Neural generators of brain potentials before rapid eye movements during human REM sleep: A study using sLORETA

Clinical Neurophysiology 119 (2008) 2044–2053 www.elsevier.com/locate/clinph

Neural generators of brain potentials before rapid eye movements during human REM sleep: A study using sLORETA Takashi Abea,d,e, Keiko Ogawac,d, Hiroshi Nittonob, Tadao Horib,f,* b

a Department of Behavioral Sciences, Graduate School of Biosphere Sciences, Hiroshima University, Higashi-Hiroshima, Japan Department of Behavioral Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima 739-8521, Japan c Faculty of Sport Sciences, Waseda University, Japan d Japan Society for Promotion of Science, Chiyoda-ku, Tokyo, Japan e Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan f Sleep Research Institute of Fukuyama Transporting Shibuya Longevity Health Foundation, Fukuyama, Japan

Accepted 11 May 2008 Available online 11 July 2008

Abstract Objective: Brain activity preceding rapid eye movements (REM) during human REM sleep has remained poorly understood. Slow negative brain potential (pre-REM negativity) appears before REMs. Current sources of this potential were investigated to identify brain activity immediately preceding REMs. Methods: In this study, 22 young healthy volunteers (20–25 years old) participated. Polysomnograms were recorded during normal nocturnal sleep. Brain potentials between 200 ms before and 50 ms after the onset of REMs and pseudo-triggers (3000 ms before the onset of REMs) were averaged. Standardized low-resolution brain electromagnetic tomography (sLORETA) was used to estimate current sources of pre-REM negativity. Results: Pre-REM negativity appeared with the maximal amplitude at right prefrontal sites immediately before REMs. However, this negativity did not appear before pseudo-triggers. Current sources of the pre-REM negativity were estimated in the ventromedial prefrontal cortex, uncus, insula, anterior cingulated cortex, basal forebrain, parahippocampal gyrus, premotor cortex and frontal eye field. Conclusions: The pre-REM negativity reflects brain activity coupled with the occurrence of REMs. Results of this study suggest that emotion, memory, and motor-related brain activity might occur before REMs. Significance: Pre-REM negativity is expected to be a psychophysiological index for elucidating functions of REM sleep. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Pre-rapid-eye-movement negativity; EEG; sLORETA; Rapid-eye-movement sleep; Ventromedial prefrontal cortex

1. Introduction Aserinsky and Kleitman (1953) discovered rapid eye movements (REMs) that occur during sleep. The state during which these REMs occur is called REM sleep. Visually clear and emotionally rich reports are obtained from peo*

Corresponding author. Address: Department of Behavioral Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima 739-8521, Japan. Tel.: +81 82 424 6580; fax: +81 82 424 0759. E-mail address: [email protected] (T. Hori).

ple after awakening during REM sleep (Hobson and McCarley, 1977; Okuma, 1992; Hobson et al., 2000). Many researchers have suggested the functional importance of REM sleep in memory and brain plasticity (Gais et al., 2000; Karni et al., 1994; Laureys et al., 2001; Maquet et al., 2000; Mirmiran and Van Someren, 1993; Peigneux et al., 2003; Stickgold et al., 2000; Van Someren et al., 1990; Wagner et al., 2001) and emotional processing (Cartwright et al., 1998; Fosse et al., 2001; Maquet et al., 1996; Wagner et al., 2001). The circuit of emotion and memory is thought to be activated in relation to REM. Calvo and Ferna´ndez-Guardiola

