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1Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki; and 2Research Institute of Science and Technology for Society, Japan Science and Technology Agency, Saitama, Japan
Submitted 31 January 2006; accepted in final form 4 April 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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; Jeffreys and Axford 1972; Kawashima et al. 1996; Pratt et al. 1982), visual-evoked magnetic fields (VEFs; Inui et al. 2006b; Moradi et al. 2003; Portin et al. 1999; Yoneda et al. 1995), and intracranial recordings (Arroyo et al. 1997; Ducati et al. 1988). Less is known about the timing of the processing stream beyond the primary visual cortex (V1), although some VEP (Di Russo et al. 2001: Foxe and Simpson 2002; Vanni et al. 2004), VEF (Vanni et al. 2001), and intracranial recording (Arroyo et al. 1997) studies have shown the distributions of latencies that are roughly consistent with the hierarchical processing through V1 and the extrastriate cortex. In a previous study (Inui et al. 2006b), we showed that the activity in V1 with an onset latency of about 30 ms is the earliest activity after visual stimulation using simultaneous recordings of VEFs and electroretinograms. However, at such an early period, the precise timing of cortical activities in the visual system has not been clarified in humans.
We previously examined the cortical processing in response to somatosensory (Inui et al. 2004), auditory (Inui et al. 2006a), and noxious stimuli (Inui et al. 2003a,b) using magnetoencephalograms (MEGs) in humans. The results show several common features of processing among these sensory modalities. First, there are several parallel streams (Inui et al. 2003a, 2004, 2006a). For example, there are at least two streams in auditory processing running posterosuperiorly (from the primary auditory cortex to the belt region and then to the posterior region, such as the posterior parietal cortex and planum temporale) and anteriorly (primary auditory cortex-belt-anterior superior temporal gyrus). Second, the time delay between the two sequential activations is about 4 ms, for example, 3.6 ms between areas 3b and 1 and 4.4 ms between areas 1 and 5 for somatosensory processing, and 4.0 ms between the medial and lateral parts of Heschl's gyrus for auditory processing (Inui et al. 2004, 2006a). Third, "early" cortical activities exhibit reversals of polarity after 10 ms once, or in some cases twice, resulting in a characteristic biphasic or triphasic time course (Inui et al. 2003b, 2004, 2006a). Finally, later activities that follow several "early" activities with the biphasic structure do not show such a reversal of polarity and are long lasting (Inui et al. 2003a, 2004, 2006a). For example, activities in the planum temporale (auditory), secondary somatosensory cortex (tactile and pain), or limbic structures (pain) belong to this type.
These findings are consistent with anatomical (e.g., Felleman and Van Essen 1991; Kaas and Collins 2001) and electrophysiological (e.g., Iwamura 1998) studies in monkeys that show a hierarchical and parallel organization of sensory processing. In the present study, we sought to know whether these common features of sensory processing could be applied to the human visual system.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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). Stimulation and recordings
Experiments were conducted in a fully darkened shielded room. Before the experiment, subjects were dark-adapted for 15 min. Subjects lay supine on a bed with head fixed to the biomagnetometer with adhesive tape to prevent movement. Flash stimuli were applied to the right eye of the subjects as described in detail in our previous study (Inui et al. 2006b). In brief, flash stimuli of 20 Joules (1,460 cd as a point source) were delivered with a xenon light stimulator (SLS-3100, Nihonkoden, Tokyo, Japan) at an interval of 1.4 to 2.0 s. The duration of the flash was about 7 ms. The light was placed outside the room and applied to the subjects through a small square window (3 x 13 cm) at a distance of 2 m from the eye, which yielded an illuminance of about 370 lux at the eye. The illuminance was measured by a strobe tester (Strobe Tester II, Minolta, Tokyo, Japan). The direction of the light was about 48° below the line of fixation. The left eye was patched. To mask the auditory noise caused by the stimulator, rubber earplugs were provided, and white noise of 50 dB was delivered from a speaker during the experiment.
