Generator sites of spontaneous MEG activity during sleep

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Electroencephah)graphy and clinical Neurophysioh>gy, g2 ( I g92) 182- It)6 ~' 1992 Elsevier Scientific Publishers Irchmd, Ltd. 0013-464t)/92/$05.00

EEG 9163(I

Generator sites of spontaneous MEG activity during sleep Sing-Teh Lu, Matti Kajola, Sirkka-Liisa Joutsiniemi *, Jukka Knuutila and Riitta Hari Low Temperature Laboratory,, th,lsinki University of Technolog,9', 02150 Espoo (Finland)

(Accepted for publication: 18 October 1991)

Summary We have recorded spontaneous magnetoencephalographic (MEG) activity during overnight natural sleep in 4 healthy adults with a 24-channel SQUID gradiometer, mainly over the sides of the head. All sleep stages were obtained. The MEG wave lk)rms resembled the EEG phenomena recorded simultaneously from the scalp midline, but the electric and magnetic signals did not always coincide. The source locations of different signals were studied by using a current dipole model. The equivalent sources of magnetic transients, resembling and often coinciding with the electric vertex waves and K-complexes, as well as the transients during REM sleep, were concentrated within a volume of 4 × 4 × 3 cm 3 in the inferior parietal lobe. For spindles and slow waves, no such focal generators were found.

Key words: Magnetoencephalography; Sleep; K-complex; Vertex wave; Slow-wave sleep; Spindle; Current dipole: Source h~calization: (Man)

N o c t u r n a l E E G r e c o r d i n g s are c o n v e n t i o n a l l y analyzed by classifying s l e e p stages on the basis of occurr e n c e a n d a b u n d a n c e of d i f f e r e n t wave forms. Since the g e n e r a t i o n sites a n d m e c h a n i s m s of the E E G signals a r e not known, the r e c o r d i n g s c a n n o t be u s e d to m o n i t o r functions o f d i f f e r e n t b r a i n a r e a s d u r i n g sleep. R e c e n t l y , with the d e v e l o p m e n t of m u l t i c h a n n e l magn e t o m e t e r s , m a g n e t o e n c e p h a l o g r a p h i c ( M E G ) studies of g e n e r a t o r s of s p o n t a n e o u s b r a i n r h y t h m s have bec o m e feasible. In e a r l i e r s i n g l e - c h a n n e l M E G studies of s l e e p ( H u g h e s et al. 1976; N a k a s a t o et al. 1990; U e n o a n d l r a m i n a 1990), it was difficult to d r a w conclusions a b o u t the r e l a t i o n s h i p s b e t w e e n the electric a n d m a g n e t i c activity o r a b o u t the source locations. H e r e we r e p o r t the first m u l t i c h a n n e l M E G r e c o r d ings d u r i n g sleep; with the large s e n s o r a r r a y it was possible to d e t e r m i n e the source locations from a r e c o r d i n g at o n e site, w i t h o u t moving the i n s t r u m e n t . Since e v o k e d r e s p o n s e s of the a u d i t o r y cortex w e r e m o n i t o r e d s i m u l t a n e o u s l y (Lu et al. in prep.), most of the r e c o r d i n g s w e r e o b t a i n e d from the l a t e r a l a s p e c t s of the head.

Correspondence to: Dr. R. HarL Low Temperature Laboratory, Helsinki University of Technology, 02150 Espoo (Finland).

* Present address: Tammiharju Hospital, 106(10 Tammisaari, Finland.

Methods

Subjects and experimental setup F o u r h e a l t h y a d u l t s (3 females, 1 male; ages 2 0 - 5 0 y e a r s ) v o l u n t e e r e d for the e x p e r i m e n t s . Subjects 1 a n d 4 were a u t h o r s of this p a p e r , and subjects 2 and 3 (a mother and her daughter) were paid volunteers. None of the subjects h a d histories of m e d i c a l a b n o r m a l i t i e s or s l e e p disorders. T h e r e c o r d i n g s w e r e m a d e in the m a g n e t i c a l l y s h i e l d e d r o o m of o u r l a b o r a t o r y . T h e r o o m was d a r k d u r i n g the sleep m e a s u r e m e n t s ; the awake stage r e c o r d i n g s w e r e m a d e with lights on but o t h e r w i s e u n d e r i d e n t i c a l c o n d i t i o n s . T h e subject was lying on a b e d with h e r / h i s h e a d fixed by a v a c u u m cast to p r e v e n t h e a d m o v e m e n t s a n d was i n s t r u c t e d to relax a n d to fall a s l e e p w h e n e v e r s h e / h e was ready. No s l e e p d e p r i v a t i o n n o r m e d i c a t i o n was used. In spite of the r a t h e r u n u s u a l s l e e p i n g conditions, the subjects fell a s l e e p within 5 - 3 0 min after the lights were switched off. All s l e e p stages w e r e r e a c h e d , except for subject 3 in w h o m R E M s l e e p was not r e c o r d e d . M e a s u r e m e n t s on subjects 2 a n d 4 w e r e m a d e d u r i n g 1 night for 7 - 8 h. Subject 1 was s t u d i e d d u r i n g 3 nights ( 7 - 8 h / n i g h t ) a n d subject 3 d u r i n g 2 nights (for 3 a n d 8 h, r e s p e c tively). S p o n t a n e o u s M E G a n d E E G activities were m o n i t o r e d c o n t i n u o u s l y d u r i n g the night on a r e a l - t i m e display and s e l e c t e d p a r t s were r e c o r d e d on a digital

