J Neurol (2007) 254:1427–1432 DOI 10.1007/s00415-007-0570-3

Takahiro Ono Yoko Hasegawa Kazuhiro Hori Takashi Nokubi Toshimitsu Hamasaki

Received: 7 October 2006 Received in revised form: 15 December 2006 Accepted: 8 January 2007 Published online: 15 October 2007

T. Ono, D. D. S., Ph. D. (쾷) · Y. Hasegawa, D. D. S., Ph. D. · K. Hori, D. D. S., Ph. D. · T. Nokubi, D. D. S., Ph. D. Division of Oromaxillofacial Regeneration Course of Integrated Oral Science Osaka University Graduate School of Dentistry 1–8 Yamada-oka, Suita Osaka 565-0871, Japan Tel.: +81-6/6879-2954 Fax: +81-6/6879-2957 E-Mail: [email protected] T. Hamasaki, Ph. D. Dept. of Biomedical Statistics Osaka University Graduate School of Medicine 2–2 Yamada-oka, Suita Osaka 565-0871, Japan

ORIGINAL COMMUNICATION

Task-induced activation and hemispheric dominance in cerebral circulation during gum chewing

■ Abstract In elderly persons, it is thought that maintenance of masticatory function may have a beneficial effect on maintenance of cerebral function. However, few studies on cerebral circulation during mastication exist. This study aimed to verify a possible increase in cerebral circulation and the presence of cerebral hemispheric dominance during gum chewing. Twelve healthy, young right-handed subjects with normal dentition were enrolled. Bilateral middle cerebral arterial blood flow velocities (MCAV), heart rate, and arterial carbon dioxide levels were measured during a handgrip exercise and gum chewing. During gum chewing, electromyography of the bilateral masseter muscle was recorded. MCAV and heart rate significantly increased during exercise

Introduction

■ Key words cerebrovascular ultrasound · Doppler transcranial monitoring · hemispheric dominance · gum chewing

tion may be effective in preventing a decline in brain function. Studies using positron emission tomography (PET) [14] and functional magnetic resonance imaging (fMRI) [16, 17] scans reported that during bilateral mastication, the primary sensorimotor area, sensory area, opercular part, islet, supplementary motor area, cerebellum, thalamus, right frontal area, and other regions are activated, and the degree of the activation was influenced by hardness of chewing gum [16] and age [17]. A study using Xe-enhanced CT [20] reported that areas from the prefrontal cortex to temporal regions, caudate nucleus, and thalamus were significantly activated by

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Oral feeding is integral for elderly persons to live an independent life. Recently, attention has focused on the relationship between mastication and higher brain function. In experiments with mice, it was reported that cutting off upper molars reduced learning ability in a water maze and neuron density in the hippocampal CA1 region [18], and soft-diet feeding after weaning reduced synaptic formation in the cerebral cortex and impaired special learning ability in adulthood [26].These findings suggest that maintenance of efficient masticatory func-

compared to values at rest. During gum chewing, there were no differences in the rate of increase in MCAV between the working and non-working sides, but during the handgrip exercise, the rate of increase in MCAV was significantly greater for the non-working side than for the working side. During gum chewing, muscle activity on the working side was significantly greater than that on the non-working side. These results suggest that during gum chewing, cerebral circulation increases bilaterally and does not show contralateral dominance, as it does during the handgrip exercise.