VEFs were recorded with a 37-channel biomagnetometer (Magnes, Biomagnetic Technologies, San Diego, CA) as described previously (Inui et al. 2006b). The VEF signals were triggered by the onset of the delivery of a flash. The accuracy of the delivery of a flash and the MEG trigger was confirmed by recording the light using a photodiode. The magnetic fields were recorded with a pass-band of 0.1–200 Hz at a sampling rate of 2,083 Hz, and then digitally filtered with a 150-Hz low-pass filter. The window of analysis was from 50 ms before to 100 ms after the stimulus onset, and the prestimulus period was used as the DC baseline. In one trial, 500 responses were collected and averaged. Two trials were performed with an interval between them of a few minutes. After the reproducibility had been confirmed (Inui et al. 2006a), the results of the two trials were then averaged and used for the analysis.
Analysis of VEF data
Source locations and the time courses of source activities were determined using multiple source analysis and brain electric source analysis (NeuroScan, Mclean, VA), as described previously (Inui et al. 2004, 2006a). The model adequacy was assessed by examining: 1) the percentage variance (Hari et al. 1988), 2) the F-ratio (ratio of reduced chi-square values before and after adding a new source) (Supek and Aine 1993), and 3) residual waveforms (i.e., the difference between the recorded data and the model). The percentage variance measures the goodness-of-fit (GOF) of the model, comparing the recorded data and the model. The integral probability of obtaining an F-ratio value equal to or greater than the obtained value is calculated to evaluate whether a model with a larger number of dipoles represents a statistically significant improvement of the fit over a model with a smaller number of dipoles. When the P value was <0.05, the new dipole was considered to be significant. We continued to add a source to the model until the addition of a dipole did not significantly improve the fit. These procedures, using the F-ratio, were based on a previous report by Supek and Aine (1993). The procedure used to assess the model's accuracy was basically the same as that described in previous studies (Inui et al. 2004, 2006a). In the present study, the onset latency of each cortical activity was defined as the latency point at which the activity started to rise steeply from the baseline.
Magnetic resonance imaging (MRI) scans (Siemens Allega scanner, 3.0 T) were obtained from all subjects. T1-weighted coronal, axial, and sagittal image slices obtained every 1.5 mm were used for superimposition of the MEG source locations. The same anatomical landmarks used to create the MEG head-based three-dimensional (3D) coordinate system (the bilateral preauricular points and nasion) were visualized in the MR images by affixing to these points high-contrast cod liver oil capsules (3 mm in diameter). The common MEG and MRI anatomical landmarks allowed easy transformation of the head-based 3D coordinate system used for MEG source analyses into the MRI coordinate. The location of each cortical source was expressed in Talairach coordinates.
Data were expressed as means ± SD. A one-way ANOVA followed by Bonferroni/Dunn's post hoc test was used for the statistical comparison of the latency among each source activity in each hemisphere. P values <0.05 were considered to be significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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In all subjects, a clear magnetic component at around 37 ms (termed 37M) was the earliest magnetic response, as described previously (Inui et al. 2006b). Figure 1A shows the detailed topographies of the recorded magnetic fields in a representative subject. The topography of 37M showed a dipolar pattern of field distribution consistent with a source pointing superiorly at around the peak latency or at an earlier point than the peak latency. However, the distribution pattern usually became complicated at a latency just later than the peak of 37M, indicating that at least one source was active just after the peak latency of 37M, in addition to the first source. At 41, 52, and 86 ms, the isocontour maps show a characteristic symmetric two-dipole (quadrupole) pattern. These field distribution patterns are consistent with two mirror-symmetric sources pointing medially (41 ms), laterally (52 ms), and then medially again (86 ms). Similar symmetric two-dipole patterns were identified in nine of eleven subjects. At 64 and 100 ms, the magnetic responses were strongest in the lower sensors, suggesting a source with a more inferior location than that of the other sources. These topographies suggested that at least four distinct sources were active within 50 ms after the onset of stimulation, and at least one additional source was active at later latencies in this subject. After the fitting of six sources using similar procedures to those explained in Fig. 2, the data obtained at every latency point were successfully explained by the model in this case. Figure 1Ab shows the theoretical field distribution with the six-dipole model. Figure 1B shows the time course of each cortical activity. Figure 1C shows the location of each source superimposed on the subject's MR images. These results showed that the bilateral sources in the middle occipital area (Sources 2 and 3) were responsible for the symmetric two-dipole pattern of distribution, a source around the calcarine fissure (Source 1) was mainly responsible for 37M, a dorsomedial source on the superior wall of the occipital lobe (Source 4) also helped to shape 37M, and the lower fields at later latencies were attributed to symmetric sources on the ventral surface of the occipital lobe.