1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.05.008

T. Abe et al. / Clinical Neurophysiology 119 (2008) 2044–2053

(1984) recorded brain potentials which were time-locked to phasic contraction of the lateral rectus muscles of eyeballs during REM sleep in cats. They found propagation of ponto-geniculo-occipital (PGO) activity in the amygdala, anterior and posterior cingulated gyrus, and hippocampus. Calvo et al. (1987) also reported that electrical stimulation of the amygdala during REM sleep increased the PGO wave density. As formulated here, the amygdala is suggested to provide physiological feedback to the PGO activity (Calvo et al., 1987; Datta, 1997). The occurrence of REMs is known to be correlated with PGO activity during REM sleep in animals (Callaway et al., 1987; Datta, 1997; Vanni-Mercier and Debilly, 1998) and in humans (Miyauchi et al., 2004; Peigneux et al., 2001; Wehrle et al., 2005). These studies advance the hypothesis that brain activity in the limbic system and REMs share some relationship in humans. Brain imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have clarified brain activation in the limbic and paralimbic systems during REM sleep (Braun et al., 1997, 1998; Hong et al., 1995; Maquet et al., 1996; Miyauchi et al., 2004; Nofzinger et al., 1997; Peigneux et al., 2001; Wehrle et al., 2005, 2007). Maquet et al. (1996) showed that the amygdala and anterior cingulate cortex, which participate in emotion processing, were activated during REM sleep. Nofzinger et al. (1997) reported activation of limbic and paralimbic regions during REM sleep; those regions contain the amygdala, orbital gyrus, and anterior cingulate cortex. Moreover, results of some studies have associated limbic and paralimbic activations with REMs. Peigneux et al. (2001) found that the parahippocampal gyrus and anterior cingulate cortex were more activated in relation to the number of eye movements during REM sleep than during wakefulness. Results of an event-related fMRI study (Miyauchi et al., 2004) showed that the amygdala and anterior cingulate cortex were activated during REMs. However, the temporal resolution of these imaging studies is too low to clarify the temporal dynamics of neural activity. It is necessary to augment temporal resolution using other non-invasive methods. Human electroencephalographic (EEG) studies have examined brain potentials after REMs in detail. Brain potentials associated with visual information processing appear after REMs during REM sleep (Miyauchi et al., 1987, 1990; Niiyama et al., 1988; Ogawa et al., 2002, 2003, 2005, 2006). These brain potentials are called lambda-like responses. Ogawa et al. (2006) reported that the current sources of this lambda-like response were estimated in visual cortices. Recently, Abe et al. (2008) reported that gamma-band EEG activity during REM sleep is greater after the occurrence of REMs than before REMs. Nevertheless, brain activity preceding REMs has remained poorly understood. Several EEG studies have shown that presaccadic negativity and presaccadic positivity observed before saccades in wakefulness do not appear before REMs during REM sleep (Abe et al., 2004b; Ogawa et al., 2002, 2005). Abe

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et al. (2004b) averaged EEGs in the period 200 ms before and 50 ms after the onset of REMs and saccades. During wakefulness, presaccadic positivity appeared at centroparietal sites starting about 150 ms before saccades. During REM sleep, no presaccadic positivity was found, but a slow negative potential appeared before REMs. This negative potential has been called pre-REM negativity (Abe et al., 2004a,b); it is expected to be an index which clarifies brain activity preceding REMs during REM sleep. A magnetoencephalographic (MEG) study found brain activity in the amygdala, parahippocampal cortex, and orbital gyrus during the 100 ms immediately preceding REMs in REM sleep (Ioannides et al., 2004). In fact, MEG is sensitive to a current component that is parallel to the scalp. Because EEG is sensitive to a component that is vertical to the scalp, EEG and MEG provide complementary information related to neural activity. Pascual-Marqui et al. (1994) developed low-resolution brain electromagnetic tomography (LORETA), which is a method to estimate the current source density of scalp-recorded EEG or MEG. A preliminary study using LORETA indicated the current sources of the pre-REM negativity as the amygdala, parahippocampal cortex, and orbital gyrus (Abe et al., 2004a). Results of this study were consistent with those of the MEG study (Ioannides et al., 2004). Nevertheless, the localization error of LORETA is not completely zero. Recently, Pascual-Marqui (2002) developed standardized low-resolution brain electromagnetic tomography (sLORETA). The sLORETA is a linearly distributed solution that computes images of electric neuronal activity from EEG and MEG. This method is based on standardized values of the current density estimates given by the minimum norm solution. The sLORETA functions on the assumption that the EEGs measured on the scalp are generated by highly synchronized post-synaptic potentials occurring in large clusters of neurons (Pascual-Marqui (2002)). The sLORETA uses a three-shell spherical head model registered to the digitized Talairach and Tournoux (1988) atlas (Brain Imaging Centre, Montreal Neurological Institute). The solution space is restricted to cortical gray matter and the hippocampus. The sLORETA yields images of standardized current source density of a total of 6430 voxels at 5-mm spatial resolution under these neuroanatomical constraints. This method achieves zero localization error in noise-free simulations (Pascual-Marqui, 2002). Furthermore, this method shows less localization error in the presence of noise and multiple sources than other methods do, such as minimum norm least squares and LORETA (Pascual-Marqui, 2002; Wagner et al., 2004). The sLORETA provides a means to examine the brain potential before REMs more precisely. This study examined the current sources of pre-REM negativity using sLORETA to clarify brain activity preceding REMs during human REM sleep. Emotion-related and memory-related structures are expected to be activated before REMs during human REM sleep.