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gum chewing. In addition, a study using f-MRI reported that the activation of the primary sensorimotor area associated with tongue movement during bilateral mastication is more prominent on the hemisphere ipsilateral to the habitual masticatory side [21]. Identification of activated areas of the brain during mastication has been enabled by measuring changes in regional cerebral blood flow using brain mapping techniques with high spatial resolution. These brain mapping techniques, however, have a low temporal resolution, making it difficult to quantitatively analyze overall changes in cerebral circulation associated with mastication. In contrast, transcranial Doppler (TCD) ultrasound [2] allows continuous measurement of blood flow velocity of major cerebral vessels over a long period on a realtime basis, and is well suited to overall evaluation of cerebral circulation. Middle cerebral artery blood flow velocity (MCAV) measured using TCD ultrasound has been reported to change corresponding to activated areas of the brain measured by Xe-enhanced CT [5], PET scans [23], and single photon emission computed tomography (SPECT) [3, 4]. These reports confirmed that measuring MCAV was an appropriate technique for evaluating changes in the cerebral circulation caused by cerebral activation. TCD ultrasound also allows simultaneous measurement of bilateral MCAV that controls 80 % of the arterial blood flow in the cerebral hemispheres [10], which enables a comparison of the difference in cerebral circulation between the two hemispheres [9, 23]. To our knowledge, however, few studies have qualitatively evaluated cerebral circulation during mastication using TCD ultrasound [11, 25], and even basic findings are lacking because of inadequate standardization of experimental systems. In this study, we measured bilateral MCAV during gum chewing using TCD ultrasound in a standardized experimental system to investigate the presence of hemispheric differences in cerebral circulation during mastication as well as to quantitatively evaluate changes in cerebral circulation induced by mastication. The tasks used included gum chewing with the working side being determined and, as a control, a handgrip exercise, in which a continuous increase in cerebral circulation during exercise and hemispheric dominance were established using TCD ultrasound [6, 9, 23]. Measuring MCAV as an index of the cerebral circulation is based on the premise that the vessel diameter remains unchanged during measurement. We recorded transcutaneous partial pressure of arterial carbon dioxide (PaCO2), because PaCO2 is the largest factor in changing vessel diameter [1, 12]. Electromyography of the bilateral masseter muscle was also simultaneously recorded to examine the relationship between masseter muscle activity and cerebral circulation.

Subjects and methods ■ Subjects Twelve subjects (7 men and 5 women; mean age ± SD, 26.6 ± 3.5 years) who had no missing teeth except for the third molar and no previous history of cranial nerve disease were enrolled. Before the experiment, all subjects were identified as right-handed (LQ, 33.3–100; mean ± SD, 92.5 ± 19.2) based on the Edinburgh Handedness Inventory [15]. The experimental protocol was approved by the institutional review board before the experiment, and the aims and methods of the study were fully explained to subjects both orally and in writing. Subjects who gave informed consent were eligible for the study. ■ Data recordings Bilateral MCAV was measured simultaneously using a transcranial Doppler ultrasound unit (Multi Dop T, DWL, Sipplingen, Germany) as an index of cerebral circulation. Subjects were instructed to sit on a chair, with the head and neck supported by a head rest and both arms on the arm rest, and to wear an eye mask and gently close their eyes. MCAV was measured with a 2-MHz ultrasound probe fixed over the upper anterior auricle of the subject using a dedicated headband (Marc 600, Spencer Technologies, Seattle, USA). Before measurement, subjects were asked to open and close their mouths to ensure that the probe maintained a constant position while chewing gum. The sample volume was set at 10 mm and the depth ranged from 48 to 60 mm. PaCO2 and heart rate were measured using a transcutaneous blood gas monitor (Surface Monitor 9900MK, Kohken Medical, Tokyo, Japan) at the same time as MCAV was measured. The activity of the bilateral masseter muscles was also measured simultaneously with the activity of the masticatory muscles during gum chewing. An evaluation system of mandibular movement (K6-I, Myo-Tronics, Taren Point,Australia) and surface electrodes (Duo-trode, Myo-Tronics, Taren Point, Australia) were used for measurement, and analog signals from the surface electrodes were fed into an external personal computer. Integrated waveform was used for analysis. ■ Tasks Using two pieces of commercially available chewing gum (Free zone, Lotte, Tokyo, Japan), subjects were instructed to chew gum, with the right or left side of the jaw being determined as the working side, and the rhythm was set at 1.0 Hz using a metronome. Chewing gum was put into the subject’s mouth by an examiner immediately before the start of mastication and removed from the mouth by the examiner immediately after the end of mastication. The handgrip exercise consisted of repeated handgrip (300 s) with maximum effort using a grip training tool (GoFit Handgrip, Tech Corporation, Hiroshima, Japan). The exercise rhythm was set at 1.0 Hz by a metronome for both hands. For each task, 180 s during pre-task rest, 300 s during a task, and 300 s during post-task rest were measured continuously. The measurement was performed three times for each task (left and right hand grasping, mastication on the left and right side) for each subject on three consecutive days using the Latin square method in random order. For both experiments, the metronome ran continuously throughout the task. ■ Data analysis MCAV was input to an external personal computer, and heart rate and PaCO2 were output to a personal computer every second. The activity of the masticatory muscles when each subject performed a maximum voluntary contraction (MVC) for 2 s was recorded, which was assumed to be 100 %MVC, and the masseter muscle activity during

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measurement was expressed as a relative value (%MVC). The data were averaged every 5 s, and the data during a task were transformed to percent change from pre-task (mean = 0 %). Changes in MCAV, heart rate, PaCO2 and %MVC were compared before and during a task using the random effect model with replication data. Changes in left and right MCAV during a task were compared for each handgrip exercise and chewing of gum using t-test with the random effect model. The activity of the left and right masseter muscles during gum chewing were compared in a similar manner. Furthermore, the percent change in MCAV on the same side as the working side was compared between gum chewing and the handgrip exercise using the t-test with a random effect model. All tests of significance were 2-sided, and P < 0.05 was taken to indicate significance.

