Hitoshi Maezawa

The role of area postrema neurons expressing H-channels in the induction mechanism of nausea and vomiting

The area postrema is one of the circumventricular organs, lacks a blood-brain barrier, and is well known as the chemoreceptor trigger zone for emesis. Area postrema neurons are sensitive to emetic chemical substances carried in the blood plasma. Our previous study demonstrated the presence of 3 types of neurons characterized by different ion channels expressed in each cell type, but the type or types of area postrema neurons involved in the induction of nausea and/or emesis have remained unclear. To clarify the role of the most populous cells, which express the hyperpolarization-activated cation channel (H-channel), in induction of nausea and/or emesis, we investigated the effects of ZD7288 (an H-channel inhibitor) on apomorphine-induced conditioned taste aversion (CTA) to saccharin and c-Fos expression in the area postrema. We found that ZD7288 inhibited the acquisition of CTA and reduced apomorphine-induced c-Fos expression in the area postrema, indicating the involvement of the cells expressing H-channels in the induction of nausea and/or emesis. Finally, we discuss the role of cells expressing H-channels in the mechanism of nausea and/or vomiting.

Somatosensory evoked magnetic fields following electric tongue stimulation using pin electrodes

Quantitative evaluation of the sensory disturbance of the tongue is important clinically. However, because the conventional electrophysiological approach to the peripheral nerve cannot be used in the mandible owing to the deep route of the lingual nerve, we applied evoked potentials in the central nervous system. Somatosensory evoked magnetic fields (SEFs) following electric stimulation were recorded in 10 healthy subjects by means of pin electrodes placed on the tongue mucosa. Three or four components (P25m, P40m, P60m, and P80m) were identified over the contralateral hemisphere with unilateral stimulation. Because none of the components were consistently detected in all subjects, we evaluated the root mean square (RMS) of 18 channels over the contralateral hemisphere. To estimate the activated cortical response, we calculated the difference in mean RMS amplitude between 10 and 150 ms and that of the baseline period (aRMS=RMS[10, 150]-RMS[-50, -5]). The aRMS values for right-sided and left-sided stimulation were 10.18+/-7.92 and 10.99+/-8.98 fT/cm, respectively, and the mean laterality index, expressed by [(left-right)/(left+right)] was 0.025+/-0.104. This parameter can be useful for evaluating patients with unilateral sensory abnormality of the tongue.

Evaluation of tongue sensory disturbance by somatosensory evoked magnetic fields following tongue stimulation

Quantitative measurement is required in clinical situation for sensory disturbance of the tongue due to lingual nerve injury. To assess disabled sensory function of the tongue, somatosensory evoked magnetic fields (SEFs) were measured following electric tongue stimulation in 13 patients with sensory disturbance by unilateral lingual nerve injury and in 10 age-matched healthy volunteers. Affected- and healthy-sides of the tongue were stimulated separately with the same intensity. Although the healthy-side stimulation induced clear responses over the contralateral hemisphere of all participants, the affected-side stimulation evoked hardly traceable responses in 6 patients and no activity in the remaining 7 patients. We evaluated the cortical activity via activated root-mean-square (aRMS), which is the time-averaged activity between 10 and 150 ms from the 18-channel RMS over the contralateral hemisphere. The laterality index of aRMS, expressed as [(left-right)/(left+right)], was out of the pre-defined normal range (-0.287 to 0.337) in 12 patients, and within the range in all healthy volunteers. The test sensitivity and specificity of the procedure were 92.3% and 100%, respectively. Tongue SEFs are reproducible and objective method to evaluate sensory disturbance of the tongue.

Electrophysiologically identified presynaptic mechanisms underlying amylinergic modulation of area postrema neuronal excitability in rat brain slices.

Amylin, which is co-secreted together with insulin by pancreatic beta cells, is considered to be an important peptide hormone involved in the control of feeding behavior and energy homeostasis. Although the area postrema has been implicated to be a primary target of amylin, there are no studies of the mechanisms by which amylin may alter the excitability of area postrema neurons. To investigate the mechanism for amylinergic modulation of neuronal excitability, we performed perforated patch-clamp recordings from area postrema neurons in rat brainstem slices. Amylin-induced changes in excitatory responses, such as increases in the frequency of mEPSCs (miniature excitatory postsynaptic currents) and changes in the amplitude distribution of mEPSCs, were found in cells not displaying the hyperpolarization-activated cation current (I(h)). Area postrema cells displaying I(h) did not respond to amylin application. Inhibitory responses to amylin were never encountered. Bath application of CNQX (AMPA type glutamate receptor antagonist) abolished the effects of amylin. Depolarization of cells during amylin application was sufficient at 1 μM to cause action potential discharge by responding cells. We conclude that amylin receptors are located mostly on presynaptic glutamatergic terminals connecting to the area postrema neurons not displaying I(h) and amylin concentrations can increase glutamate release enough to cause cell firing. Modulation of amylinergic activity may offer a novel target to influence food intake and obesity.