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Similar procedures were applied to magnetic fields obtained for the remaining subjects. By applying our criteria, four to seven sources were included in the model for each subject. The first source (Source 1 in Figs. 1 and 2) responsible for 37M was located in a midline area of the occipital lobe around the calcarine fissure, usually on its lower wall, corresponding to the primary visual cortex (V1 source). The mean Talairach coordinates across subjects are shown in Table 1. Two symmetric bilateral sources were identified in both the dorsal (Source 2 in Fig. 2) and ventral (Sources 3 and 4 in Figs. 1 and 2) parts of the middle occipital area. Because these source activities were clearly differentiated by orientation, we analyzed these sources separately. The source in the ventral middle occipital area (MOv) was identified in all 11 subjects in the right hemisphere, and in 10 subjects in the left hemisphere. The source in the dorsal middle occipital area (MOd) was identified in eight subjects in the left hemisphere and in four subjects in the right hemisphere. On average, the location of the MOd source was about 10 mm superior to that of the MOv source in Talairach coordinates. Another source that was already active around the later part of 37M was located on the superior wall of the occipital lobe near the midline (Source 4 in Fig. 1). According to its location, we refer to this as the dorsomedial area (DM; Allman and Kaas 1975). The DM source was identified in five subjects. About 10 ms later than the V1 source activity, a source located in the temporo-occipito-parietal cortex became active (Sources 5 and 6 in Fig. 2), which corresponded to the human MT/V5 area (hMT source) according to earlier studies (Sunaert et al. 1999; Tootell et al. 1995; Watson et al. 1993). The hMT source was identified in six subjects in the left hemisphere. Because the hMT source in the right hemisphere was identified in only one subject (Fig. 2), the right hMT source was not included in further analysis. Finally, a source on the ventral surface of the occipital lobe (VO source, Sources 5 and 6 in Fig. 1) was identified in the left hemisphere in five subjects, and in the right hemisphere in four subjects.
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Figure 3 shows the time course of each source activity of all subjects and Fig. 4A shows their group average. Figure 4B shows the mean location and orientation of each source superimposed on MR images of a standard brain. In general, the activity in V1, MOd, DM, and hMT reversed its polarity once or twice in some subjects at an interval of about 10 ms, which resulted in a biphasic or triphasic waveform. Typical triphasic waveforms are depicted in Fig. 5. On the other hand, the VO sources showed long-lasting activities without a reversal of polarity over such a short period. The MOv source showed intermediate features. That is, the activity of this source reversed its polarity about 10 ms after its onset, but the activity that followed was very long in duration.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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Methodological limitations
We should describe the methodological limitations of the present study. First, the stimulus used was a flash delivered 2 m from the subject's eye; therefore it reached a wide area of the retina. If we could use a focal stimulation, the interpretation of the results would be easier. For example, the four MO sources appear to represent four respective quadrants of the retina in this study. This would be confirmed if we used a focal stimulation applied to each of the retinal areas. On the other hand, previous studies in humans with MEG or electroencephalograms that used focal stimulation failed to clearly identify the initial activities. This is probably explained by the fact that our stimulus was strong enough and synchronized to detect initial activities using MEG. Like studies in monkeys that deal with precise temporal information in a broad area of the visual cortex (Givre et al. 1994; Schroeder et al. 1998), a diffuse flash light seemed to evoke robust and sharp responses in V1, as well as higher visual areas, in this study. In addition, if we want to understand the timing of activation in the visual areas, we should use a constant stimulus across recordings in different cortical areas. Although optimizing stimulus parameters for focal neuronal preferences is useful and sometimes necessary, optimization can produce serious error in studies aimed at the timing of activation because stimulus qualities affect the latency. Therefore the present study, using a diffuse flash, can be compared with the results in monkey studies that examined the timing of visual areas using a constant stimulus. Second, the activation of neurons in a wide area of the retina raises problems in an MEG-based study. When the orientations (i.e., the direction of the intracellular current flow) of two proximal sources are opposite, the magnetic fields arising from the two sources cancel each other out. If two proximal sources have a similar orientation, the summated magnetic fields appear to arise from a single dipole whose location is deeper than the actual dipoles. In the visual cortex, for example, neurons on the upper and lower walls of the calcarine fissure, which represent the lower and upper fields of the retina, respectively, create dipoles in opposite directions. Therefore in the present study, magnetic fields recorded from this area may be a result of canceling to some degree. This may slightly affect the localization of each source. Third, the area covered by the device was limited, which may, at least in part, explain why the DM or hMT source was not detected in about half of the subjects.