Fig. 1 Percent changes in middle cerebral artery blood flow velocity (MCAV) over time for each task

Results Task-induced percent changes in MCAV, heart rate, and PaCO2 are shown in Fig. 1 and Tables 1 and 2. In this experiment, MCAV was determined to be a reliable index of the cerebral circulation because PaCO2 did not change significantly for any task (Table 2). During mastication,MCAV increased immediately after the start of a task as shown in Fig. 1. During the task, it maintained an increased level when compared with the situation before the task and decreased immediately after the end of the task. Fluctuation waves of left and right MCAV were almost identical for all tasks. MCAV during the handgrip exercise showed a tendency to increase gradually after the start of a task and decrease immediLeft Handgrip

20

% MCAV

15 10 5 0 −5 0

180

480

780 (sec)

480

780 (sec)

480

780 (sec)

480

780 (sec)

Right Handgrip

20

% MCAV

15 10 5 0 −5

0

180 Left Chewing

20

% MCAV

15 10 5 0 −5

0

180 Right Chewing

20

% MCAV

15 10 5 0 −5

0

180 Left MCA

Right MCA

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Table 1 Percent change in middle cerebral artery blood flow velocity (MCAV) for each task, and comparisons between left and right middle cerebral artery (MCA) values and between handgrip and gum chewing

MCAV change ratio (%)

Left tasks Left handgrip Mean (CI) Left chewing Mean (CI) Handgrip-chewing difference p-value Right tasks Right handgrip Mean (CI) Right chewing Mean (CI) Handgrip-chewing difference p-value

L-R MCAV difference p-value

Left

Right

7.5 (5.4–9.5)

11.2 (8.8–13.5)

L
5.2 (2.3–8.1) Handgrip>chewing p=0.0040

6.7 (3.9–8.7) Handgrip>chewing p<0.0001

p=0.1167

9.0 (7.0–11.0)

6.0 (3.8–8.2)

L>R, p=0.0003

6.7 (5.3–8.2) Handgrip>chewing p=0.0003

6.4 (5.6–7.2) – p=0.5397

p=0.5157

CI Confidence interval

Table 2 Task-induced changes in heart rate and partial pressure of arterial carbon dioxide (PaCO2) during handgrip and gum chewing tasks and left masseter %MVC, right masseter %MVC, and differences between left and right masseter %MVC during gum chewing change ratio (%)

Left handgrip Mean (CI) Right handgrip Mean (CI) Left chewing Mean (CI) Right chewing Mean (CI)

%MVC

L-R %MVC difference p-value

Heart rate

PaCO2

Left masseter

Right masseter

10.6 (7.1–14.1)

0.05 (–0.43–0.54)

–

–

–

7.7 (5.2–10.1)

0.01 (–0.03–0.01)

–

–

–

7.9 (5.2–10.5)

0.88 (0.55–1.22)

20.5 (19.1–22.0)

14.1 (13.2–15.0)

L>R, p<0.0001

7.7 (5.7–9.7)

0.43 (0.08–0.79)

14.1 (11.3–16.9)

18.9 (16.9–21.0)

L
CI Confidence interval

ately after the end of the task.During a task,MCAV on the non-working side constantly showed a higher rate of increase compared with the working side. MCAV and heart rate increased significantly during a task compared with before a task for all tasks (Tables 1 and 2). Although MCAV on the non-working side was significantly higher (left handgrip; P < 0.0001, right handgrip; P = 0.0003) than that on the working side during handgrip, showing a contralateral dominance in the cerebral circulation, there was no difference between left and right MCAVs during gum chewing (Table 1). In addition, the activity of masticatory muscle during gum chewing (%MVC) was significantly greater (left handgrip; P < 0.0001, right handgrip; P = 0.0173) on the working side than on the non-working side (Table 2). A comparison of the percent change in MCAVs between tasks revealed that MCAVs during handgrip exercise were significantly greater than those during gum chewing except for right MCAV when the working side was on the right (Table 1). Heart rate during a task was significantly

higher during left handgrip than right handgrip exercise (P = 0.0206).