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2. Methods 2.1. Participants The participants in this study were 22 right-handed healthy volunteers (11 women and 11 men, 20–25 years old, mean 22.5 years). The participants were not allowed to ingest caffeine or alcohol, or to take naps during the day before the experimental night and the experimental day. All participants gave written informed consent to their participation. The relevant institutional ethical committee approved the study protocol. 2.2. Procedure Polysomnograms were recorded during 1–3 nights at the laboratory after an adaptation night. Participants went to bed at their habitual retiring time and were awakened by the experimenter at their habitual waking time. 2.3. EEG recording From 26 scalp sites (Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T7, T8, P7, P8, F9, F10, P9, P10, Fpz, Fz, Cz, Pz, POz, and Oz according to the extended 10–20 system), EEGs were recorded using Ag–AgCl electrodes affixed with collodion. Electrooculograms (EOG) were recorded from four electrodes placed at the outer canthi of both eyes and above and below the left eye. The system reference (the mean amplitude between C3 and C4), was used for recordings. The data were re-referenced off-line to the linked earlobes. A submental electromyogram (EMG) was recorded bipolarly. The electrode impedance was maintained as less than 5 kX. The sampling rate was 1000 Hz. Time constants were 5.0 s for EEG and EOG and 0.03 s for EMG. A high-cut filter was set at 300 Hz. 2.4. Data analysis All sleep stages were scored visually in continuous 20 s epochs according to the standard Rechtschaffen and Kales (1968), with supplements and amendments of the Sleep Computing Committee of the Japanese Society of Sleep Research (2001). Onsets of REMs were determined using the following method. First, REM sleep was scored using those criteria. Then, eye movements fulfilling all the following three criteria in the periods scored as REM sleep were identified as REMs: amplitude (>30 lV), duration (<0.5 s), and slope (>248.3 lV/s) (Takahashi and Atsumi, 1997). Finally, the apex of the spike potential at the onset of REM was determined visually. Defining the onset point of REMs in this manner was done for the following reasons. The spike potential occurs at the onset of REMs during REM sleep in raw EOG waveforms. The spike potential originates from the extra-ocular muscle (Thickbroom and Mastaglia, 1985b) or from the oculomotor neurons innervating the ocular muscle units (Riemslag et al.,