Contralateral dominance of corticomuscular coherence for both sides of the tongue during human tongue protrusion: An MEG study.

Sophisticated tongue movements contribute to speech and mastication. These movements are regulated by communication between the bilateral cortex and each tongue side. The functional connection between the cortex and tongue was investigated using oscillatory interactions between whole-head magnetoencephalographic (MEG) signals and electromyographic (EMG) signals from both tongue sides during human tongue protrusion compared to thumb data. MEG-EMG coherence was observed at 14-36 Hz and 2-10 Hz over both hemispheres for each tongue side. EMG-EMG coherence between tongue sides was also detected at the same frequency bands. Thumb coherence was detected at 15-33 Hz over the contralateral hemisphere. Tongue coherence at 14-36 Hz was larger over the contralateral vs. ipsilateral hemisphere for both tongue sides. Tongue cortical sources were located in the lower part of the central sulcus and were anterior and inferior to the thumb areas, agreeing with the classical homunculus. Cross-correlogram analysis showed the MEG signal preceded the EMG signal. The cortex-tongue time lag was shorter than the cortex-thumb time lag. The cortex-muscle time lag decreased systematically with distance. These results suggest that during tongue protrusions, descending motor commands are modulated by bilateral cortical oscillations, and each tongue side is dominated by the contralateral hemisphere.

Evaluation of lip sensory disturbance using somatosensory evoked magnetic fields

OBJECTIVE To evaluate lip sensory dysfunction in patients with inferior alveolar nerve injury by lip-stimulated somatosensory evoked fields (SEFs). METHODS SEFs were recorded following electrical lip stimulation in 6 patients with unilateral lip sensory disturbance and 10 healthy volunteers. Lip stimulation was applied non-invasively to each side of the lip with the same intensity using pin electrodes. RESULTS All healthy volunteers showed the earliest response clearly and consistently at around 25ms (P25m) and at least one of the following components, P45m, P60m, or P80m, over the contralateral hemisphere. The ranges of the peak latencies were 23-33, 42-50, 56-67, and 72-98ms for right-side stimulation and 23-34, 46-49, 52-68, and 71-90ms for left-side stimulation. Affected-side stimulation did not evoke P25m component in any patients, but invoked traceable responses in 5 patients whose latencies were 57, 89, 65, 53, and 54ms. Unaffected-side stimulation induced P25m in 2 patients at 27 and 25ms, but not in the other 4 patients. CONCLUSION The P25m component of lip SEFs can be an effective parameter to indicate lip sensory abnormality. SIGNIFICANCE Lip sensory dysfunction can be objectively evaluated using magnetoencephalography.

Somatosensory evoked magnetic fields following tongue and hard palate stimulation on the preferred chewing side

Although oral sensory feedback is essential for mastication, whether the cortical activity elicited by oral stimulation is associated with the preferred chewing side (PCS) is unclear. Somatosensory evoked fields were measured in 12 healthy volunteers (6 with the right side as the PCS and 6 with the left side as the PCS) following tongue and hard palate stimulation. Three components were identified over the contralateral (P40m, P60m, and P80m) and ipsilateral [P40m(I), P60m(I), and P80m(I)] hemispheres. Since no component was consistently detected across subjects, we evaluated the cortical activity over each hemisphere using the activated root-mean-square (aRMS), which was the mean amplitude of the 18-channel RMS between 10 and 150ms. For tongue stimulation, the aRMS for each hemisphere was 8.23 ± 1.55 (contralateral, mean ± SEM) and 4.67 ± 0.88 (ipsilateral)fT/cm for the PCS, and 5.11 ± 1.10 (contralateral) and 4.03 ± 0.82 (ipsilateral)fT/cm for the non-PCS. For palate stimulation, the aRMS was 5.35 ± 0.58 (contralateral) and 4.62 ± 0.67 (ipsilateral)fT/cm for the PCS, and 4.63 ± 0.56 (contralateral) and 4.14 ± 0.60 (ipsilateral)fT/cm for the non-PCS. For hard palate stimulation, the aRMS did not differ between the PCS and non-PCS, whereas for tongue stimulation, the contralateral hemisphere aRMS was significantly greater for the PCS than for the non-PCS. Thus, our results show that lateralized cortical activation was associated with the PCS for tongue, but not hard palate, stimulation; a potential reason for this may be the different sensory-inputs between these two areas, specifically the presence or absence of fine motor function.

