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1Department of Physiology, Nihon University, School of Dentistry, Tokyo; 2Division of Functional Morphology, Dental Research Center, 6Department of Pharmacology, and 7Department of Prosthodontics, Nihon University School of Dentistry, Tokyo; 3Division of Applied System Neuroscience Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo; 4Department of Oral and Maxillofacial Surgery, Nihon University, School of Dentistry, Tokyo, Japan; and 5Department of Physiology, College of Osteopathic Medicine, University of New England, Biddeford, Maine
Submitted 23 February 2005; accepted in final form 28 May 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Casey 1999; Casey et al. 2001; Coghill et al. 1994; Cruccu et al. 2003; Derbyshire et al. 1998; Rainville et al. 1997; Rios et al. 1999; Talbot et al. 1991; Vogt et al. 1996). Hutchison et al. (1999) also reported in a human recording study that ACC neurons were activated by noxious stimulation of the body. There are many reports describing the functional role of the ACC in processing noxious information as well as many other aspects, such as the emotional or attentional component of pain (Davis et al. 1994, 2000; Devinsky et al. 1995; Fleming et al. 1994). Furthermore, it has been reported that ACC lesions increase pain threshold to peripheral noxious stimulation in animal behavior experiments (Donahue et al. 2001). Recent fMRI studies have also shown that peripheral painful stimulation applied to the human hand induced predominant activation of the ACC region as well as the insular, primary and secondary somatosensory cortices (Bantick et al. 2002; Davis et al. 1998). It has been reported in humans that ACC neuronal activity is modulated when performing an attention-demanding task (Davis et al. 2000). The effect of attention on pain-related brain activity was also reported in a human imaging study (Brooks et al. 2002). They reported that the brain regions activated by heating of the hand were insula, cingulate, SII, cerebellum, and inferior frontal gyrus, and the activities of those areas were modulated by an attention task. These studies revealed that the ACC region in the cerebral cortex is involved in processing attention as well as pain sensations.
There are many nociceptive neurons in the ACC of rabbits, rats, and monkeys, and they have specific response characteristics to noxious stimulation as compared with nociceptive neurons in other cortical areas (Koyama et al. 1998, 2000, 2001; Kung et al. 2003; Sikes and Vogt 1992; Yamamura et al. 1996). Specifically, many ACC neurons respond to noxious heat and/or mechanical stimulation of the whole body surface. Anatomical and electrophysiological studies have shown that nociceptive neurons are found in area 24, according to the cytoarchitectonic criteria by Vogt et al. (1987). Anatomical tracing studies have also reported that the ACC area receives strong input from medial thalamic nuclei (Wang and Shyu 2004). Sikes and Vogt (1992) classified nociceptive neurons according to their response properties to mechanical stimulation of the receptive field, such as noxious-specific neurons and noxious-tap neurons. Noxious-specific neurons exclusively responded to noxious mechanical and/or heat stimulation of the peripheral receptive fields, whereas noxious-tap neurons responded to both noxious stimulation and nonnoxious mechanical tap stimulation of the receptive field. Furthermore, recently Koyama et al. (2001) have identified many neurons in the ACC of the awake behaving monkeys that responded to the cue light preceded to the noxious electrical stimulus to the paw. These suggest that the medial thalamic-ACC pathway is involved in the prediction of pain as well as pain perception.
With the exception of those experiments done by Koyama et al. (1998, 2000, 2001), exploration of the functional role of the ACC neurons in nociception was performed in anesthetized animals. There are many differences in the response characteristics of CNS neurons in awake and anesthetized animals. Given this, it is very important to evaluate how the ACC nociceptive neurons contribute to processing of noxious information in the CNS in the awake condition. Therefore in the present study, we studied how ACC nociceptive neurons are modulated during noxious stimulus intensity detection, during escape from the noxious stimulus, and during change in the focus of their attention from heat to light in awake behaving monkeys.
