Masaki Fumoto

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.

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.

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

&NA; 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.

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.

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.

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.

Reduced prefrontal cortex activation during divergent thinking in schizophrenia: a multi-channel NIRS study.

Relationships between deficits in verbal fluency and poor social functioning have been revealed in patients with schizophrenia. In previous studies, we demonstrated that deficits in idea fluency, which is ranked as a more complex type of verbal fluency and reflects divergent thinking ability, were more closely related to social dysfunction than deficits in simple word fluency. Although functional neuroimaging studies have provided detailed data regarding prefrontal dysfunction during word fluency tasks, the regions that relate to deficits in fluency of ideas and thoughts have not yet been clarified in schizophrenia patients. The purpose of the present study was to identify the prefrontal sub-regions responsible for deficits in idea fluency using near-infrared spectroscopy (NIRS), which is more practical than other imaging methods, and to investigate the relationships between lesions and idea fluency deficits and social dysfunction in patients with schizophrenia. Eighteen outpatients with schizophrenia and 16 healthy subjects were recruited for this case-controlled study. Using 24-channel NIRS, we measured changes in hemoglobin concentration in the prefrontal cortical surface area during idea and letter fluency tests. The analyses revealed that schizophrenia patients generally exhibited a smaller increase in the concentration of oxyhemoglobin in the frontopolar region than the controls during both the tests. However, the areas in which reduced activations were demonstrated in the patients differed remarkably between the idea and letter fluency tests: reduced activations were observed in the ventral region during the former test and in the dorsal region of the frontopolar cortex during the latter test. The reduced activations in each sub-region appeared to affect the related cognitive impairment, since the patients showed significant poorer performances than the controls on both the tests. Moreover, hypoactivity during idea fluency was significantly correlated with poor social functioning as assessed using the Global Assessment of Functioning (GAF) in the patient group. The results of the present study suggest that the ventral region within the frontopolar cortex is responsible for divergent thinking, which is associated with poor social functioning in patients with schizophrenia.

Soleus H-reflex dynamics during fast plantarflexion in humans

The relationship between the size of the soleus (Sol) Hoffmann (H-) reflex and the level of background (BG) electromyographic (EMG) activity was examined during plantarflexing at different force levels. The experiments were carried out on seven healthy male subjects aged 20-37 years. The subjects were asked to perform fast plantarflexion under a reaction-time condition. The amounts of contraction force were 10, 20, 50 and 80% of maximum voluntary contraction (MVC). Since the maximum size of the M-wave (Mmax) changed systematically during the plantarflexion, we tried to maintain the size of the reference M-wave, an indicator of the efficiency of the electrical stimulation, at a constant value (20% of Mmax) throughout the experiment. The size of the H-reflex was rapidly increased at the very beginning of the movement, and then it tended to decrease in the later phase of the movement. Consequently, even with the same level of BG EMG, the size of the H-reflex was always larger in the early rising phase of the EMG activity than in the later falling phase. The maximum size of the H-reflex was poorly correlated with the force exerted. In contrast, the size of the F-response was proportional to the force exerted. The non-linear relationship between the size of the H-reflex and the BG EMG suggests that the level of the presynaptic inhibition onto Ia terminals was modified depending on the required force level and during the course of the movement.

927 GUM CHEWING EVOKES ACTIVATION OF VENTRAL PREFRONTAL CORTEX AND SUPPRESSION OF NOCICEPTIVE RESPONSES: INVOLVEMENT OF BRAIN SEROTONERGIC SYSTEM

Backgrounds and Aims: To our knowledge, quantification of palpation pressures used by experienced practitioners of osteopathy in the cranial field has not been reported to date. The objective of this study was to evaluate the pressure of palpation used by professional osteopaths during a cranial test procedure, and to determine the relationship between palpation pressures and years of practice (yop) experience. Methods: 43 participants (32 men and 11 women; aged 25–65 years) were enrolled after written consent was obtained. Data on palpation pressures employed during the study were obtained using a FlexiForce tactile force sensor device which recorded a 3-seconds pressure measurement. Practitioners’ yop and percentage of daily practice employing osteopathic cranial treatment were also recorded. Results: The palpation pressures recorded throughout the study procedure ranged from 0 to 1.81N/cm, with the mean pressure of the 3-seconds tests ranging from 0.01 to 1.69N/cm. Comparison among treatment groups was carried out using non-parametric analysis of variance with the Kruskall-Wallis test, followed by Dunn’s test for multiple group comparisons. The results suggested that practitioners with >20 yop use significantly less pressure than practitioners with less than 20 yop (p =0.024). Conclusions: This study is the first to provide data on the palpation pressures used during osteopathic cranial treatment. The results suggest that the application of cranial palpation is extremely variable. Highly experienced practitioners may use less pressure and demonstrate less variation; however, a significant proportion of less experienced practitioners use comparable pressure.

Changes in somatosensory evoked potentials and Hoffmann reflexes during fast isometric contraction of foot plantarflexor in humans.

In the present study, the extent to which the early component of somatosensory evoked potentials (SEPs) and the Hoffmann (H-) reflex induced by stimulation of the posterior tibial nerve are altered during the ascending and descending phases of fast plantarflexion was investigated. SEPSs and H-reflex of the soleus following tibial nerve stimulation were examined during fast plantarflexion when performed by nine normal subjects. The analyses focused on differences in amplitude modulation of the P30-P40 component of SEP and the H-reflex between the ascending and descending phases of full-wave rectified and averaged soleus electromyographic (EMG) activity. The H-reflex amplitude was significantly increased and decreased during the ascending and descending phases more than under resting control conditions, respectively. The reduction of SEP amplitude was 49% for the ascending phase and 83% for the descending phases with respect to the resting situation. Modulation of SEP during the ascending and descending phases was robustly retained even during ischemic nerve blockade of large diameter afferent fibers. These findings suggest that the transmission of afferent inputs from muscle spindles to motoneurons and to the somatosensory cortex during fast isometric contraction of the plantar flexor is regulated in a time-dependent fashion by descending commands.