Breathlessness-related Brain Activation: Electroencephalogram Dipole Modeling Analysis

Dyspnea is the feeling of shortness of breath and is a primary symptom of cardiopulmonary disease. Dyspneic symptoms include sensations such as labored respiration, chest tightness, air hunger, and uncomfortable or unpleasant urges to breathe. In this study, we investigated the brain areas associated with dyspnea using electroencephalogram dipole (EEG/DT) modeling. We hypothesize that good temporal resolution of EEG/DT recordings will enable determination of the neuroanatomical substrates of dyspnea in time course measures of inspiration. We measured EEG and respiration simultaneously during CO2 rebreathing, which induced dyspnea in the subjects and allowed us to find inspiration-related potentials during dyspnea. The waveform of the potentials was composed of a negative peak at 100ms and a positive peak at 250ms. Our EEG/DT modeling estimated their source generators in the left superior frontal and left orbitofrontal cortex (OFC) at 100ms after inspiration onset. In the next 100ms, the anterior cingulate cortex was activated, followed by the superior frontal and OFC. At 200ms to 300ms, dipoles finally converged in the left insula and amygdala. The first component of inspiration-related potentials thus involved frontal areas that play a role in the intention to inspire and emotional guidance, while the late component incorporated areas related to emotional reaction. We suggest that dyspnea with increasing ventilation could involve intentions or efforts to continue inspiration activities, and consequently, the perception of dyspnea could be associated with unpleasant emotions

Early Onset of Ventilatory and Airway Response to Hypercapnia is Mediated by Medullary 5-HT1A Receptors in Infant Rats

Medullary 5-hydroxytryptamine (5-HT) neurons are involved in ventilatory responses to hypercapnia. Underdeveloped medullary 5-HT neurons and reduced 5-HT1A receptor binding activity in the dorsomedial medulla oblongata (DMM) have been found in infants with sudden infant death syndrome (SIDS). The DMM includes the solitary tract nucleus, which receives primary afferent inputs from the lung, and the hypoglossal nucleus, which affects genioglossal muscle tone. We hypothesized that hypercapnia would elicit 5-HT release in the DMM and that local 5-HT1A receptors would affect ventilatory and airway responses to hypercapnia. This hypothesis was investigated in unanesthetized infant Wistar rats by microdialysis of the DMM coupled with double-chamber plethysmography. After microdialysis probe placement, the rats were acclimatized to the chamber for over 5h, and artificial cerebrospinal fluid (aCSF) or a 5-HT1A receptor antagonist, WAY-100635, was then perfused into the DMM, and extracellular fluid was collected. Respiratory flow curves were recorded while the rats inhaled five concentrations of CO2 in O2 for 10 min each (0% [100% O2], 5%, 7%, 9%, and 0% again). 5-HT concentration was measured using high-performance liquid chromatography with electrochemical detection. 5-HT release in the DMM and hypercapnic ventilatory and airway responses increased dose dependently with CO2 concentration during both aCSF and WAY-100635 perfusion, with no difference between groups. However, early-onset ventilatory and airway responses to hypercapnia were significantly delayed or reduced by WAY-100635 perfusion in the DMM. These results suggest that 5-HT release in the DMM is dependent on hypercapnia, while early ventilatory and airway responses to hypercapnia are mediated by 5-HT1A receptors in the DMM. Blunted early onset of hypercapnic ventilatory and airway responses may be one cause of SIDS

Effects of Respiratory Muscle Stretch Gymnastics on Children\u27s Emotional Responses

Respiratory muscle stretch gymnastics (RMSG) are designed to decrease chest wall stiffness, reduce dyspnea at rest and improve the quality of life. The focus of this study was to determine whether a RMSG program affects the psychological state of healthy subjects. A previous study showed that there is a positive correlation between anxiety level and respiratory rate (RR). We hypothesize that RMSG will decrease the RR related to alterations in anxiety or other factors that are associated with the quality of life in healthy children. Forty-four primary school children living in Tokyo participated in the study and were randomly assigned to either gymnastics or control groups. Baseline assessment of both groups included completion of the Questionnaire for Measuring Health-Related Quality of Life in Children (Kid-KINDL) and the State-Trait Anxiety Inventories for Children (STAI-C). RRs were recorded initially and the children in the gymnastics group were instructed on how to perform RMSG. The RR was measured again and the participants completed the state anxiety scale. The gymnastics group was told to perform the gymnastics once a day for one week, whereupon post-testing using the testing protocol used for the baseline measurement was performed again on both groups. RR and anxiety level significantly decreased while Kid-KINDL increased after one week of RMSG in high trait anxiety subjects of the gymnastics group. We suggest that the decrease in RR after RMSG reduces anxiety levels in children, and contributes to an improvement in their Kid-KINDL score