1988). Therefore, the spike potential is reasonable to use as a signal of the onset of REMs. Moreover, only one onset point of REMs can be determined using this method. Both EEG and EOG in the epochs between 200 ms before and 50 ms after the onset of each eye movement were averaged (REM-onset-triggered potential). These brain potentials associated with leftward and rightward eye movements were initially calculated separately. The EEG and EOG between 200 ms before and 50 ms after the pseudo-triggers were averaged (pseudo-triggered potential) to confirm unexpected spontaneous changes (noise level). Pseudo-triggers were set at 3000 ms before the onset of REMs. The epoch in relation to this pseudo-trigger was excluded from further analyses when other eye movements had appeared between the pseudotrigger and onset of REM. Epochs of REM-onset-triggered and pseudo-triggered potentials containing more than one eye movement, or artifacts over ±80 lV, were excluded from averaging. Baseline correction was achieved by subtracting the mean amplitude of the first 50 ms epoch from the amplitude of each time point in the averaged waveform. The sLORETA (Pascual-Marqui, 2002) was used to estimate current sources of the pre-REM negativity. Source analysis was performed for the mean amplitude of the period between 150 and 20 ms before REMs. Current density magnitudes in three dimensions (sLORETA-xyz values) were calculated for each voxel. 2.5. Statistical analysis The mean amplitudes between 150 and 20 ms before triggers at 30 electrode sites (EEGs and EOGs) were compared with the baseline (i.e. 0 lV) using t-tests to test the presence of the pre-REM negativity. Scalp topographical distributions of the pre-REM negativity were examined using a two-way repeated-measures analysis of variance (ANOVA) with factors of anterior/posterior scalp location (Fp-line [Fp1, Fp2, Fpz], F-line [F3, F4, Fz], C-line [C3, C4, Cz], P-line [P3, P4, Pz], O-line [O1, O2, Oz]), and lateral scalp location (left [Fp1, F3, C3, P3, O1], midline [Fpz, Fz, Cz, Pz, Oz], and right [Fp2, F4, C4, P4, O2]) on the mean amplitudes between 150 and 20 ms before REM: 15 electrodes were used in a 3  5 grid. EEG records of the temporal region were not included in this analysis. Degrees of freedom greater than one were reduced using Greenhouse-Geisser e correction to control Type I errors associated with the violation of the sphericity assumption in repeated-measures ANOVA. Post hoc tests were performed by multiple comparisons using Bonferroni’s multiple test procedure. The sLORETA images were compared to zero with voxel-by-voxel t-tests. Statistical significance was assessed using a randomization test (Nichols and Holmes, 2002) which corrects for multiple comparisons. For this study, the significance level was set to 0.05. Means ± standard errors are reported in the Results section.

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3. Results The brain potentials associated with leftward and rightward eye movements were calculated. The mean numbers for averaging were, respectively, 156.4 ± 76.3 (range = 46–318) and 175.1 ± 84.5 (range = 49–332) for leftward and rightward eye movements. These numbers did not differ significantly: t(21) = 1.86, p = 0.08. Averaged potentials between 150 and 20 ms before leftward and rightward REMs were compared using an electrode-wise paired t-test. The pre-REM negativities of leftward and rightward eye movements did not reach a significant level in any channel. For that reason, brain potentials were pooled in both directions. Consequently, the mean numbers for averaging were 331.5 ± 32.8 (range = 95–602). Fig. 1 depicts the brain potential for 200 ms before to 50 ms after the onset of REMs. The spike potential, which reflects the oculomotor execution process (Thickbroom and Mastaglia, 1985b; Riemslag et al., 1988), appeared at the onset of REMs. This potential has the largest negativity at peri-orbital sites and the largest positivity at parietooccipital sites. The negative potential appearing before REMs is dominant in the prefrontal part. This potential was significantly more negative than the baseline (0 lV) over broad scalp areas (Fp1/2, Fpz, F3/4, F7/8, F9, Fz, C3/4, T7/ 8, Pz). The negative potentials at superior, right, and left EOG were also significant: t (21) = 6.16, t(21) = 3.75, and t(21) = 6.00, respectively, for superior, right, and left EOG, ps < 0.05. However, the negative potential at inferior EOG was not significant: t(21) = 0.64, p = 0.53. Fig. 2 shows the REMs-onset-triggered and pseudo-triggered potentials in prefrontal regions. The mean numbers for averaging of the pseudo-triggered potentials were 39.2 ± 2.9 (21–67). The pre-REM negativity did not appear in the pseudo-triggered potential. The mean amplitudes