MEG DURING SLEEP

tape for later off-line analysis. The total recording times were 2 - 4 h / n i g h t (in 2.5-10 min periods). Auditory stimuli (tone pips once every 1.1 sec) were presented during 50-80% of the time for subjects 1, 3 and 4, and continuously for subject 2 through a head phone in the pillow. On visual inspection of the recordings, no transients (K-complexes or vertex waves) were timelocked to the sounds; this is most probably because the stimuli were repeated relatively fast.

Recording and data analysis" The magnetic signals outside the head were measured with a 24-channel SQUID gradiometer (Ahonen et al. 1991). This device uses a planar flux transformer configuration: its two orthogonal figure-of-eight loops per sensor unit measure the tangential derivatives OB./Ox and OB,/Oy of B,., the field component normal to the head, simultaneously at 12 locations 30 mm apart. While a conventional axial gradiometer detects field extrema on both sides of a current dipole, a planar gradiometer detects the largest signal just above the dipole. The sensors cover an area of 12.5 cm in diameter and the source location can often be determined during a single experiment without moving the instrument; this is especially important for studies of spontaneous brain activity. Signals were measured over the side of the right hemisphere in all subjects, with the magnetometer center approximately above the crossing of the sylvian and rolandic fissures. In addition, recordings were obtained over the upper part of the right hemisphere near the midline in subject 1, and over the left hemisphere in subject 4. The locations and orientations of the 24 sensors with respect to external landmarks on the scalp were determined before each measurement, by recording the magnetic field produced by 3 small coils fixed on the scalp at known positions (Knuutila et al. 1987). The passband of the M E G recordings was 0.05-100 Hz (3 dB points, roll-off for the high-pass filter 35 d B / d e c a d e and over 80 d B / d e c a d e for the low-pass filter). The data were digitized at 297 Hz. We also recorded the electro-oculogram (FOG; vertical in all subjects, also horizontal in subjects 2 and 4), E E G from electrodes Fz, Cz, and Oz referred to the mastoid contralateral to the M E G recording, the electrocardiogram (ECG) between the two wrists (subjects 2 and 4), and the surface electromyogram (EMG) from submental muscles. Passbands were 0.1-100 Hz (6 dB points) for EEG, F O G , and ECG and 30-10,000 Hz for EMG. The wide passband for E M G recordings, in spite of the low sampling rate, was adequate since only the mean EMG amplitude was of interest. One or two M E G channels were occasionally noisy but, to avoid any disturbance to the sleeping subject, no attempt was made to adjust them during the recordings.

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To determine the equivalent source locations of the magnetic signals, representative epochs of 200-2000 msec were chosen from the continuous record for further analysis. The baseline for amplitude measurements was defined as the mean of the visually determined no-signal region for the magnetic counterparts of vertex waves and K-complexes and as the mean amplitude of the whole analysis period for spindles and slow waves. Our classification of sleep stages was based on electric signals, according to guidelincs of Rechtschaffen and Kales (1968): Waking: rhythmic alpha activity in the occipital lead. Stage la: alpha rhythm is waxing and waning, discontinuous, and "spreads" towards anterior scalp regions. Stage lb: mixed theta activity and occasional sharp vertex waves appear. Stage 2: sleep spindles and K-complexes appear. Stage 3: slow-wave sleep, 20-5(/% of the epoch consists of 0.5-2.5 Hz activity, at least 75 /,V peak-topeak. Stage 4: slow-wave sleep at least 50% of the epoch. REM sleep: rapid eye movements in the F O G channel, low-voltage E E G background, decreased tone in the submental muscles. "Equivalent current dipoles" (ECDs), i.e., current dipoles that best explain the measured field pattern, were determined by using a spherically symmetric conductor model. The origin and radius (95-115 ram) of the sphere were chosen to fit best the local curvature of the head in the measurement area. The fitting algorithm, which was used to compute the locations and strengths of the ECDs, took into account the measured sensor locations and orientations so that the effects of primary and w)lume currents were properly dealt with (Sarvas 1987).