Discussion In this study,the bilateral increase in cerebral circulation during unilateral mastication was quantitatively demonstrated by a significant increase in bilateral MCAV during gum chewing. The fact that MCAV on the non-working side was higher than that on the working side during the handgrip exercise, which was used as a control, indicates the sufficient accuracy of our experimental system in demonstrating contralateral hemispheric dominance during exercise. Subjects enrolled in this experiment were all right-handed,and the rate of increase in left MCAV during right handgrip was lower and the rate of increase in heart rate during left handgrip was higher than during right handgrip. These findings are consistent with a previous report [19].

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Studies using f-MRI [16, 17] reported that the primary sensorimotor area is activated bilaterally during bilateral gum chewing [21, 22] and that the hemispheric dominance in the neuronal activity during tongue movement is associated with the habitual masticatory side. However, the habitual masticatory side might or might not be prominent in individuals [13]. In this experiment, subjects were not shown to have a prominent habitual masticatory side via evaluating mandibular movement locus during free gum chewing using a video camera and motion capture system, and thus were not analyzed for an association between cerebral circulation and habitual masticatory side. Mastication, by nature, is not a movement on one side of the body like handgrip, and the masticatory muscles on both sides are working even during unilateral mastication. Bilateral output of movement to control muscle activity is therefore considered necessary, although the input of oral sensation involved in controlling a bolus has dominance on the working side. In addition, although input pathways from the stomatognathic apparatus to the cerebral cortex and output pathways from the cerebral cortex to the muscles of the head and neck show cross dominance, the dominance may be less prominent compared with the spinal nerves that innervate the extremities [7]. Thus, the brain nerve activity associated with masticatory movement may not exhibit complete contralateral dominance. In this study, we found another possible reason cerebral circulation does not exhibit contralateral dominance by comparing bilateral masseter muscle activities during mastication. Although the intensity of contraction in the masseter muscle during gum chewing is lower than the intensity of isometric contraction such as clenching, a rhythmic contraction and relaxation cycle is repeated. In these circumstances, a “muscle pump effect” that facilitates pumping of the blood to the heart through the vein tends to persist. The external carotid artery that supplies blood flow to the masseter muscle and the internal carotid artery that bifurcates into the middle cerebral artery are branches of the common carotid artery. Similar to the blood flow from the masseter muscle, the blood circulating through the brain perfuses the pterygoid venous plexus. Thus, the muscle pump effect in the masticatory muscle may increase cerebral circulation by increasing venous blood flow. In our experiment, the consistently greater masseter mus-

cle activity on the working side than on the non-working side suggested the possibility that cerebral circulation was increased more by a greater muscle pump effect being exerted on the working side and the increase in ipsilateral MCAV [24]. Thus, it could be considered that the hemispheric difference in cerebral circulation was not observed during gum chewing because opposite factors counteracted each other. In another experiment, we showed that hemispheric dominance in cerebral circulation was found on the working side during clenching that involved intensive isometric contraction of the masseter muscle with maximal force, with the working side being strictly determined [8]. This might be because of a greater muscle pump effect compared with gum chewing due to intensive isometric contraction of masseter muscle and larger increase of MCAV on the working side compared with that on the non-working side. However, these considerations remain speculative, and another experimental system is required to confirm the influence of the muscle pump effect during the contraction of the masseter muscle on the cerebral circulation. The fact that cerebral circulation increases bilaterally during functional movement of the stomatognathic system even when the working side was predetermined might indicate a possible beneficial effect on the recovery of higher brain function through rehabilitation. It was suggested that cerebral circulation could increase bilaterally even in those who chewed unilaterally due to missing teeth, dysfunction of the jaw, or other reasons or those who have decreased muscle function because of higher brain dysfunction. While activation in cerebral circulation during gum chewing was lower than that during the handgrip exercise, our results suggest the possibility that the recovery and maintenance of masticatory function might help prevent a decline in brain function, because mastication is a mild and life-long daily exercise. ■ Acknowledgements The authors gratefully acknowledge the encouragement of the late Honorary Professor Shinichiro Watanabe of the Osaka University School of Medicine.We also thank Dr. Masayuki Ohta of the Osaka University Graduate School of Dentistry and Dr. Yoshihisa Tachibana of the National Institute for Physiological Sciences for advice. We are also grateful to Dr.Yasuko Hashimoto, Director of Hashimoto Hospital, for financial support of this study.

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