Critical roles for breathing in the genesis and modulation of emotional states.

Breathing can be classified into metabolic and behavioral categories. Metabolic breathing and voluntary behavioral breathing are controlled in the brainstem and in the cerebral motor cortex, respectively. This chapter places special emphasis on the reciprocal influences between breathing and emotional processes. As is the case with neural control of breathing, emotions are generated by multiple control networks, located primarily in the forebrain. For several decades, a respiratory rhythm generator has been investigated in the limbic system. The amygdala receives respiratory-related input from the piriform cortex. Excitatory recurrent branches are located in the piriform cortex and have tight reciprocal synaptic connections, which produce periodic oscillations, similar to those recorded in the hippocampus during slow-wave sleep. The relationship between olfactory breathing rhythm and emotion is seen as the gateway to interpreting the relationship between breathing and emotion. In this chapter, we describe roles of breathing in the genesis of emotion, neural structures common to breathing and emotion, and mutual importance of breathing and emotion. We also describe the central roles of conscious awareness and voluntary control of breathing, as effective methods for stabilizing attention and the contents in the stream of consciousness. Voluntary control of breathing is seen as an essential practice for achieving emotional well-being.

Relationships between trait and respiratory parameters during quiet breathing in normal subjects.

Respiratory patterns are influenced and altered by various emotional changes. In the present study, we investigated how respiratory patterns differ from individual to individual during quiet breathing. We examined the State-Trait Anxiety Inventory and various respiratory parameters in 16 healthy male subjects. Tidal volume was significantly larger and respiratory rate (RR) was significantly higher in both the higher trait (HT) and higher state (HS) anxiety groups compared to the lower trait and lower state anxiety groups. Inspiratory (T I) and expiratory time (T E) was significantly shorter in both the HT and HS anxiety groups. There was no significant difference in minute ventilation between these two groups. End-tidal CO2%, heart rate, and oxygen uptake ([Formula: see text]) also showed no significant differences. V T showed a negative correlation and RR showed a positive correlation with trait scores. T I and T E showed a negative correlation with trait anxiety scores. However, no other respiratory parameter showed any correlation. These results suggest that the respiratory rhythm reflected by RR is affected by the activity generated in the higher center in accordance with the level of trait anxiety during quiet breathing in awake humans.

Coupling of dyspnea perception and occurrence of tachypnea during exercise.

During exercise, tidal volume initially contributes to ventilatory responses more than respiratory frequency, and respiratory frequency then increases rapidly while tidal volume stabilizes. Dyspnea intensity is also known to increase in a threshold-like manner. We tested the possibility that the threshold of tachypneic breathing is equal to that of dyspnea perception during cycle ergometer exercise (n = 27). Dyspnea intensity was scored by a visual analog scale. Thresholds were expressed as values of pulmonary O2 uptake at each breakpoint. Dyspnea intensity and respiratory frequency started increasing rapidly once the intensity of stimuli exceeded a threshold level. The thresholds for dyspnea intensity and for occurrence of tachypnea were significantly correlated. An intraclass correlation coefficient of 0.71 and narrow limits of agreement on the Bland-Altman plot indicated a good agreement between these thresholds. These results suggest that the start of tachypneic breathing coincides with the threshold for dyspnea intensity during cycle ergometer exercise.

Is Skin-Touch Sham Needle Not Placebo? A Double-Blind Crossover Study on Pain Alleviation.

It remains an open question whether placebo/sham acupuncture, in which the needle tip presses the skin, can be used as a placebo device for research on pain. We compare the analgesic effect of the skin-touch placebo needle with that of the no-touch placebo needle, in which the needle tip does not touch the skin, in a double-blind crossover manner including no-treatment control in 23 healthy volunteers. The subjects received painful electrical stimulation in the forearm before and during needle retention to the LI 4 acupoint and after the removal of the needle and rated pain intensity using a visual analogue scale. We found no significant difference in analgesic effects among the skin-touch placebo needle, no-touch placebo needle, and no-treatment control at every point before, during, and after the treatments (p > 0.05). The results indicate that the skin-touch placebo needle can be used as a placebo device in clinical studies on pain.

Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses.

The neural cascade of olfactory processing: a combined fMRI-EEG study.

Olfaction is dependent on respiration for the delivery of odorants to the nasal cavity. Taking advantage of the time-locked nature of inspiration and olfactory processing, electroencephalogram dipole modeling (EEG/DT) has previously been used to identify a cascade of inspiration-triggered neural activity moving from primary limbic olfactory regions to frontal cortical areas during odor perception. In this study, we leverage the spatial resolution of functional magnetic resonance imaging (fMRI) alongside the temporal resolution of EEG to replicate and extend these findings. Brain activation identified by both modalities converged within association regions of the orbitofrontal cortex that were activated from approximately 150-300 ms after inspiration onset. EEG/DT was additionally sensitive to more transient activity in primary olfactory regions, including the parahippocampal gyrus and amygdala, occurring approximately 50 ms post-inspiration. These results provide a partial validation of the spatial profile of the olfactory cascade identified by EEG source modeling, and inform novel future directions in the investigation of human olfaction.

Where is the rhythm generator for emotional breathing?

As a result of recent progress in brain imaging techniques, a number of studies have been able to identify anatomical correlates of various emotions (Pujol et al., 2013; Tettamanti et al., 2012; van der Zwaag et al., 2012). However, emotions are not solely a phenomenon within the brain-they are also composed of body responses. These include autonomic and behavioral responses, such as changes in heart rate, blood pressure, skin conductance, and respiration. Among these physiological responses, respiration has a unique relationship to emotion. While the primary role of respiration concerns metabolism and homeostasis, emotions such as disgust, anger, and happiness also influence respiratory activities (Boiten et al., 1994). While respiratory change that accompanies emotions can occur unconsciously, respiration can also be voluntarily altered associating with an activation of the motor cortex. There may be no physiological expression for the association between the three areas of the brain that regulate respiration: the brainstem, the limbic system, and the cerebral cortex. The brainstem works to maintain homeostasis, the limbic system is responsible for emotional processing, and the cerebral cortex controls intention. Investigating the interaction between these brain regions may lead to an explanation about why they are so widely dispersed in the brain, despite their common role in the regulation of respiration. In this chapter, we review our findings on breathing behavior and discuss the mechanisms underlying the relationship between emotion and respiration.

Proprioceptive illusions created by vibration of one arm are altered by vibrating the other arm.

There is some evidence that signals coming from both arms are used to determine the perceived position and movement of one arm. We examined whether the sense of position and movement of one (reference) arm is altered by increases in muscle spindle signals in the other (indicator) arm in blindfolded participants (n = 26). To increase muscle spindle discharge, we applied 70-80 Hz muscle vibration to the elbow flexors of the indicator arm. In a first experiment, proprioceptive illusions in the vibrated reference arm in a forearm position-matching task were compared between conditions in which the indicator arm elbow flexors were vibrated or not vibrated. We found that the vibration illusion of arm extension induced by vibration of reference arm elbow flexors was reduced in the presence of vibration of the indicator elbow flexors. In a second experiment, participants were asked to describe their perception of the illusion of forearm extension movements of the reference arm evoked by vibration of reference arm elbow flexors in response to on/off and off/on transitions of vibration of non-reference arm elbow flexors. When vibration of non-reference arm elbow flexors was turned on, they reported a sensation of slowing down of the illusion of the reference arm. When it was turned off, they reported a sensation of speeding up. To conclude, the present study shows that both the sense of limb position and the sense of limb movement of one arm are dependent to some extent on spindle signals coming from the other arm.

The Potential of Double Blinding with Two Placebo Acupuncture Needles: A Randomized Controlled Pilot-Trial.