Results

Figs. 1-7 show examples of magnetic and electric recordings in subjects 1 and 2 during the different stages of sleep. During wakefulness (Fig. 1), the occipital E E G displays rhythmic 10-11 Hz alpha activity in subject 1 and 8-9 Hz activity in subject 2. The simultaneous M E G over the lateral aspect of the head is of rather low amplitude but displays rhythmic activity of the same frequency within (}.5 Hz. During light drowsiness (stage la; Fig. 2), the occipital electric alpha becomes discontinuous, "spreads" more anteriorly and its frequency slows down by about 1 Hz. Simultaneously rhythmic activity of the same frequency appears in MEG, more clearly in subject 1 and especially in the middle lower channels.

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MEG DURING SLEEP During deep drowsiness and light sleep (stages lb and 2; Figs. 3 and 4) vertex waves of 150-250 msec duration appear in the frontocentral E E G leads. Similar wave forms are seen in MEG; we will designate them " V waves." The magnetic and electric V waves do not always coincide. Magnetic spindles of 11-15 Hz in frequency and 0.3-2 sec in duration appear during stage 2 (Fig. 4). Sometimes they are superimposed on high-amplitude transients, thereby resembling the typical electric "Kcomplexes," and we shall call them K-complexes as well. Thc magnetic V waves and K-complexes were often repeatedly seen in similar wave form and distribution but clear differences were also evident between successive transients. A typical K-complex lasted 0.81.2 sec. During slow-wave sleep (stages 3 and 4; Figs. 5 and 6), the 0.5-2 Hz polymorphic M E G activity is widely spread and there arc no consistent differences between the signals detected by the two orthogonal loops, indicating that the orientation of the source currents changes frequently. In subject 1, where recordings were available from 2 locations, the magnetic recordings showed much less slow-wave activity in the uppermost than the lower part of the right hemisphere, in the presence of the same amount of electric slow-wave activity. Three subjects reached R E M sleep, defined on the basis of rapid eye movements, decreased muscular tone, and absence of spindles and K-complexes in the EEG. REM appeared around 1-2 a.m. for 15-20 min and between 4:30 and 6 a.m. for 35-60 min. During the REM stage the M E G activity was lower in amplitude and faster in frequency than during other sleep stages (Fig. 7). Sharp magnetic transients resembling the V waves were frequently seen. Fig. 8 shows examples of different magnetic signals, chosen to illustrate the variability in wave form and distribution from one signal to another in the same subject. Fig. 8a compares the distribution of the auditory evoked magnetic fields (AEFs), recorded during wakefulness, and V waves. The main A E F deflection, Nl00m, peaks about 100 msec after the tone onset. The amplitude maximum is more posterior for the V wave than for N l00m, suggesting different source locations. Furthermore, the different amplitude ratios of signals on x- and y-gradients during A E F and V wave suggest different orientations for the source currents. During R E M sleep, magnetic transients do not coincide with electric signals on the midline scalp (Fig. 8b). In Fig. 8c, the two electric K-complexes resemble each other whereas the magnetic distributions are different. The same is true for the spindles (Fig. 8d). The typical maximum amplitudes of different wave forms were 400 l T / c m for V waves, 600 f T / c m for K-complexes, 800