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between 150 and 20 ms before pseudo-triggers in Fp1, Fpz, and Fp2 were not different from the baseline: t(21) = 0.38, p = 0.71 for Fp1; t(21) = 0.51, p = 0.62 for Fp2; and t(21) = 0.02, p = 0.99 for Fpz. Fig. 3(a) shows the scalp topography of mean amplitudes between 150 and 20 ms before REMs. The topography of the pre-REM negativity is dominant in prefrontal regions. Fig. 3(b) shows the anterior/posterior distribution of the pre-REM negativity. Two-way ANOVA showed a significant main effect of the anterior/posterior site: F(4, 84) = 12.49, p < 0.01, e = 0.39. Post hoc comparisons showed that the negative potential in the Fp-line (averaged amplitude of three sites) was more negative than those in F-, P-, and O-lines. Additionally, the negative potential in the O-line was smaller than those in F- and P-lines. Fig. 3(c) portrays the mean potentials in prefrontal sites. The mean potential in the right prefrontal region was the largest at the Fp-line. A two-way ANOVA showed a significant interaction between two variables (anterior/ posterior  lateral): F(8, 168) = 9.08, p < 0.01, e = 0.43. Follow-up analyses of this interaction relied upon a oneway ANOVA, together with post hoc comparisons. This analysis showed that the negative potential at the Fp-line was larger on the right site than on the midline site: F(2, 42) = 7.37, p < 0.01, e = 0.87. Fig. 4 and Table 1 present current sources of the preREM negativity before REMs, as estimated by sLORETA (Pascual-Marqui, 2002). Current sources of this potential were inferred to be the ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC), uncus, insula, anterior parahippocampal gyrus, basal forebrain, temporal pole, and premotor cortex. Current sources in the premotor cortex included the frontal eye field (BA8). The premotor cortex and frontal eye field were estimated only in the right hemisphere.

Fig. 1. Grand mean waveforms between 200 ms before and 50 ms after the onset of rapid eye movements (REMs) during REM sleep. The spike potential appeared at the onset of REMs. Slow negative potential (pre-REM negativity) appeared before REMs in dominant with prefrontal regions.

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mation related to pre-REM negativity using 26 electrodes appears to be acceptable. 4.1. Pre-REM negativity

Fig. 2. Pseudo-triggered and rapid eye movement (REM)-onset-triggered potential. REM-onset-triggered potentials were identical to the brain potentials presented in Fig. 1. Pseudo-triggers were set at 3000 ms before the onset of REMs. Pre-REM negativity appeared immediately before the onset of REMs.

4. Discussion Results of this study reconfirmed that the pre-REM negativity (1) appeared before REMs (Figs. 1 and 2), and (2) that it was dominant in the right prefrontal site (Fig. 3). Moreover, this study revealed that (3) pre-REM negativity did not appear in pseudo-triggered potentials (Fig. 2); and (4) the current sources of the pre-REM negativity were estimated to be in emotion-, memory-, and motor-related brain regions (Fig. 4, Table 1). Current sources of the pre-REM negativity were estimated using 26 electrodes. Although the electrodes were few, Pascual-Marqui (2002) demonstrated that sLORETA on 25 electrodes shows lower localization errors (mean 4.6 mm, median 0.0 mm) using simulation data including noise and multiple sources. As discussed below, the current sources of the pre-REM negativity were consistent with the brain regions activated during REM sleep, as revealed by earlier studies using PET and fMRI (Braun et al., 1997, 1998; Hong et al., 1995; Maquet et al., 1996; Miyauchi et al., 2004; Nofzinger et al., 1997; Peigneux et al., 2001; Wehrle et al., 2005, 2007). Therefore, current source esti-