BACKGROUND: Whether acupuncture treatment employing multiple penetrating, skin-touch placebo, or no-touch placebo needles designed for double blinding actually do blind practitioners and patients has not been investigated. We aimed to investigate this question. SUBJECTS: 120 patients with functional neck/shoulder stiffness but in otherwise healthy condition were randomly assigned to a treatment using four penetrating, four skin-touch placebo, or four no-touch placebo needles. Each of six acupuncturists applied four needles to four acupoints in the neck/shoulder of 20 patients. Acupuncturists and patients were asked to guess the treatment mode and their confidence in their guesses on 100 mm visual analog scales. RESULTS: The kappa coefficients between practitioner guesses and treatment type and between patient guesses and treatment type were 0.15 and 0.44, respectively. The median score of practitioner confidence was 46.8, and no significant difference in confidence between correct and incorrect guesses was revealed for any treatment. The median score of patient confidence for correct guesses was 77.6. The kappa coefficient between practitioner and patient guesses was 0.06. CONCLUSIONS: The practitioners were blinded to the nature of treatment using the same multiple needles, but patient blinding was insufficient. Further improvement is necessary to achieve satisfactory patient blinding with these acupuncture needles.

[Mechanisms underlying the improvement of arterial oxygenation using positive end-expiratory pressure during surgery under sevoflurane anesthesia and propofol anesthesia: a retrospective clinical study].

BACKGROUND: The use of positive end-expiratory pressure (PEEP) is a practical intervention to improve oxygenation during anesthetic management; however, the underlying mechanisms have not been elucidated. METHODS: Parameters of ventilator settings and results of arterial blood gas analyses were collected from medical records of adult patients undergoing surgery under general anesthesia with pressure-controlled ventilation in our hospital from January 2009 to March 2010. We analyzed the changes in dynamic compliance (Cdyn) and alveolar-arterial oxygen difference (A-aDo2). RESULTS: A total of 139 patients were enrolled; anesthesia was maintained with sevoflurane in 82 patients, and with propofol in 57 patients. After the application of PEEP, significant decreases in A-aDo2 were accompanied with significant increases in Cdyn under sevoflurane anesthesia. However, significant decreases in A-aDo2 were not always accompanied by significant increases in C(dyn) under propofol anesthesia. CONCLUSIONS: These results suggest that the mechanisms for improved oxygenation by PEEP under sevoflurane anesthesia are different from those under propofol anesthesia. The improved oxygenation after the application of PEEP under sevoflurane anesthesia is mainly due to reduction of atelectasis, whereas reduction of atelectasis as well as reduction of intrapulmonary shunt is associated with the improved oxygenation after the application of PEEP under propofol anesthesia.

Analgesia Is Enhanced by Providing Information regarding Good Outcomes Associated with an Odor: Placebo Effects in Aromatherapy?

No previous report has described whether information regarding an odor used in aromatherapy has placebo effects. We investigated whether placebo analgesia was engendered by verbal information regarding the analgesic effects of an odor. Twelve of 24 subjects were provided with the information that a lavender odor would reduce pain (informed), whereas the other 12 subjects were not (not-informed). Concurrent with respiration recording, the subjects were administered a lavender-odor or no-odor treatment during application of painful stimulation to the forefinger. The subjects reported their experience of pain and its unpleasantness on a visual analogue scale after the painful stimulation. The lavender-odor treatment significantly alleviated pain and unpleasantness compared with the no-odor treatment in the informed (P < 0.01) and not-informed groups (P < 0.05). The no-odor treatment in the informed group significantly alleviated pain and unpleasantness compared with both the no-odor and lavender-odor treatments in the not-informed group (P < 0.05). Rapid and shallow breathing induced by the painful stimulation became slow and deep during the lavender-odor and no-odor treatments in both groups. Information regarding a lavender odor, the lavender odor itself, and slower breathing contributed to reduced perceptions of pain and unpleasantness during painful stimulation, suggesting that placebo effects significantly contribute to analgesia in aromatherapy.

Markers of brain illness may be hidden in your olfactory ability: a Japanese perspective.