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METHODS |
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). Animal preparation
Two Japanese Macaca monkeys weighing 5.5–6.4 kg (Macaca fuscata, 3–4 yr old) were used for the present study. Before the start of training, the monkey’s water was restricted to 200 ml/day for 1 wk. The training took place daily until criterion performance was reached at which time initial surgery was performed.
The monkeys were anesthetized initially with ketamine hydrochloride (10 mg/kg ip). Anesthesia was subsequently maintained with a mixture of halothane (2–3%), nitrous oxide (60%), and oxygen. Monkeys were then placed in a stereotaxic frame. A head holder for chronic experiments was implanted onto the surface of the skull and stabilized using stainless steel screws and dental acrylic resin. During the initial surgery, body temperature was maintained at 37–38°C with a heating pad, and the heart rate was continually monitored by electrocardiographic (ECG) recording. Expired CO2 concentration was also monitored and maintained at a level between 3.0 and 4.0%. After the initial surgery, the monkeys were tested daily until the ability to discriminate the change in intensity of the light illumination had been re-established. Then, the monkeys were trained for 2–3 mo to perform three different types of detection tasks. After completion of training of this performance, they were anesthetized with ketamine and halothane (2–3%), nitrous oxide (60%), and oxygen for implantation, and a metal chamber was installed over the anterior cingulate cortex. Teflon-coated stainless steel wire electrodes were also embedded into the orbicularis-oris muscles to monitor movement of the mouth.
After completing each surgical procedure, the monkeys were routinely sedated with a small amount of ketamine (2–3 mg/kg im) and given penicillin (10,000 U/kg im) and glucose-saline (40–50 ml of a 5% glucose solution in 0.18% NaCl sc). Furthermore, the analgesic ketoprofen (5 mg/kg im) was administered daily after surgery for 3–4 days.
Behavioral tasks
A schematic illustration of the behavioral tasks used in the present study is shown in Fig. 1A. The behavioral task introduced in the present study was primarily developed and refined by Bushnell et al. (1984), Dubner et al. (1989), Duncan et al. (1987), Kenshalo et al. (1988, 1989), and Maixner et al. (1986, 1989). The thermal probe was placed on the right whisker pad region. The monkeys were seated quietly in the monkey chair for 2–3 h, and an illuminated button was placed in front of them. When the cue light was illuminated, it signaled to the monkey to button press to initiate a trial. When the monkeys pressed the button, three different types of tasks were presented randomly. These tasks were 1) heat detection task: the monkey presses the button, and a heat stimulus (T1: 45–47°C) was presented to the facial skin. After a random period ranging from 4 to 8 s, the stimulus intensity (T2: 0.2, 0.4, 0.6, or 0.8°C) increased above the baseline stimulation (T1). When monkeys detected the presentation of the T2 stimulus temperature within 3 s, they got 0.3 ml orange juice as the reinforcer. 2) Light detection task without heat: the monkey pressed the button and the light illumination (V1: 2.0V as indicated as the voltage applied to the bulb) was presented in front of the panel. After a random period ranging from 4 to 8 s, the visual stimulus intensity increased (V2: 2.5V) above the baseline stimulation. And 3) light detection task with heat: when the monkey pressed the button, the heat stimulation of the facial skin and illuminated light on the front panel were presented simultaneously. After a random period ranging from 4 to 8 s, V2 increases above the V1, but no temperature increment in the heat stimulation was presented.
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Recording procedure
When the monkeys recovered from surgery and their ability to discriminate changes in intensity of heat and visual stimulation was restored, behavioral testing was carried out while simultaneously recording unit activity in the contralateral ACC. Recordings were made daily from ACC neurons the activity of which was evoked by heat stimulation of the face during the detection task, using glass-coated tungsten microelectrodes, but no sessions lasted >2 h. When single or multiunit neuronal activity was encountered, neurons were first classified as heat sensitive neurons, i.e., neurons with modified firing during heating of the face. Then mechanical receptive fields of each neuron were analyzed to see if mechanical stimulation of the facial skin was effective at activating these neurons. The receptive fields were studied only in neurons that had modulated firing during heating of the face. There are many limitations when using awake behaving monkeys in this type of research. It is important that the monkeys are able to terminate any type of noxious stimuli. In the present study, the heat stimulus that was applied to the facial skin was the only noxious stimulus used, and the monkeys were able to stop it at any time by releasing the button. We did not introduce any natural noxious stimuli, such as pinching or squeezing of the skin.