Pre-REM negativity appeared dominantly with right prefrontal regions. This potential did not appear in pseudo-triggered potential, which was time-locked to 3000 ms before REMs. This result suggests that pre-REM negativity appeared immediately before REMs during REM sleep rather than appearing irrespective of the occurrence of eye movements. Presaccadic negativity, which reflects a voluntary preparatory process initiating saccades in wakefulness, appears with a front-central scalp distribution before saccades during wakefulness (Becker et al., 1972; Everling et al., 1997; Kurtzberg and Vaughan, 1982; Moster and Goldberg, 1990; Thickbroom and Mastaglia, 1985a). Ogawa et al. (2002, 2005) demonstrated that the presaccadic negativity did not appear before REMs during REM sleep. Topographical distributions of the pre-REM negativity in REM sleep and presaccadic negativity in wakefulness are different. For that reason, the pre-REM negativity and presaccadic negativity are thought to have separate origins in the brain. This study averaged the EEG period between 200 ms before and 50 ms after REMs. Ogawa et al. (2005) compared the mean amplitudes between 600 and 128 ms before REMs to a zero level (0 lV). The results showed no significant difference from the zero level. This study was set at the first 50 ms interval in the averaged waveforms as baseline periods. Potentials, which predict REMs, were not observed in the periods between 200 and 150 ms before REMs. Therefore, it is reasonable to consider the interval as a baseline. Nevertheless, a negative slope is clearly visible in the baseline periods with dominance in prefrontal sites, as shown in Fig. 1. Considered from these waveforms, the pre-REM negativity between 150 and 20 ms before REMs is thought to be a part of the activity that had already developed before the averaged interval. Although

Fig. 3. Topographical distribution of the mean amplitudes between 150 and 20 ms before rapid eye movements (REMs) during REM sleep. (a) Topography of the pre-REM negativity before REMs. (b) Anterior/posterior distribution of the pre-REM negativity. Each bar shows averaged amplitudes of left, right, and midline site in the same line. Only the differences with Fp-line are shown. (c) Distribution of the pre-REM negativity in prefrontal regions. *p < 0.05.

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Fig. 4. Current sources of the pre-rapid-eye-movement (pre-REM) negativity before REMs during REM sleep at (a) MRI slices and (b) cortical voxels. Montreal Neurological Institute (MNI) coordinates are indicated in Fig. 4(a). Red represents significant activation compared to zero, p < 0.05. L, left; R, right; A, anterior; P, posterior; S, superior; I, inferior; VMPFC, ventromedial prefrontal cortex; ACC, anterior cingulate cortex.

it is a subject of future investigation to determine the onset of the pre-REM negativity, one can say that this study estimated the current sources of a part of the pre-REM negativity, which was the potential increase that occurred

immediately before the REM onset. Ioannides et al. (2004) reported that reciprocal interaction between the frontal eye fields and pontine had occurred in the interval of 250–400 ms before REMs. This activity had been

Table 1 Brain areas estimated as the current sources of pre-rapid-eye-movement (pre-REM) negativity occurring before REMs during REM sleep Side

Anatomical region

Left hemisphere x

Bilateral Bilateral Right Bilateral Bilateral Bilateral Bilateral Bilateral Left Right Bilateral Bilateral Bilateral Bilateral Bilateral

Anterior cingulate cortex Inferior frontal gyrus Inferior temporal gyrus Insula Medial frontal gyrus Middle frontal gyrus Middle temporal gyrus Orbital gyrus Parahippocampal gyrus Precentral gyrus Rectal gyrus Subcallosal gyrus Superior frontal gyrus Superior temporal gyrus Uncus