There is evidence that impaired human cognitive abilities are reflected by loss of olfactory abilities. Declining olfactory perception may be a biomarker for impairment of cognitive function and of impending neurogenerative disorders. As olfactory perception may differ between culture and ethnic group, we sought to confirm this relationship with Japanese participants. In this study, we examined possible relationships between age and olfactory abilities in healthy Japanese subjects (control subjects) over a wide range of ages and compared this relationship with that observed in three neurodegenerative disorders; patients with Parkinson's disease (PD), Type 1 myotonic dystrophy (DM1) and Alzheimer's disease (AD). In control subjects, both threshold and recognition abilities decreased with age. Ability to detect odors was generally intact in most control subjects, however, we found that the abilities of individuals in the three different patient populations to recognize odors were impaired relative to control subjects. All three types of patients exhibited decreased or impaired odor-recognition compared with age-matched controls. Previous studies showed the causes of olfactory impairments in PD and AD patients were attributable to pathological changes and MRI signal abnormalities in limbic areas, including the amygdala (AMG), entorhinal cortex (ENT), hippocampus (HI), and orbitofrontal cortex (OFC). Another study reported that DM1 patients have bilateral lesions in anterior temporal areas, including the subcortical white matter, AMG, ENT and insula. Our findings underscore the need to pay careful attention to significant decreases of odor identification abilities caused by diverse forms of abnormal brain function, especially in the AMG, ENT and HI.

Effects of dorsomedial medullary 5-HT2 receptor antagonism on initial ventilatory airway responses to hypercapnic hypoxia in mice.

The anatomical factors involved in upper airway closure of obstructive sleep apnea (OSA) have been established. However, the mechanisms of repetitive OSA are not well understood. We found that dorsomedial medullary 5-HT2 receptor activity is compensated for by hypercapnia and elicits the immediate onset of poikilocapnic hypoxic ventilatory airway responses. Therefore, the aim of this study was to test the hypothesis that hypercapnia compensates for the immediate onset of poikilocapnic hypoxic ventilatory airway responses induced by dorsomedial medullary 5-HT2 receptors. Adult male mice (C57BL/6N) were intraperitoneally anesthetized with pentobarbital sodium. Microdialysis probes were inserted into the dorsomedial medulla oblongata of the mice. The mice were placed in a double-chamber plethysmograph and were allowed to acclimatize and recover from anesthesia. Mice were then exposed to hypercapnic hypoxic gases (7 % O2/5 % CO2 in N2) with or without 5-HT2-antagonist (10(-5) M LY-53857) perfusion. Respiratory curves through the head and body chambers were recorded to measure ventilatory airway variables. Extracellular fluid was collected every 5 min for HPLC analysis of 5-HT concentration. Hypercapnic hypoxia elicited neither delayed onset of ventilatory augmentation nor immediate airway narrowing with dorsomedial medullary 5-HT2 antagonism. Hypoxic polypnea was shifted downward. The increases in dorsomedial medullary 5-HT release and ventilatory volume were not affected with or without 5-HT2 activity. In conclusion, the onset of poikilocapnic hypoxic ventilatory airway responses mediated via dorsomedial medullary 5-HT2 activity is compensated for by hypercapnia. Maintenance of PCO2 level and CO2 responsiveness, especially with lowered 5-HT2 activity, may be important for preventing repetitive OSA.

CO2 homeostasis is maintained in conscious humans by regulation of tidal volume, but not of respiratory rhythm.

Automatic regulation of tidal volume (VT) maintains CO2 homeostasis when spontaneous respiratory rhythm is replaced with a cortically triggered rhythm. We examined whether automatic regulation of respiratory frequency (fR) could maintain CO2 homeostasis at rest if the VT is cortically designated in experiments performed in 21 conscious humans. First, volitionally controlled fR at levels lower than baseline resulted in a larger VT, maintaining end-tidal CO2 fraction constant at eupneic levels. However, when fR was volitionally controlled at levels higher than baseline, end-tidal CO2 fraction decreased unexpectedly. Next, when the VT was volitionally constrained but fr was freely chosen, end-tidal CO2 fraction decreased. The present study revealed some limitations in the control of CO2 homeostasis by automatic regulation of fR, probably because respiratory rhythm is susceptible to non-metabolic factors. This study also showed the importance of automatic regulation of VT in maintaining CO2 homeostasis at rest. Nevertheless, automatic regulation of VT was incomplete when fR was volitionally imposed at high levels.