Neuronal recordings were fed into a tape recorder (bandwidth: DC 20 kHz) for off-line data analysis. After recording from heat-sensitive neurons, electrodes were advanced into the subcortical white matter and lesions were made by passing a 10-µA DC (20 s) for subsequent analysis of the location of recording sites. Lesions were not made closer than 1.0 mm apart, and the total ranged from 5–10 lesions per hemisphere. The monkeys were tested daily until 100 penetrations had been made in each hemisphere (1 or 2 penetrations per 1–2 h daily recording sessions).
Data analysis
The waveforms of single or multiple neuronal activities were analyzed using a microcomputer system. The waveforms of each neuron were identified using Spike 2 microcomputer software (CED LTD). Peristimulus time histograms (1 bin = 100 ms) were then developed in response to various stimuli. Because each neuron showed fluctuations in firing, we measured spontaneous discharge frequency [background (BG) activity; spikes/100 ms] for 60 s before the monkeys pressed the button, and then spontaneous discharge frequency was subtracted from the peak spike frequency during application of the stimuli. Stimulus-response functions for each heat-sensitive neuron were constructed as a function of stimulus intensity. The correlation between peak firing frequency and detection latency during the T2 stimulus presentation was precisely analyzed as well. Furthermore, an analysis was made of the correlation of peak firing frequency between "escape" and correct trails to see whether escape from the noxious stimulus may modulate ACC nociceptive neurons. The heat stimulation of the facial skin was considered to have induced an effect if the peak firing frequency during application of stimuli was higher than the mean BG activity +2 SD as illustrated in Fig. 4Aa. We also measured the mean firing frequency during heating of the face when the firing rate was reduced during stimulation and the reduction rate was described as the ratio of mean firing frequency for 10 s before the on set of the stimulus to that during stimulus.
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After completion of the neuronal recordings, the monkeys were deeply killed with sodium pentobarbital (80 mg/kg ip) and perfused transcardially with 3,000 ml of 10% paraformaldehyde, and the brains were removed. Fifty-micrometer-thick serial sections were cut along the path of the electrode penetrations. Every section was then counterstained with cresyl violet, and the locations of recording sites were subsequently analyzed using a light microscope.
Statistical analysis
Statistical analyses were performed by using ANOVA followed by Scheffe’s test or Dunnett test. Paired t-test were also used when appropriate. Differences were considered significant at a P value of <0.05. Data were presented as means ± SE.
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RESULTS |
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Heat detection task
The frequency histograms of heat detection latencies were illustrated in Fig. 1B. Mean heat detection latencies were calculated from 1,500 trials. As illustrated in Fig. 1B, heat detection latency was different at different T1 temperatures. T2 detection latencies were significantly shorter at higher T1 temperature than lower T1. Furthermore, the detection latency was longer at any T1 temperatures when the T2 temperature shift was smaller (T1 = 45°C, T2 = 0.2: 2.2 ± 0.1 s, T2 = 0.4: 2.2 ± 0.2 s, T2 = 0.6: 2.2 ± 0.1 s, T2 = 0.8: 1.8 ± 0.2 s; T1 = 46°C, T2 = 0.2: 1.9 ± 0.2 s, T2 = 0.4: 1.7 ± 0.2 s, T2 = 0.6: 1.3 ± 0.1 s, T2 = 0.8: 1.0 ± 0.1 s; T1 = 47°C, T2 = 0.2: 1.5 ± 0.2 s, T2 = 0.4: 1.3 ± 0.23 s, T2 = 0.6: 0.9 ± 0.1 s, T2 = 0.8: 0.8 ± 0.1 s; n = 1,500 trials). We could not find any differences in light detection latencies at different T1 temperatures (Fig. 1B).