y

0

Right hemisphere z

t-Value

BA

x

y

z

t-Value

BA

5 15 40 35 10 35 50 15

5 13 2 14 64 12 3 43

4 22 38 5 11 55 34 23

5.92 5.77 5.50 5.16 6.04 5.89 5.93 5.16

25 47 20 13 10 6 21 11

30 10 5 25 50 25

11 13 4 6 13 2

65 22 13 65 26 38

5.97 5.79 5.88 6.23 5.85 5.22

6 11 25 6 38 20

20

5 9

4 17

5.99 5.79

25 47

40 5 20 45 5 20

15 63 53 8 38 4

1 3 7 34 23 17

4.76 5.83 5.63 5.19 4.80 5.63

13 10 10 21 11 34

5 10 5 25 15

52 4 63 13 4

24 13 12 30 21

4.88 6.34 5.72 5.56 5.20

11 34 11 38 34

Coordinates are given for the stereotactic space of Talairach and Tournoux (1988). All regions show significant differences from zero, p < 0.05. BA, Brodmann’s area.

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considered as a build-up of excitability for triggering REMs (Ioannides et al., 2004). The averaged interval in this study is thought to be set at a period after the end of the reciprocal interaction between the frontal eye fields and pontine.

is followed by enhancement of brain stem activity. Consequently, the occurrence probability of REMs might be increased in humans.

4.2. Activities of emotion-related brain regions

Many reports have shown that the parahippocampal cortex is activated in relation to REMs (Braun et al., 1998; Peigneux et al., 2001; Miyauchi et al., 2004; Wehrle et al., 2007). Results of this study were consistent with them. The parahippocampal gyrus plays an important role in long-term memory (Squire and Zola, 1996). Parahippocampal activity during encoding of pictures predicts their retrieval (Brewer et al., 1998). Kilpatrick and Cahill (2003) found functional connectivity of the amygdala and parahippocampal gyrus using PET. The influence of the amygdala on parahippocampal regions is greater during viewing of emotional films than during viewing of neutral films (Kilpatrick and Cahill, 2003). Hu et al. (2006) demonstrated that the recognition accuracy of emotionally arousing pictures was greater after sleep. Hu et al. (2006) also assumed that REM sleep facilitates emotional declarative memory consolidation. Considering the memory consolidation function of sleep, activity of the parahippocampal regions associated with emotion-related brain regions before REMs might contribute to some memory consolidation such as emotional declarative memory.

This study showed that the uncus, which shares parts of the amygdala, VMPFC, ACC, and insula, is activated during 150–20 ms before REMs. It has been suggested that the amygdala, ACC, and VMPFC induce emotions (Bechara et al., 1999; Damasio, 1994) and that such emotions are represented in the somatosensory cortices and insula (Damasio, 1994; Damasio et al., 2000). That these brain regions participate in emotions has been confirmed experimentally in humans (Adolphs et al., 1994; Critchley et al., 2000; Damasio et al., 2000; Kawasaki et al., 2005; Lane et al., 1997; Morris et al., 1998). Results of this study suggest that emotion-related brain activity occurs before REMs during human REM sleep. Brain imaging studies have revealed various activation regions of REM sleep (Braun et al., 1997, 1998; Maquet et al., 1996; Miyauchi et al., 2004; Nofzinger et al., 1997; Peigneux et al., 2001; Wehrle et al., 2005, 2007). These studies found activation in the VMPFC, ACC, amygdala, and insula during REM sleep. A MEG study demonstrated that the orbitofrontal cortex, amygdala, and parahippocampal cortex are activated before REMs (Ioannides et al., 2004). The brain regions estimated to be activated before REMs in this study are consistent with results of those studies. This study also identified the activity of insula before REMs, which the MEG study did not find. The activity of insula before REMs was coincident with the activity of amygdala and VMPFC. The pre-REM activation of the insula might participate in the representation of emotion after the activity of amygdala and VMPFC. The discrepancy related to the identification of insula between this study and the MEG study (Ioannides et al., 2004) is thought to result from the following methodological differences. First, EEG and MEG measure different orthogonal directions of the neural populations. Second, different source imaging methods were used. Instead of activation being maintained continuously during REM sleep, results of this study suggest that emotion-related brain activity increases before REMs. This result complements temporal resolution of PET and fMRI studies, which show emotion-related brain activation during REM sleep (Maquet et al., 1996; Miyauchi et al., 2004; Nofzinger et al., 1997; Peigneux et al., 2001). The enhanced activity of emotion-related brain regions is thought to increase the probability of occurrence of REMs in humans. Electrical stimulation of the amygdala in REM sleep raises the occurrence density of PGO waves in cats (Calvo et al., 1987; Datta, 1997). Results of the present study suggest that emotion-related brain activity