Hyperpnoeic response independent of limb movements at exercise onset in mice.

We have shown that constant-load treadmill exercise in mice produces an abrupt ventilatory increase to a maximal level at exercise onset. We examined what caused this abrupt response. We measured ventilation during 30-min constant-load exercise on a treadmill, below the lactate threshold, in conscious mice. Video analysis showed that hyperpnoea started before locomotion began. Incremental changes in speed did not further increase ventilation during the early phase of exercise. Next, we measured ventilatory responses to a sudden movement of the treadmill belt on which the mice were kept in a stationary position by a mesh cover. Hyperpnoea started concurrently with the sudden belt movement. In the absence of locomotion, ventilation increased to the extent reached during exercise hyperpnoea. Finally, the abrupt response showed plasticity but was attenuated by experience. The present study shows the importance of factors independent of limb movements in the hyperpnoeic response during the early phase of treadmill exercise in mice.

Dopamine D1 receptors control exercise hyperpnoea in mice.

Previously, we undertook simultaneous recording of ventilation and pulmonary gas exchange in mice and revealed that dopamine D(2) receptors participate in exercise hyperpnoea via behavioural control of ventilation with unchanged pulmonary gas exchange. Here, we examined the hypothesis that D(1) receptors also contribute to exercise hyperpnoea using a D(1) receptor antagonist (SCH 23390; SCH) that crosses the blood-brain barrier, with the same recording technique and protocol as in the previous study. The respiratory responses of mice injected with saline or SCH (50 µg (kg body weight)(-1), i.p.) were compared during constant-load exercise at 6 m min(-1). Each mouse was set in an airtight treadmill chamber equipped with a differential pressure transducer and open-circuit system with a mass spectrometer. At rest, SCH-injected mice had significantly reduced respiratory frequency, minute ventilation and pulmonary gas exchange compared with saline-injected mice. Ventilation during hyperoxic gas inhalation and hypercapnic ventilatory responses between groups were similar. Abrupt increases and sequential declines to the steady-state level were produced by treadmill exercise in both groups of mice. Treatment with SCH lowered the increased levels of respiratory frequency, tidal volume and minute ventilation during the steady state, as well as reducing the O(2) uptake, CO(2) output and body temperature throughout treadmill exercise. These data suggest that D(1) receptors contribute to a resting ventilation level and exercise hyperpnoea during the steady state in parallel with metabolic changes. Notably, the metabolic control of D(1) receptors was important for maintenance of the steady state, and D(1) receptors in hypothalamic nuclei could be involved in this modulation.

Inhibitory Effect of Acupuncture on Vibration-Induced Finger Flexion Reflex in Humans: Comparisons Among Radial, Median, and Ulnar Nerve Stimulation.

BACKGROUND: Vibration-induced finger flexion reflex (VFR) is inhibited with acupuncture to TE 5 or LI 4 at the skin innervated by the radial nerve. OBJECTIVE: The aim of this study was to determine if acupoints in regions innervated by the radial nerve are specific to inhibit VFR. MATERIALS AND METHODS: This experiment was performed using a crossover design with 3 acupuncture groups (needle insertion to the right LU 11, PC 9, or SI 1) and a control group (no needle treatment). Each acupoint was randomly needled on separate days. Ten healthy volunteers were recruited for this study. VFR was induced by applying vibration on the volar side of the right middle fingertip. An acupuncture needle was inserted in the acupoint and retained for 5 minutes. For the main outcome measure, maximum finger flexion force (MFFF) was measured during vibration and was compared among four groups. RESULTS: MFFFs in the acupuncture groups were significantly lower (p<0.05) than that in the control group. However, no significant difference was observed in MFFFs in the three intervention groups after acupuncture to LU 11, PC 9, and SI 1. CONCLUSIONS: Acupuncture to the right LU 11, PC 9, or SI 1 point inhibited the ipsilateral VFR, which suggests that afferent inputs from the radial nerve with needle insertion were not specific, compared with those from the median and ulnar nerves to suppress neuronal activities in the VFR reflex circuits.