Activation in each cortical area
V1.
The onset latency of the V1 source was the shortest in all subjects, confirming our previous report that the V1 activity, with an onset latency <30 ms, was the earliest cortical activity after flash stimuli (Inui et al. 2006b). Although the mean onset latency of 27.5 ms was roughly consistent with the shortest response latency of striate neurons in single-unit recording studies, both in monkeys and humans, as discussed elsewhere (Inui et al. 2006b), if we apply the 3/5 rule for extrapolating from monkey to human sensory response latencies [i.e., across visual, auditory, and somatosensory systems, the peak latencies of the evoked potential (EP) components tend to be about 3/5 of the latency of the corresponding human EP components; Schroeder et al. 2004] to the present results, the onset latency of the V1 source is slightly shorter than the expected latency. However, when we try to compare our results with those in other studies, we should consider factors known to affect the response latency, including 1) species, 2) use of anesthesia (anesthesia increases the response latency), 3) stimulus conditions (decrease in intensity increases the latency), and 4) type of measurement (field potentials are more sensitive than action potentials to estimate the shortest response latency). In this regard, studies using current source density (CSD) and flash stimuli in awake monkeys are the most suitable to compare with our results. To our knowledge, the only monkey studies to show V1 latencies as early as those in this study are those of Givre et al. (1994, 1995) and Schroeder et al. (1998), in which the latency of the visual areas after flash stimuli was examined by the use of CSD in awake macaques. Therefore our results appear to be compatible with those in monkeys. In addition, it is interesting that the shortest response latency grouping identified by Schroeder et al. (1998) was the extreme peripheral representation, where there were neurons that responded as early as 17–18 ms. Using the 3/5 rule, this would extrapolate to a value close to that observed in this study. In both the present and our previous (Inui et al. 2006b) studies, the V1 source is localized in the anterior/deeper area within the striate cortex, which corresponds to the peripheral representation.
MIDDLE OCCIPITAL AREA (MO).
Four sources were identified in the middle occipital area, about 20 mm lateral to the midline. They were two sets of symmetric bilateral sources, one in the dorsal part and another in the ventral part. They were almost simultaneously activated, with a time delay of 4–5 ms relative to the V1 activity. Based on their simultaneous activation and locations, we considered that these sources were in the second visual area (V2), and each of the four sources represented each quarter of the field. In both humans (DeYoe et al. 1996) and monkeys (Allman and Kaas 1974; Gattass et al. 1981), V2d and V2v together provide a complete representation of the visual hemifield, splitting in half with the inferior field represented dorsally and the superior field represented ventrally. However, there remains the possibility that the MO source activities contain activities from other sources located nearby, such as in the third visual area (V3). The time course of activity of the MOv sources appears to support this possibility. Although the V1, DM, MOd, and hMT sources show a clear biphasic waveform with a reversal of polarity after 10 ms, which probably reflects the rapid projection of these sources, the second activity from the MOv sources showed prolonged activity (>30 ms), which was consistent with a later long-lasting activity, rather than "early" activity. Therefore it seems possible that the later part of the MOv source contains activity from a source other than V2, such as ventral V3.
In primates, numerous inactivation or lesion studies have unambiguously demonstrated that visual responses in V2 are relayed from that in V1 (for review, see Salin and Bullier 1995). Based on these observations and dense connections between V1 and V2, the time delay of 4–5 ms relative to the V1 activity in the present study appears to indicate that MO sources were driven directly by the V1 source.
Dorsomedial visual area (dm).