Receptive field properties
In the present study, we introduced only innocuous brush and tactile stimulation for identification of the receptive fields, not noxious mechanical stimulation. Two of 21 ACC nociceptive neurons responded to innocuous tactile stimulation of the skin. One of them received input from the entire area of the facial skin and the other one received input from the whole body surface (not shown in this manuscript). In studies using an awake behaving monkey, it is quite difficult to accurately identify the marginal line of the receptive fields. This was especially difficult considering that no noxious mechanical stimulation was used in this study.
Distribution of the ACC nociceptive neurons
Figure 2 illustrates the distribution of nociceptive neurons encountered in the ACC. Nociceptive neurons in the ACC were distributed in area 24 according to the cytoarchitectonic criteria from Vogt et al. (1987). We could not observe any distribution differences in the neurons based on their physiological characteristics, such as receptive field properties and response properties to heat or light stimulation.
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Nociceptive neurons encountered in the ACC showed a gradual increase in firing during heating of the face. Figure 3 illustrates an example of an ACC nociceptive neuron that responded to heating of the face but not to light presentation (Aa–Ad: heat response, Ba–Bc: light stimulation). Firing frequency of this neuron gradually increased during heating of the face (Fig. 3A). The number of spikes also increased during heating of the face and was not modulated in the light trial as shown in Fig. 3A. Furthermore, modulation of the firing was not observed in this example when the T2 temperature shift (0.4°C) was applied (Fig. 3Aa). Heat responses were recovered after frequent heat stimulation as illustrated in Fig. 3C. We did not observe any sensitization of heat responses after heating of the face. There were large EMG activities when the monkey got reward (Fig. 3, A and B); however, this neuron did not respond to these oral movements (see Fig. 3, Aa and Ba). Most of the nociceptive neurons in the ACC did not alter their firing during mouth movements that were associated with reward presentation. When the monkey detected the change in stimulus temperature, neuronal activity did not increase over the response to the T1 temperature shift.
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Figure 5, A and B, illustrates the stimulus-response function of heat-responsive ACC neurons. A graded increase in firing frequency after the increase in T1 stimulus temperature from 45 to 47°C was observed (Fig. 5B: mean ± SE, 45°C: 19.0 ± 3.6 spikes/s, 46°C: 20.7 ± 2.0 spikes/s, 47°C: 24.9 ± 5.4 spikes/s). The firing frequency was not significantly greater during the application of 47°C as compared with that of the 45 and 46°C stimuli (P > 0.05). Figure 5C showed stimulus-response functions for T2 stimulus. Firing frequencies were not significantly different after increase in T2 stimulus intensities at any T1 temperatures.
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The effect of light presentation on heat responses is illustrated in Fig. 6. Figure 6Aa illustrates the heat response of an ACC nociceptive neuron and heat stimulus during heat trial, and Fig. 6Ab is the response of the same neuron as indicated in Fig. 6Aa during the light detection with heat trial. Heat responses were significantly depressed when monkeys detected the change in the magnitude of the light illumination when heat was simultaneously applied (Fig. 6B: heat response: 20.7 ± 2.0 spikes/s, light responses: 16.3 ± 3.0 spikes/s, n = 16, P < 0.05). In the present study, the monkeys needed to pay attention to the heat when they detected the change in heat stimulus intensity, whereas they needed to concentrate their attention on the light illumination to detect the change in the magnitude of light illumination. Therefore it is highly likely that the monkeys moved their attention from the heat to the light illumination when monkeys were working on the light detection task. It was thus shown that change in attention from the heat at different modality, light in this case, causes the modulation of ACC nociceptive responses. On the other hand, we did not observe any effect of the light presentation on depressed responses (heat: 7.6 + 2.6 spikes/s; heat + light: 7.9 + 3.2 spikes/s, P > 0.05).