Optogenetic Stimulation of 5-HT Neurons in the Median Raphe Nucleus Affects Anxiety and Respiration

Anxiety affects respiration, and in turn perturbs the internal environment, although the neuronal systems controlling anxiety-related respiration remain unclear. Recent reports indicate that serotonin（5-HT）neurons in the median raphe nucleus（MRN）enhance anxiety. In the present study, we aimed to clarify the contribution of 5-HT neurons in the MRN to anxiety and respiratory control using mice expressing a channelrhodopsin-2 variant-enhanced yellow fluorescent protein（ChR2 ［C128S］-EYFP; a step-function opsin）in the central 5-HT neurons. We applied an optogenetic method to bigenic mice expressing ChR2［C128S］-EYFP in 5-HT neurons and to monogenic mice without such expression. Photostimulation of free-moving mice was performed using a wireless system through an optical fiber pre-inserted above the MRN, and respiratory variables were measured using whole-body plethysmography. Anxiety was evaluated using an elevated-plus maze test. In the bigenic mice, we confirmed ChR2［C128S］-EYFP expression in tryptophan hydroxylase 2（a brain 5-HT synthase）-positive neurons in the raphe nuclei of the mesopontine, such as the MRN and the dorsal raphe nucleus. Blue light illumination to the MRN of the bigenic mice significantly increased respiratory rate and minute ventilation without affecting tidal volume, and significantly decreased the time spent in the open arms of the elevated plus maze without changing distance traveled, compared with monogenic mice. These results suggest that 5-HT neuron activity in the MRN increases anxiety-like behavior without affecting locomotor activity, enhances respiratory rhythm and minute ventilation without changing tidal volume, and can mimic anxiety-related respiratory responses in humans

Amygdala Response During Anticipatory Anxiety in Patients with Tension-type Headache

Tension-type headache (TTH) is the most prevalent primary headache disorder, affecting 0.5%〜4.8% of the population worldwide. Psychological factors play an important role in the pathogenesis of TTH. For instance, depression and anxiety are thought to enhance central sensitization, and thus increase the frequency of headaches. In this study, we used the Minnesota Multiphasic Personality Inventory (MMPI) and measures of anxiety to analyze personality traits associated with TTH. Specifically, we were interested in the relationship between these variables, respiratory responses, and brain activity. Our results showed that individuals with TTH had significantly higher state anxiety scores compared with healthy controls. In addition, individuals with TTH showed a greater increase in RR during a stressful task involving anticipation of an electrical stimulation. During anticipatory anxiety, there was bilateral amygdala (AMG) activation in TTH patients, while only the right AMG was activated in healthy controls. Interestingly, patients in the TTH group with high levels of state anxiety and high scores on schizophrenia scales had the following MMPI personality traits: peculiar perception, poor familial relationship, difficulties concentrating, and lack of deep interest. We suggest that the psychological factors associated with the above-mentioned brain activation might induce peripheral muscle pressure, which then triggers headaches

Large Right Pulmonary Vein Is a Predictor of Atrial Fibrillation Recurrence after Pulmonary Vein Isolation in Patients with Persistent Atrial Fibrillation

Pulmonary vein isolation（PVI）is an effective treatment for atrial fibrillation（AF）. However, outcomes differ between paroxysmal AF and persistent AF. We analyzed the predictors of recurrence by examining the recurrence group after ablation. Of 372 consecutive patients with AF who underwent PVI between June 2016 and December 2018, we evaluated 250 patients（age, 67±12y, 65％ men）whose left atrium（LA）was constructed using the PENTARAY catheter（BioSense Webster, Los Angeles, CA）, a multipolar electrode catheter with a novel shape and excellent mapping capability. We measured the LA total volume（LATV）, right pulmonary vein＋antrum volume（RPAV）, left PV＋antrum volume（LPAV）, LA central volume（LACV）, and LA bipolar voltage. Of the 250 patients, 78 had persistent AF（recurrence, 20）and 172 had paroxysmal AF（recurrence, 16）. In all patients, LATV, LACV, RPAV, and LPAV were significantly larger in patients with persistent AF than those with paroxysmal AF. The mean LA bipolar voltage in patients with persistent AF was significantly lower than those with paroxysmal AF. In cases of persistent AF, RPAV was significantly larger in the recurrence group than that in the non-recurrence group（15.9±4.8 vs 13.4±5.4ml; P＜0.05）. In cases of paroxysmal AF, there were no differences in any volume between the recurrence and non-recurrence groups. In conclusion, larger right PV is a predictor of AF recurrence after PVI in patients with persistent AF. The right PV is close to the atrial septum and the septopulmonary bundle, and the expansion of RPAV reflects the disruption of these structures, which may be involved in this result