We found one more source activity with a similar onset latency to the MO sources in the dorsomedial part of the occipital lobe. We considered that this source probably corresponded to the dorsomedial visual area (DM) or V6 in monkeys. DM is a subdivision of the monkey extrastriate cortex, located rostral to V2 near the dorsal midline, first reported for owl monkeys (Allman and Kaas 1975), and the existence of its homologue has been confirmed in other New World monkeys (Krubitzer and Kaas 1993; Rosa et al. 2005; Weller et al. 1991), prosimian primates (Beck and Kaas 1998; Rosa et al. 1997), and macaques (Beck and Kaas 1999; Galletti et al. 1999; Krubitzer and Kaas 1993; Stepniewska and Kaas 1996). Anatomical and electrophysiological studies in primates (Rosa et al. 2005) demonstrated that DM receives strong, topographically organized projections from V1. These studies have established DM as one of three main target areas of projections from the striate cortex (V2, MT, and DM; Krubitzer and Kaas 1993).
In an MEG study, Vanni et al. (2001) found almost simultaneous activations in DM and V1 at around 55–77 ms after visual stimuli, which is consistent with the present results. In addition, coordinates for the DM source in their study were very similar to ours. In the present study, the onset latencies of DM and the four MO sources did not differ, but were significantly longer than the onset latency of V1, indicating that all of these five sources depended for their activity on the V1 source. Therefore our results suggested the existence of two distinct parallel pathways, V1–V2 and V1–DM. In a single-unit recording study in owl monkeys, Petersen et al. (1988) measured the response latency of neurons in this area and suggested that its activity depends on a feedforward projection from V1. Anatomical findings in monkeys (Beck and Kaas 1999; Krubitzer and Kaas 1993; Wagor et al. 1975)—that DM is interconnected strongly with V1, V2, MT, and the posterior parietal cortex—are consistent with the view that DM is in a node in the dorsal stream of visual areas, which is involved in the spatial or motion processing of visual stimuli (Ungerleider and Mishkin 1982).
MIDDLE TEMPORAL AREA (HMT).
The MT is a small visual area that exists in the temporal lobe of all primates, including humans, containing neurons that are activated by moving stimuli. This region was labeled the homologue of monkey MT/V5 (Zeki et al. 1991) and is referred to as hMT. The Talairach coordinates of the hMT source in this study (lat 46, post 70, sup 8) are in good agreement with those reported in previous studies as a motion-selective area (Zeki et al. 1991: 38, 74, 8; Watson et al. 1993: 41, 69, 2; Tootell et al. 1995: 45, 76, 3; Sunaert et al. 1999: 45, 66, 3). Although MT is known to be involved in motion perception, this region also contains neurons that are activated by flash stimuli in monkeys (Schroeder et al. 1998).
A previous VEP study (Buchner et al. 1997) demonstrated a component originating from the vicinity of V5 with a peak at around 45 ms, which is consistent with our results that the hMT source activity peaked at 44.8 ms. The possible contribution of V5 to an early period of VEPs (40–75 ms) was also reported by Morand et al. (2000). The onset latency of hMT was significantly longer than that for DM and MO and, in turn, the onset latencies for DM and MO were significantly longer than that for V1. Therefore we considered that hMT was the third stage of hierarchical processing, although MT receives direct projections from the lateral geniculate nucleus (Sincich et al. 2004) and V1 (Maunsell and Van Essen 1983; Zeki 1969) in monkeys. The latency difference of 9.9 ms between V1 and hMT seems too long for a serial activation between them, compared with the 4- to 6-ms time delay between V1 and MO or DM. In a single-unit recording study in macaques by Movshon and Newsome (1996), the response latency of V1 neurons antidromically activated by stimulation in MT was 1.0–1.7 ms. As possible areas responsible for the hMT activity in this study, V2 (Anderson and Martin 2002; Maunsell and Van Essen 1983; Ungerleider and Desimone 1986) and DM (Galletti et al. 2001; Wagor et al. 1975) have been shown to send projections to MT in monkeys.
A CSD study of macaques using flash stimuli (Schroeder et al. 1998) found shorter average latencies for MT than for V1, which conflicts with the present results. Their results, as well as those by Raiguel et al. (1989), suggest the possibility that MT can be driven without a relay in V1. However, Schroeder et al. (1998) also found that the latencies in the peripheral retinal representation of V1 are the shortest subset of V1 latencies and are shorter than those in MT. When the shortest latency of V1 is compared with the latency of MT (see Fig. 13 in Schroeder et al. 1998), V1 is shorter than MT by about 6–9 ms, which is consistent with the present results. Because there are several lines of evidence both in monkeys and humans that motion-selective MT neurons can be activated without a relay in V1 (Barbur et al. 1993; Girard et al. 1992; Rodman et al. 1989; Sincich et al. 2004), the hMT source in the present study might represent activities of neurons that are different from neurons that are activated selectively by moving stimuli.