191 t T / c m for slow waves, 300 f F / c m for spindles and 400 f T / c m for transients during R E M sleep. Fig. 9 shows the locations of ECDs for all subjects during the V waves, K-complexes, slow waves, and R E M transients. Only dipoles with goodness-of-fit values of at least 90% were included, and ECDs with source depths exceeding 50 mm and with strengths exceeding 500 h a m were excluded. This was because the source depth and strength arc strongly correlated (cf., Hari et al. 1988); in the worst case dipole depths (between 10 and 50 mm) explained almost 80% of the dipole strength. The d e p t h / s t r e n g t h criterium resulted in rejection of less than 1(1~5~ of all ECDs. Typical strengths were 100-300 nAm for dipoles located 30-40 mm beneath the scalp; the 95~4 confidence limits for the depth estimates were 6-12 mm. The equivalent sources of vertex waves and K-complexes are clustered in an area of 4 x 4 cm e in the xy-planc, a few centimeters toward the parietal lobc from the sources of N100m, which is generated at the auditory cortex on the superior surface of the temporal lobe (Hari 1990). Since the M E G signals primarily originate from currents in the fissural cortex, Fig. 9 also shows the estimated courses of two fissures from which the different wave forms might come: these estimates were obtained by drawing lines orthogonal to the main orientation of the ECDs. The main source orientations were similar for V waves, K-complexes, and REM transients, the "fissures" forming an angle of 30-45 ° with the sylvian fissure, whose course is derived from the orientation of lhe ECD for N100m. For subject 4, recordings were available from both hemispheres with rather symmetric source locations and "fissure" orientations. Sources of REM transients (shown for 3 subjects in Fig. 9) also clustered to the same area as the sources of V waves and K-complexes. During slow-wave sleep the ECDs were more widely distributed but concentrated in the lower parts of the lateral recording sites. A single dipole model could not explain the observed spindle distributions satisfactorily; even during one spindle, multiple ECDs operated successively or simultaneously, sometimes several centimeters apart. Principal component analysis showed that to explain at least 90% of the field variance, 4 - 6 components were needed for about 1 sec. Neither was it possible to explain the spindle distribution with a 2-dipole timevarying model. These results emphasize the complexity of the sources underlying spindles.

Discussion This is the first report of multichannel MEG recordings during sleep. In spite of different sensitivities of

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194

the E E G and M E G methods to currents of different orientations and locations, the primary currents are the same for both signals (Williamson and Kaufman 1981; Hari and Lounasmaa 1989). The observed similarities between the M E G and E E G wave forms were thus to be expected, and it was possible to classify sleep stages on the basis of both recordings. Both methods have their advantages in sleep studies. The subject is able to move more freely during E E G recordings, whereas M E G studies can be focused easily on activity of local areas in the fissural cortex.

Vertex waves, K-complexes and REM transients The ECDs of magnetic V waves, K-complexes, and REM transients were in a rather localized area which agrees with the inferior parietal lobe. This brain region seems to be involved in the regulation of attention since its lesions can lead to neglect syndromes. Interestingly, Doricchi et al. (1991) recently observed that in patients with left visual hemi-inattention, rapid eye movements (REMs) towards the left were virtually absent during sleep. We may thus hypothesize that the inferior parietal lobule is phasically activated during some sleep stages, The functional role of this is obscure at present but seems to agree with the early hypothesis that K-complexes are linked to arousal and orientation (Roth et al. 1956). The main ECD orientation for V waves and K-complexes, pointing towards the Fz location, agrees with the electric scalp distribution, with larger amplitudes at Fz than at Cz (cf., Fig. 8a and c). The sources are bilateral and may evidently function independently since the midline E E G did not always coincide with the magnetic signals of the lateral aspect of the head. In a recent M E G study with a single-channel magnetometer combined with E E G mapping (Ueno and Iramina 1990), it was suggested that the K-complexes have bilateral deep (possibly thalamic) sources pointing towards frontal areas. ECDs show similar orientations in the present study. However, dipole moments of the observed strength can hardly be generated in the thalamus. This is because the number of structures in which current flow can be modelled with dipoles - - such as the pyramidal cells - - is considerably smaller in the thalamus than in the cortex. Assuming a cortical source, a dipole moment of 200 nAm would necessitate activation of 40-100 cm 2 of the cortex (cf., Hari 1990), corresponding to an area of 7-11 cm in diameter. If the source was deeper, e.g., thalamic, it would have to be stronger to produce the observed signals, and be thus still more extended. Consequently, we consider the sources of K-complexes to be cortical, although probably driven by subcortical input. In the early E E G studies, similarities were emphasized between the electric K-complexes and the "nonspecific" auditory evoked "vertex" potentials (Roth et

S.-T. LU ET AL.

al. 1956). M E G studies have later indicated that an important part of the auditory vertex potential arises from the supratemporal auditory cortex (see Hari 1990 for a review). The present data, showing different locations and orientations of the ECDs for N 100m and for V waves and K-complexes, indicate that the generators of these p h e n o m e n a are distinct. Our data differ from early suggestions about the generation of vertex waves at cytoarchitectonic areas 6 and 9 (Brazier 1949). However, we did not record activity from the whole head, and differences can also arisc from M E G ' s selectivity to tangential currents. Some of the discrepancies concerning multiple sources cannot be resolved without combined E E G and M E G recordings, both covering the whole head.

