor antagonist, injected into the lateral ventricle blocked both the cortical activation and the yawning response induced by light stimulation, suggesting a role of brain histaminergic neurotransmission in modulating the light-induced arousal/yawning responses.

Yawning/cortical activation induced by microinjection of histamine into the paraventricular nucleus of the rat.

The effects of microinjection of histamine into the paraventricular nucleus (PVN) of the hypothalamus on yawning responses were investigated in anesthetized, spontaneously breathing rats. Yawning responses were evaluated by monitoring the intercostal electromyogram (EMG) as an index of inspiratory activity and digastric EMG as an indicator of mouth opening. We also recorded the electrocorticogram (ECoG) to determine the arousal response during yawning. Autonomic function was evaluated by measuring blood pressure and heart rate. Microinjection of histamine into the medial parvocellular subdivision (mp) of the PVN elicited a yawning response, i.e. a single large inspiration with mouth opening, and an arousal shift in ECoG to lower voltage and faster rhythms. Microinjection of HTMT dimaleate, an H1 receptor agonist, into the PVN also caused the yawning/arousal response. Pretreatment with pyrilamine, an H1 receptor antagonist, inhibited the histamine induced yawning behavior. These data demonstrate that a histamine receptive site for triggering yawning/arousal responses exists in the PVN, and suggest that these responses are mediated by activation of H1 receptor within the PVN.

Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat.

Orexin-A is a neuropeptide which has been suggested to be involved in sleep and arousal mechanisms. Orexin-A, for example, stimulates arousal when administrated intracerebroventricularly to rats. We attempted to identify specific neural sites of orexin-A and orexin-B action. Orexin-A and orexin-B were microinjected into the medial parvocellular subdivision of the paraventricular nucleus (PVN) in anesthetized, spontaneously breathing rats, and cortical arousal and yawning responses were assessed. Cortical arousal responses were monitored with the electrocorticogram (ECoG), and yawning responses were evaluated by monitoring intercostal electromyograms as an index of inspiratory activity and digastric electromyograms as an indicator of mouth opening. We also measured blood pressure and heart rate during yawning responses, since yawning is accompanied by changes in autonomic activity. Microinjection of orexin-A into the PVN elicited an arousal shift in the ECoG to lower voltage and faster rhythms. This cortical arousal response was followed by a single large inspiration with mouth opening, i.e. a yawning response. On the other hand, microinjection of orexin-B into the PVN elicited an arousal shift in the ECoG without yawning responses. These results demonstrate that an orexin receptive site for triggering arousal/yawning responses exists in the PVN, and suggest that the PVN is involved in arousal mechanisms.