Effects of corticotropin-releasing factor on intermediolateral cell column neurons of newborn rats.

Corticotropin-releasing factor (CRF) is a neuropeptide that mediates neuroendocrine, autonomic, and behavioral processes associated with the stress response. CRF-containing fibers and receptors are found in various regions of the central nervous system including the spinal cord. Here, we report excitatory effects of CRF on sympathetic preganglionic neurons in the intermediolateral cell column (IML) of in vitro spinal cord preparations from newborn rats. We also examine the receptor subtypes that are involved in the CRF effects. Application of CRF significantly depolarized the IML neurons and increased the frequency of excitatory postsynaptic potentials (EPSPs) in the IML neurons. These effects were blocked by the CRF receptor 1 antagonist, antalarmin. Menthol, a transient receptor potential channel M8 agonist, depressed EPSPs enhanced by CRF. Our findings suggested that CRF depolarized the IML neurons via direct postsynaptic action and CRF-affected interneurons located in the spinal cord send EPSPs to IML neurons. These excitatory effects of CRF may be caused through CRF1 receptors but not CRF2 receptors.

Interaction between vibration-evoked proprioceptive illusions and mirror-evoked visual illusions in an arm-matching task.

We studied the influence of false proprioceptive information generated by arm vibration and false visual information provided by a mirror in which subjects saw a reflection of another arm on perception of arm position, in a forearm position-matching task in right-handed subjects (n = 17). The mirror was placed between left and right arms, and arranged so that the reflected left arm appeared to the subjects to be their unseen right (reference) arm. The felt position of the right arm, indicated with a paddle, was influenced by vision of the mirror image of the left arm. If the left arm appeared flexed in the mirror, subjects felt their right arm to be more flexed than it was. Conversely, if the left arm was extended, they felt their right arm to be more extended than it was. When reference elbow flexors were vibrated at 70-80 Hz, an illusion of extension of the vibrated arm was elicited. The illusion of a more flexed reference arm evoked by seeing a mirror image of the flexed left arm was reduced by vibration. However, the illusion of extension of the right arm evoked by seeing a mirror image of the extended left arm was increased by vibration. That is, when the mirror and vibration illusions were in the same direction, they reinforced each other. However, when they were in opposite directions, they tended to cancel one another. The present study shows the interaction between proprioceptive and visual information in perception of arm position.

Remembering the past with slow breathing associated with activity in the parahippocampus and amygdala.

Breathing plays an important role in perception of odors and the experience of emotions. We used the dipole tracing method to analyze brain areas related to odor-induced autobiographical memory and emotions estimated from averaged electroencephalograms triggered by inspiration onset during odor presentation. Odor stimuli were perfumes subjects named that elicited a specific, pleasant and personal memory as well as two pleasant odors for controls. The perfumes induced specific emotional responses during memory retrieval, arousal level of the memory, feelings of pleasantness and a sense of familiarity with the odor. Respiration measurement indicated that tidal volume increased and respiratory frequency decreased during presentation of perfume stimuli, showing a deep and slow breathing pattern. Throughout the olfactory stimulation, electroencephalograms and respiration were simultaneously recorded. In the averaged potentials, low frequency oscillation was phase-locked to inspiration. Dipole analysis showed that perfumes activated more widespread areas of the right parahippocampal cortex and converged in the right amygdala compared to control odors. Slow breathing synchronized with odor-induced autobiographical memory and emotions may be subconsciously stored in the parahippocampal cortex and amygdala.