Slow-wace sleep In scalp E E G recordings the delta activity below 2 Hz is widely distributed all over the head. Delta is not a truc rhythmic phenomenon, nor is it considered to have any local sources. The latter statement is supported by the present M E G data although there was a trend for larger slow-wave activity over the lower than the upper measurement locations. One possible mechanism for the generation of polymorphic delta activity during sleep is partial functional deafferentation of the cortex, as suggested by animal experiments (Steriade et al. 1990). Slow-wave sleep can be considered "synchronized" activity where a large number of neurons have to fire simultaneously; consequently the dipole moments are the strongest among all sleep phenomena that we recorded.

Spindles Signal distributions indicate that spindles probably involve smaller areas for each generator than the slow-wave activity. At present, the role of the reticulate thalamic nucleus is emphasized as the trigger/modulator of the cortical spindling activity (Steriade et al. 1990). Combining this idea with our findings of diverse source areas would mean that thalamocortical fibers drive spindles at various neocortical areas. Complexity of spindle generation, with a multitude of sources and different frequencies, has been assumed from animal experiments (Buser 1987), and from depth electrode and scalp topography studies in humans (Niedermeyer 1982; Scheuler et al. 1990). It is evident that sophisticated source models ought to be applied to the interpretation of spindle distributions. The diversity of the sources also implies that results obtained by singlechannel M E G recordings, with an E E G signal as a trigger, can be misleading since activities of various source areas are intermixed.

Rhythmic activity during drowsiness The rhythmic activity during drowsiness is of special interest when evaluating the generators of alpha-like

MEG DURING SLEEP p h e n o m e n a . T h e " s p r e a d " of a lp h a to w a r d s m o r e anterior regions, with slightly lower f r e q u e n c y , has b e e n c o n s i d e r e d a sign of d e c r e a s e d vigilance ( B e n t e 1964; S a n t a m a r i a and C h i a p p a 1987). This type of s p r e a d w ou l d be in cl ear c o n t r a s t to ideas e m p h a s i z i n g local g e n e r a t o r s for the alpha activity ( L o p e s da Silva and S t o r m van L e e u w e n 1977, C h a p m a n et al. 1984). T i i h o hen et al. (1991) recently r e p o r t e d a m a g n e t o e n c e p h a l o g r a p h i c 11) Hz rhythm, with E C D s situated at the s u p r a t e m p o r a l auditory cortex. Since c u r r e n t s in this a r e a would p r o d u c e the m a x i m u m E E G amplitudes in the f r o n t o c e n t r a l midline, we can assume the s p r e a d of the electric alpha activity d u r i n g drowsiness to reflect c h a n g e d relative c o n t r i b u t i o n s from the occipital alpha and from the t e m p o r a l lobe 10 Hz g e n e r a tors (cf., Hari 1991). Such a hypothesis is s u p p o r t e d by the p r e s e n t results showing m o r e a b u n d a n t m a g n e t i c 10 Hz activity over the lateral aspects of the h e a d during stage l a than during wakefulness, in c o n t r a s t to the b e h a v i o r of the occipital electric alpha activity. In addition, the r e c e n t d e p t h e l e c t r o d e r e c o r d i n g s of Nied e r m e y e r (1990, 1991) indicate that t e m p o r a l 6 - 1 1 Hz activity, evidently arising from the convexial t e m p o r a l cortex, is m o r e resistant to vigilance d e c r e a s e than the occipital alpha. Conclusions S p o n t a n e o u s M E G and E E G activities d u r i n g sleep have c o m p l e x spatial distributions. In o r d e r to be confid e n t that the E C D s really are physiologically m e a n i n g ful, and to c o m p a r e electric and m a g n e t i c wave forms, s i m u l t a n e o u s E E G and M E G r e c o r d i n g s c o v e r i n g the w h o l e h e a d are necessary, especially b e c a u s e the sources in both h e m i s p h e r e s s e e m to f u n c t i o n separately. A l t h o u g h o u r p r e s e n t 2 4 - c h a n n e l i n s t r u m e n t has a c o v e r a g e large e n o u g h for a c c u r a t e d e t e r m i n a tions of various sources of e v o k e d responses, it is not e x t e n d e d e n o u g h to give p r e c is e i n f o r m a t i o n ab o u t the d e p t h s of d e e p sources. T h e p r e s e n t results, however, are p r o m i s i n g in that they show phasic activation of localized brain a r e a s d u r i n g sleep. M o n i t o r i n g these areas might give new insights into the poorly u n d e r stood o r g a n i z a t i o n of cortical functions d u r i n g sleep. This study was financially supported by the Academy of Finland, by the KSrber Foundation (Hamburg, Germany), and by the Sigrid Jusdlius Foundation. We thank Mr. J. Karhu, Dr. Jyrki Mfikelfi, Dr. L. Leinonen. Prof. O.V. Lounasmaa, and Ms. Ritva Paetau for comments on the manuscript.

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