VENTRAL SURFACE OF THE OCCIPITAL LOBE (VO).
The last source was estimated to be located bilaterally on the ventral surface of the occipital lobe in the lingual region or in some subjects more anterolaterally in the posterior part of the fusiform gyrus, a region corresponding to the human fourth visual area (hV4; Gallant et al. 2000), which appears homologous to V4v in macaque monkeys (DeYoe et al. 1996; Sereno et al. 1995). The onset latency of the VO source was longer than that for V1 by 19.5 ms for the left source and by 17.3 ms for the right source. When compared with the MO sources, the VO source had a latency that was about 15 ms longer. Both the late onset latency and the long-lasting time course of the VO source activity were consistent with the notion that VO is at a higher level than V1 and V2. Our previous studies showed that a "late" activity that follows several "early" activities with a characteristic triphasic time course shows a long-lasting time course like that of the VO source.
In CSD studies in awake macaques (Givre et al. 1994; Schroeder et al. 1998), the time lag between activation in V1 and V4 was <10 ms and, in addition, the mean onset latency of the supragranular layers of V1 was longer than the onset latency of V4. These data conflict with the present findings. However, first, V4 receives inputs from thin and pale cytochrome oxidase stripes in V2 (DeYoe and Van Essen 1985) and, in turn, both thin and pale stripes in V2 receive inputs from the V1 layer 4B (Sincich and Horton 2002). Neurons in layer 4B display latencies that are clearly shorter that those in the supragranular layers (Nowak et al. 1995). Thus the longer activation latency observed in supragranular V1 is not incompatible with a V1 relay to V4. Second, when the V4 latency is compared with that of the earliest V1 activity from areas representing the peripheral visual space in the study by Schroeder et al. (1998), the time lag is longer than 10 ms, which is not inconsistent with the present results.
Timing of signal transfer between cortical areas
Consistent with the previous results on somatosensory and auditory processing, the time lag between two successive activations in the present study was 4–6 ms. The difference in latency between the two cortical areas is determined by several factors, including the interarea axonal conduction time, intraarea conduction time, and neuronal integration time (for review, see Nowak and Bullier 1997). Given the anatomical evidence that the feedforward corticocortical connections originate from neurons in layer 3 and terminate in layer 4 (Felleman and Van Essen 1991; Rockland and Pandya 1979), and that excitatory neurons in layer 4 that receive feedforward connections project axons most densely to more superficial layers (Rockland 1992a; Yabuta and Callaway 1998), at least two synaptic delays are required for signals to pass from a cortical area to the next step (layer 4—superficial layers—recipient's layer 4) (for review, see Callaway 1998). As for the intraareal conduction delay, Komatsu et al. (1988) measured it using the spike-triggering average in slice preparations of area 17 of the cat visual cortex and showed that the lag between the spike of the source cell in layer 3/4 and the excitatory postsynaptic potentials (EPSPs) of the target cell in the supragranular layer was 0.7 ms (distance 0.23 mm). Using a similar method in anesthetized cats, Toyama et al. (1981) demonstrated a delay of 0.6–0.9 ms to travel from layer 3/4 to layer 2/3. A similar value (0.62 ms) was reported by Michalski et al. (1983) in cat striate cells. The axonal conduction time between areas was measured by antidromic activation of single cells. Recordings of antidromically activated neurons in cat area 17 by stimulation of areas 18 and 19 showed that there are some rapid conducting (delay <1.5 ms) axons in feedforward corticocortical connections (Bullier et al. 1988; Toyama et al. 1974). Therefore the time delay between two cortical areas in cats is assumed to be around 2 ms. In macaques, the axonal conduction time between V1 and V2 was 1.1 ms (Girard et al. 2001). These values seem compatible with our results, given a similar synaptic delay between animals and humans and a longer conduction distance for humans.