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We observed a large number of escape behaviors during the heat detection task. The response properties of ACC nociceptive neurons were precisely analyzed separately for the correct and escape trials to clarify the effect of the escape behavior on nociceptive responses. The differences of peak firing frequencies between correct trials and escape trails are shown in Fig. 7. The heat responses were significantly larger at all T1 temperatures as compared with firing rates during light trials (Fig. 7A). Eighty-nine percent (16/18) of heat-responsive neurons that increased in firing frequency during heating of the face increased in their firing frequency when the monkeys escaped from the stimulus. Firing frequencies of these neurons were significantly higher during the escape trials than for the correct trials when monkeys were working on the heat detection task at the T1 temperatures of 45°C (correct trials: 17.2 ± 2.2 spikes/s, escape trials: 29.0 ± 4.1 spikes/s, P < 0.05) and 46°C (correct trials: 17.5 ± 2.1 spikes/s, escape trials: 23.1 ± 2.2 spikes/s, P < 0.05). We did not observe any changes in the mean firing rate during light detection trials between correct and escape trials as illustrated in Fig. 7A. Furthermore, we did not observe any differences in BG activities of heat-responsive neurons between correct (T1 = 45: 20.5 + 10.3 spikes/s; T1 = 46: 20.3 + 7.1 spikes/s; T1 = 47: 24.0 + 1.9 spikes/s, n = 21 in each T1 temperature, P > 0.05) and escape trials (T1 = 45: 21.3 + 13.3 spikes/s; T1 = 46: 23.8 + 10.6 spikes/s; T1 = 47: 25.7 + 3.9 spikes/s, n = 21 in each T1 temperature, P > 0.05). This demonstrates that ACC neuronal activity increased when the monkeys escaped from the noxious stimuli.
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The correlation between the detection latencies and firing frequencies in response to the T2 stimulation is illustrated in Fig. 7B. We did not observe any correlation between firing frequency and heat detection latency during the T2 stimulus application when the T1 stimulus temperatures were from between 45 and 47°C. Most of the ACC neurons had larger responses when the monkeys detected the change in temperature shift with short detection latency.
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DISCUSSION |
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Noxious responses of ACC neurons
There are a number of papers describing response properties of ACC nociceptive neurons in several different species (Fleming et al. 1994; Koyama et al. 1998, 2000, 2001; Kung and Shyu 2002; Kung et al. 2003; Sikes and Vogt 1992). Most of these studies described response properties of ACC nociceptive neurons in anesthetized animals. The studies using anesthetized animals have shown many important physiological characteristics of ACC nociceptive neurons. Sikes and Vogt (1992) have reported that most of the ACC nociceptive neurons increase in their firing frequency after increases in noxious mechanical stimulus intensity. These nociceptive neurons had large receptive fields, sometimes extending over the whole body surface. Intracellular recording and staining studies also demonstrated that ACC nociceptive neurons have a large number of axon collaterals that were distributed in the wide area of the ACC in rats (Yamamura et al. 1996). These studies show that ACC nociceptive neurons receive noxious input from a large portion of the body and send their information to a wide area in the ACC. Such receptive field properties of ACC nociceptive neurons are not suited to the detection of the focal area inducing pain. Sikes and Vogt (1992) also reported that a small number of ACC nociceptive neurons had decreased firing frequency during noxious mechanical stimulation of the body surface. Three nociceptive neurons that we obtained in the present study showed decreases in firing frequency during the heat detection task. This indicates that noxious stimulation can produce depressive effects on ACC neurons during stimulation and facilitates the excitability after the end of the stimulation. It is likely that the interruption of noxious heating is a similar phenomenon to escape from pain, making the monkeys comfortable. These ACC neurons may contribute to modulating pain behavior, along with the heat-responsive neurons in monkeys. It is probable that these neurons are somehow involved in escape behavior from pain.