4.3. Activities of memory-related brain regions

4.4. Activities of motor-related brain regions Current sources of the negative potential were estimated at the right premotor area and frontal eye field. Some PET studies have shown that the right premotor cortex and right frontal eye field are activated in relation to REMs during REM sleep (Hong et al., 1995; Peigneux et al., 2001). The results of this study were consistent with these prior findings. The quantities of rightward and leftward eye movements, projected into analysis, were not significant. Therefore, the difference of the number of REMs is unlikely to have caused the restricted activity only in the right hemisphere. Motor-related brain activity before REMs during REM sleep is thought to differ from the mechanism which controls eye movement during wakefulness. The first reason is that presaccadic negativity and presaccadic positivity during wakefulness do not appear before REMs in REM sleep (Abe et al., 2004b; Ogawa et al., 2002, 2005). Presaccadic positivity, reflecting the movement planning of eye movements, appears before saccades during wakefulness (Becker et al., 1972; Csibra et al., 1997; Everling et al., 1997; Kurtzberg and Vaughan, 1982; Moster and Goldberg, 1990; Thickbroom and Mastaglia, 1985a). Presaccadic positivity is expected to appear in REM sleep if the activity of the motor-related region controls REMs in REM sleep using the same mechanism as that under wakefulness. However, presaccadic positivity did not appear

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before REM in REM sleep (Abe et al., 2004b). The second reason is that motor-related brain activity preceding REM is restricted to the right hemisphere. Leftward and rightward REMs were included in this study. Both hemispheres are involved in the control of saccadic eye movement (Luna et al., 1998). Therefore, if the cortex controls eye movement using the same mechanism as that used when awake, motor-related brain activity is expected to be observed in bilateral regions. Amzica and Steriade (1996) reported that motor cortex activity is observed in relation with PGO waves during REM sleep. Eye movement is not always accompanied by PGO waves (Callaway et al., 1987; Datta, 1997). Premotor activity before REMs in REM sleep is thought to be initiated by the activity of pontine neurons. Such a process might cause a reciprocal interaction between the premotor cortex and the pontine nucleus before REMs. Actually, results of the MEG study suggest a reciprocal interaction between the frontal eye fields and the pontine nucleus 250–400 ms before REMs during REM sleep (Ioannides et al., 2004). Activity of the right premotor cortex before REMs might have some function such as memory consolidation. Manthey et al. (2003) suggested that left premotor areas were more involved in the analysis of objects, whereas right premotor areas were dominant in the analysis of movements. A possible explanation is that right premotor activity reflects the analysis of movements as a part of the memory consolidation process during sleep. 4.5. Summary Results of this study indicate that pre-REM negativity appears before REMs. Current sources of this potential were inferred to be emotion-, memory-, and motor-related brain regions including the ventromedial prefrontal cortex, uncus, insula, anterior cingulated cortex, basal forebrain, parahippocampal gyrus, premotor cortex, and frontal eye field. Outputs of movement and inputs of sensory information are inhibited during REM sleep (Chase and Morales, 1990; Hobson et al., 2000; Takahara et al., 2002, 2006; Wehrle et al., 2007). For that reason, brain activity preceding REMs is unlikely to be a response to external stimulation and is largely caused by spontaneous brain activity such as PGO activity. Brain activities associated with emotion-, memory- and movement-related regions before REMs during REM sleep might have certain functions. Pre-REM negativity is expected to be a psychophysiological index that can elucidate the functions of REM sleep. Acknowledgements This study was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (No. 17605008) and from the Japan Society for the Promotion of Science (No. 05J05334).

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