Effects of treadmill exercise on the LiCl-induced conditioned taste aversion in rats

Studies have shown that exercise can enhance learning and memory. Conditioned taste aversion (CTA) is an avoidance behavior induced by associative memory of the taste sensation for something pleasant or neutral with a negative visceral reaction caused by the coincident action of a toxic substance that is tasteless or administered systemically. We sought to measure the effects of treadmill exercise on CTA in rats by investigating the effects of exercise on acquisition, extinction and spontaneous recovery of CTA. We made two groups of rats: an exercise group that ran on a treadmill, and a control group that did not have structured exercise periods. To condition rats to disfavor a sweet taste, consumption of a 0.1% saccharin solution in place of drinking water was paired with 0.15M LiCl (2% body weight, i.p.) to induce visceral discomfort. We measured changes of saccharin consumption during acquisition and extinction of CTA. The exercise and no-exercise groups both acquired CTA to similar levels and showed maximum extinction of CTA around 6 days after acquisition. This result indicates that exercise affects neither acquisition nor extinction of CTA. However, in testing for preservation of CTA after much longer extinction periods that included exercise or not during the intervening period, exercising animals showed a significantly lower saccharin intake, irrespective of having exercised or not during the conditioning phase of the trial. This result suggests that exercise may help to preserve aversive memory (taste aversion in this example) as evidence by the significant spontaneous recovery of aversion in exercising animals.

Cortico-muscular synchronization by proprioceptive afferents from the tongue muscles during isometric tongue protrusion

Tongue movements contribute to oral functions including swallowing, vocalizing, and breathing. Fine tongue movements are regulated through efferent and afferent connections between the cortex and tongue. It has been demonstrated that cortico-muscular coherence (CMC) is reflected at two frequency bands during isometric tongue protrusions: the beta (β) band at 15-35Hz and the low-frequency band at 2-10Hz. The CMC at the β band (β-CMC) reflects motor commands from the primary motor cortex (M1) to the tongue muscles through hypoglossal motoneuron pools. However, the generator mechanism of the CMC at the low-frequency band (low-CMC) remains unknown. Here, we evaluated the mechanism of low-CMC during isometric tongue protrusion using magnetoencephalography (MEG). Somatosensory evoked fields (SEFs) were also recorded following electrical tongue stimulation. Significant low-CMC and β-CMC were observed over both hemispheres for each side of the tongue. Time-domain analysis showed that the MEG signal followed the electromyography signal for low-CMC, which was contrary to the finding that the MEG signal preceded the electromyography signal for β-CMC. The mean conduction time from the tongue to the cortex was not significantly different between the low-CMC (mean, 80.9ms) and SEFs (mean, 71.1ms). The cortical sources of low-CMC were located significantly posterior (mean, 10.1mm) to the sources of β-CMC in M1, but were in the same area as tongue SEFs in the primary somatosensory cortex (S1). These results reveal that the low-CMC may be driven by proprioceptive afferents from the tongue muscles to S1, and that the oscillatory interaction was derived from each side of the tongue to both hemispheres. Oscillatory proprioceptive feedback from the tongue muscles may aid in the coordination of sophisticated tongue movements in humans.

Recovery of Impaired Somatosensory Evoked Fields After Improvement of Tongue Sensory Deficits With Neurosurgical Reconstruction

Somatosensory evoked fields (SEFs) induced by tongue stimulation can be useful as an objective parameter to assess sensory disturbances in the tongue. However, whether tongue SEFs can be useful as a clinical, objective follow-up assessment method of tongue sensation after oral surgery is unknown. We describe 2 cases in which tongue SEFs were successfully used in clinical assessment. Two patients with unilateral tongue sensory deficits caused by lingual nerve injury during lower third molar extraction were recruited. Both patients underwent surgery to repair the damaged nerve, and all tongue sensory evaluations were performed once before and once after surgery. SEFs were recorded by stimulating the affected and unaffected sides of the tongue separately, and cortical activity was evaluated over the contralateral hemisphere. The unilaterality of the deficit also was assessed. In both patients, stimulation of the unaffected side evoked reproducible cortical responses before and after surgery. Both patients also recovered some sensation after surgery, given that presurgery stimulation of the affected side failed to evoke cortical activity whereas postsurgery stimulation evoked cortical activity on both sides. Sensation was initially highly lateralized in both patients but was restored to approximately normal in the postsurgery evaluation. Finally, both patients rated their subjective tongue sensations on the affected side over 50% better after the surgical intervention. These cases indicate that tongue SEFs may have a clinical use as an objective parameter for assessing the course of tongue sensory recovery.