Previous anatomical and electrophysiological studies revealed that ACC nociceptive neurons receive peripheral noxious input via the medial thalamic nuclei (Craig et al. 1994; Fleming et al. 1994; Hsu and Shyu 1997; Kung and Shyu 2002; Wang and Shyu 2004). Dong et al. (1978) reported that nociceptive neurons in the medial thalamic nuclei were nociceptive-specific neurons, which exclusively responded to noxious mechanical and/or heat stimulation of the receptive fields, and noxious–tap neurons that responded to both noxious and innocuous tap stimuli. In the present study, we tested innocuous mechanical stimulation of the whole body surface, but only two neurons responded to innocuous tactile stimulation of the skin. Furthermore, in a human study, it was shown that some ACC neurons responded to painful mechanical and/or noxious thermal stimulation of the skin (Hutchinson et al. 1999). They also reported that no neurons in the ACC responded to nonpainful mechanical stimulation in humans. The threshold intensity for heat stimulation of the skin to activate ACC neurons was >48°C (Hutchinson et al. 1999). The firing frequency of the ACC nociceptive neurons that we obtained in the present study was not very high and was not that sensitive to temperature shifts at the stimulus temperature of 45–47°C as shown in Figs. 3 and 5. Therefore it is likely that most of the nociceptive neurons we recorded in the present study were classified as NS neurons and that two of them were noxious-tap neurons that responded to both noxious heat and innocuous mechanical stimulation of the receptive fields.
We did not observe any modulation of firing in ACC heat-responsive neurons when the monkeys moved their arms and mouth. On the other hand, the posterior part of the cingulate cortex is known to have a motor function (Picard and Strick 1997; Russo et al. 2002). It has been also reported in previous anatomical studies that the ACC and posterior part of the cingulate cortex have a strong connection each other (Hatanaka et al. 2003; Morecraft et al. 2004). It cannot be ruled out that ACC heat-responsive neurons would be involved in the modulation of motor behavior.
Discrimination ability of ACC neurons
The slope of the stimulus-response function of the ACC nociceptive neurons for noxious stimulation is thought to indicate the ability to discriminate the intensity of the stimulus in the CNS. The increment ratio of the spike frequency after graded noxious stimulation of the receptive field was not very steep when compared with that observed in primary somatosensory cortical (SI) neurons (Kenshalo et al. 2000). There are a number of papers studying brain stem, thalamic, and SI neurons using similar tasks as we used (Bushnell et al. 1984; Dubner et al.1989; Duncan et al. 1987; Kenshalo et al. 1988, 1989; Maixner et al. 1986, 1989). Brain stem, thalamic, and SI neurons responsive to heating of the face increased their firing after increases in T2 detection speed. It was suggested that these neurons are involved in the sensory discrimination of pain. It was also reported that some brain stem neurons increase in their firing during light trials after overtraining of the heat detection task (Dubner et al. 1989). These responses were termed "task-related responses." Task-related responses were not obvious in the present study. In the present study, a correlation between detection latency and firing frequency during T2 stimulus presentation was not observed at any T1 temperatures in ACC neurons. This suggests that ACC nociceptive neurons are not involved in pain discrimination. Further, we observed that firing frequency was significantly higher when monkeys escaped from the noxious stimulus before the T2 temperature shift was applied as compared with firing frequencies from correct trials. Some ACC nociceptive neurons started to fire before the T1 temperature shift occurred. Koyama et al. (1998) also reported that many of ACC neurons responded to the prediction of the cue light before the onset of noxious electrical stimulation of the paw. These findings strongly suggest that some ACC neurons may be involved in the avoidance of noxious stimuli.