The notion that the transfer of signals from a cortical area to the next step involves the intraarea conduction and interarea conduction, however, is challenged by findings in the single axon analysis of visual cortical connections (Rockland 1992b; Rockland and Virga 1990). These studies demonstrated that feedforward inputs do not terminate exclusively in layer 4, but also in lower layer 3, and that the dendrites of lower layer 3 neurons that are involved in feedforward corticocortical connections, often extend into layer 4. Such findings suggest the possibility that the intraarea relay of information is not required for the corticocortical transfer of visual information. Although the functional significance of such connections is not clear, the 4- to 5-ms latency delay in our studies might result from such direct connections between areas.
Laminar processing of the biphasic activity
The "early" cortical activity evoked by somatosensory (Inui et al. 2004), auditory (Inui et al. 2006a), noxious (Inui et al. 2003b), and visual (this study) stimuli reverses its polarity after a 10-ms interval once or, in some subjects, twice, resulting in a biphasic or triphasic profile (Fig. 5). This phenomenon suggests that there are at least two different combinations of a current sink and current source in a cortical area. Based on the anatomical schema of the feedforward projection, the first component of the "early" activity in our studies appears to originate from layer 4. In support of this, CSD studies have consistently shown a characteristic laminar activation sequence of the feedforward pathway with an initial excitation in the granular layer and a later excitation in extragranular layers, for somatosensory (Kulics and Cauller 1986; Peterson et al. 1995; Schroeder et al. 1995), auditory (Muller-Preuss and Mitzdorf 1984; Schroeder et al. 2001; Steinschneider et al. 1992), and visual (Givre et al. 1994; Schroeder et al. 1991, 1998) processing. In general, these studies reported a lag of about 10 ms between responses in the granular and superficial layers, which appear to correspond to the first and second peaks of the biphasic structure of our "early" cortical activity. An alternative explanation for the triphasic waveform of the source activity in the visual system is that different components could correspond to the asynchronous arrival of magnocellular and parvocellular inputs. Previous electroencephalographic studies have shown that M and P systems contribute differently to shape the VEP components (Klistorner et al. 1997). However, similar activation profiles among different sensory modalities, both in MEG and CSD studies, suggest that a single source of inputs can evoke the complicated activation pattern.
Like "late" activities in the secondary somatosensory cortex (tactile and pain), limbic structures (pain), and planum temporale (auditory) in our previous studies, the activity in VO lasted a long time without the 10-ms reversal of polarity. This finding suggests that the later activity that appears after several "early" activities has a laminar profile different from that of the "early" activity, which may be common among different sensory modalities. Interestingly, CSD studies in macaques demonstrated that laminar activation profiles from V1, V2, and MT showed the excitatory feedforward activation pattern, whereas those in V4 and inferotemporal cortex were quite different (Givre et al. 1994; Schroeder et al. 1998). That is, the initial response often consists of inhibition rather than excitation, lacks a clear lamina 4 focus, and begins simultaneously in multiple laminae. Therefore further CSD studies that cover higher cortical areas in the somatosensory and auditory systems may reveal a common laminar activation pattern corresponding to the long-lasting "late" activity in our study. Our MEG and these CSD results imply that long-latency higher cortical areas, such as V4, depend for their activity on the feedback or lateral connections, rather than feedforward connections (for review, see Lamme and Roelfsema 2000). Like "late" activities in other sensory modalities, the latency difference between the V4 and other sources was far longer than 4–5 ms, implying that the 4- to 5-ms time delay cannot be applied to the "late" activity. Such differences may represent different connection patterns between "early" and "late" activities (feedforward and feedback). In a CSD study of human MT, laminar activation profiles were clearly different between the early (phasic) and late (sustained) responses (Ulbert et al. 2001b).
The present results are apparently limited to correlate an MEG component with a specific laminar activation pattern. Fortunately, the CSD method has been established in humans (Ulbert et al. 2001a). Future studies using this technique will reveal the precise laminar activation mechanisms of sensory processing in humans.
In conclusion, the present and previous MEG studies have confirmed that the anatomical schema of hierarchical processing of sensory information based on animal studies can generally be applied to human sensory processing. In addition, our results showed common activation patterns among various sensory modalities, which is consistent with data obtained from CSD studies in awake monkeys. The results also suggest that later cortical activities differ from "early" activities in their mechanism of activation as well as in function. The different activation profiles of the "early" and "late" activities may correspond to the feedforward–feedback dichotomy of sensory processing (Lamme and Roelfsema 2000).
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Inui, Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan (E-mail: inui{at}nips.ac.jp)
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REFERENCES |
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