Modulation of ACC activity during escape from stimulus
We observed that all heat-responsive ACC neurons increased their firing frequency during escape from the stimulus. Most of these neurons were distributed in area 24 according to the cytoarchitectonic criteria by Vogt et al. (1987) as illustrated in Fig. 2. Area 24 was anatomically classified as the intermediate zone between the sensory and motor areas within the cingulate cortex. Previous anatomical tracing studies revealed that ACC neurons had axons that projected to the other cortical areas (Carmichael and Price 1995; Pandya et al. 1981; Shima et al. 1991; Vogt et al. 1992). The strong reciprocal connections between anterior and posterior cingulate cortices are thought to be an important functional circuit. This anatomical organization of ACC neurons suggest that anterior cingulate cortical neurons likely have functional roles for processing interactions between cognitive and motivational processes in relation to generation of motor functions. It has been also reported that the ablation of ACC induces an increment of the escape threshold to heat stimulation of the paw in rats (Donahue et al. 2001; Pastoriza et al. 1996).
Together with previous anatomical and behavioral studies our findings suggest that ACC nociceptive neurons are involved in motivational states related to escape behavior from noxious stimuli.
Attentional modulation of ACC neuronal activity
We observed that the response of ACC nociceptive neurons to heat stimulation of the face was significantly depressed when monkeys moved their attention to the light illumination. Hutchinson et al. (1999) have reported in a human recording study that ACC nociceptive neurons responded to the observation of painful stimuli delivered to the examiner. Furthermore, it has been also reported that ACC neurons in humans are modulated by a change in attention (Brooks et al. 2002; Davis et al. 2000). Bushnell et al. (1999, 2004) have reported that the primary somatosensory cortex (SI) activity is strongly modulated by cognitive factors, whereas ACC activity is modulated in correlation with the subjects’ perception of unpleasantness. Furthermore, the attention-related modulation was observed in ACC as well as the SI region in a human fMRI study (Bushnell et al. 1999). It is likely therefore that in cognitive processing, an attention movement affects the perceived pain sensation in monkeys, such observed in the present study.
These data suggest that the anterior cingulate cortex is involved in the animal’s ability to escape and/or avoid noxious stimuli because the largest responses were observed when the monkeys escaped from the noxious thermal stimulus applied to the face. Therefore we propose that ACC nociceptive neurons are involved in the attentional and motivational aspects of pain.
It has also been reported that the ACC has a variety of pain-related functions, such as aversion, pain memory, and persistent pain (Frankland et al. 2004; Johansen and Fields 2004; Ko et al. 2005; Tang et al. 2005). Noxious stimulation has been known to produce pain sensations or the aversion and fear of the noxious stimuli. ACC neurons recorded in the present study changed their firing after the application of noxious stimuli, and many of them increased their firing after escape from the stimuli. Furthermore, they had depressed firing rates when their attention was directed to the light. The present data highly support the idea that these ACC neurons are involved in motivational component of pain that may be related to aversion to and fear of noxious stimuli. However, our results did not present direct evidence for these functions of heat-responsive neurons in the ACC.
Further study is needed, with appropriate experimental designs, to clarify the functional properties of ACC neurons in aversion to noxious stimuli and fear memory of noxious stimuli.
Concluding remarks
The possible role of ACC nociceptive neurons in pain-related function is summarized in Fig. 8. It has been known that the activation of negative reinforcement behavior is an important factor related to the motivational state of pain. We observed strong modulation of ACC neuronal activity before reward intake and during escape from noxious stimuli. These response characteristics of ACC nociceptive neurons may be related to important elements involved in the motivational state of pain. We also observed no correlation between ACC neuronal activity and detection speed, suggesting that ACC nociceptive neurons lack a capacity to discriminate pain perception.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Iwata, Dept. of Physiology, School of Dentistry, Nihon University, 1-8-13 Kandasurugadai, Chiyoda-ku Tokyo, 101-8310 (E-mail: iwata-k{at}dent.nihon-u.ac.jp)
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, the planes where sections were cut. 
, nociceptive neurons without tactile receptive fields; 
, nociceptive neurons with receptive fields; 
: nociceptive neurons inhibited during heating of the face; 
, the ACC neurons without heat response. sras, superior ramus of arcuate sulcus; MFG, middle frontal gyrus; SFG, superior frontal gyrus; cgs, cingulate sulcus.
