1 Department of Physiology and , 2 Department of Neurosurgery, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Tokyo 113-8519, , 3 Hayashibara Biochemical Laboratories Inc., Okayama 701-0221 and , 4 JAIC College of Medical-Care and Welfare Technology, Fukushima 963-8834, Japan
Katsushige Sato, Department of Physiology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Email: katsushige.phy2{at}tmd.ac.jp.
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Abstract |
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Introduction |
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Recent advances in functional neuroimaging techniques, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS), have made it possible to obtain functional images of neuronal activity from the human brain. These techniques have demonstrated several activation sites in the primary somatosensory cortex induced by peripheral stimulation (Lin et al., 1996; Burton et al., 1997
; Gelnar et al., 1998
; Kurth et al., 1998
, 2000
; Hlustík et al., 2001
; Ruben et al., 2001
). However, the spatial and temporal resolutions of these techniques are not sufficient to detect neuronal activity from each Brodmann's area in the somatosensory cortex.
An optical imaging technique for intrinsic signals has been developed and used to monitor neuronal activity in the cerebral cortex of in vivo preparations (Grinvald et al., 1986; Chapman et al., 1996
; Gödecke and Bonhoeffer, 1996
). The optical method has proven to be a very useful technique for monitoring neural responses in the central nervous system, and offers advantages for studying functional organization in the cat or monkey visual cortex (Ts'o et al., 1990
; Bonhoeffer and Grinvald, 1991
; Shumuel and Grinvald, 1996
) and the rodent somatosensory (whisker barrel) cortex (Masino et al., 1993
; Dowling et al., 1996
; Tanaka et al., 2000
; Yazawa et al., 2001
). In intrinsic optical signals, it is indicated that there are at least three components (Bonhoeffer and Grinvald, 1995
; Frostig et al., 1990
; Malonek and Grinvald, 1996
). The first component originates from activity-dependent changes in the oxygen saturation level of hemoglobin. The second component originates from changes in blood volume that are probably due to dilation of venules in an area containing electrically active neurons. The third component arises from light-scattering changes that accompany cortical activation caused by ion and water movement, expansion and contraction of extracellular spaces, capillary expansion or neurotransmitter release (Cohen, 1973
; Salzberg et al., 1985
; Sato et al., 1997
; Momose-Sato et al., 1998
).
The intrinsic optical imaging technique was also applied to the human brain during neurosurgery. Haglund et al. (Haglund et al., 1992) first demonstrated the usefulness of this technique for functional localization in the human brain. They obtained maps during stimulation-evoked epileptiform afterdischarges and cognitively evoked functional activity. Functional images induced by language tasks were also shown by Cannestra et al. (Cannestra et al., 2000
) and Pouratian et al. (Pouratian et al., 2000
); they detected neuronal responses from the Broca's and Wernicke's areas in awake patients.
There are a few reports of intrinsic optical imaging from the human somatosensory cortex in response to median/ulnar nerve stimulation (Toga et al., 1995) or digit stimulation (Shoham and Grinvald, 1994
; Cannestra et al, 1998
). Although these reports showed neural responses in the primary somatosensory cortex, they did not separate optical responses among the Brodmann's subdivisions. In the present study, we applied this intrinsic optical imaging technique to brain tumor patients during neurosurgery, and succeeded in clearly detecting neural responses induced by peripheral stimulation in Brodmann's subdivisions individually. Furthermore, we made functional local maps in the primary somatosensory cortex, and produced supportive data for hierarchical organization in the human brain. The preliminary results have appeared in abstract form (Nariai et al., 2000
; Sato and Nariai, 2000
).
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Materials and Methods |
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We measured intrinsic optical signals from the somatosensory cortex in 11 anesthetized patients undergoing surgical resection of parietal or temporal lobe brain tumors. The patient data are summarized in Table 1. Except for case 4, patients had no past history of neurosurgery. Informed consent was obtained from all patients prior to the surgery and intraoperative intrinsic optical imaging. We also obtained approval from Tokyo Medical and Dental University. The patients were anesthetized with isoflurane, and the head was fixed to the operating table via a Mayfield apparatus. Craniotomy and dura reflection were performed, and the surface of the cerebral cortex around each brain tumor was exposed.
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Peripheral Nerve Stimulation
For the optical imaging, the median nerve (for five patients), digit I and V (for five patients) or the supraorbital branch of the ophthalmic nerve (N V1) and the mental branch of the mandibular nerve (N V3) (for two patients) were stimulated transcutaneously with surface electrodes driven by an electrical stimulator. The stimuli, consisting of 10 pulses, were delivered at 5 Hz for 2 s with an interstimulus interval of 20 s. The stimulation intensity was 10 mA, which produced the maximal SEP responses in the somatosensory cortex (Y. Ohta and T. Nariai, unpublished results). Bonhoeffer and Grinvald (Bonhoeffer and Grinvald, 1993) reported that stimulation for >2 s caused large blood vessel artifacts in the optical maps, presumably due to larger contributions of activity-dependent changes in blood volume and blood flow. In the present study, we could not test multiple stimulation paradigms for the optical imaging because of the limited recording time available during neurosurgery, and used a single stimulation paradigm as described above.
Intraoperative Intrinsic Optical Imaging
After identifying the central sulcus, the recording site of the cerebral cortex was stabilized with a glass plate. This procedure minimized brain movements in the z-axis, as well as in the x- and y-planes. No significant brain damage was induced by this procedure, although the possibility that the plate could affect the local brain environment cannot be excluded. The somatosensory cortex was illuminated using a xenon lamp driven by a stable DC power supply via an operating microscope (Carl Zeiss, Inc., Thornwood, NY). The depth of focus of the operating microscope was set to ~500 µm under the cortical surface. Reflected light from the cortex was passed through interference filters of different wavelengths. The filter used for visualizing the surface of the cortex and its vascular pattern had a transmission maximum at 540 ± 30 nm, and the filter used for intrinsic imaging had a passband at 605 ± 5 nm (Asahi Spectra Co., Tokyo, Japan). We used 605 nm for two reasons. First, this wavelength coincides with the peak of the different spectra between the oxyhemoglobin and deoxyhemoglobin, and maximizes the contribution of oximetry signals relative to other intrinsic signals (Frostig et al., 1990; Bonhoeffer and Grinvald, 1993
). Second, in our previous studies on the rat somatosensory cortex (Tanaka et al., 2000
; Yazawa et al., 2001
), brainstem (Yazawa et al., 1999
) and spinal cord (Sasaki et al., 2000
), we detected the largest intrinsic signal at a wavelength of 605 nm. In the present study, we could not examine the wavelength dependency of the optical signals because of the limited recording time (~30 min).
Intrinsic imaging was performed using a differential video acquisition system, IMAGER 2001 (Optical Imaging, Germantown, NY) via a charge-coupled device camera fitted to an operating microscope. Two or three recording sessions were allowed for each patient. One recording session consisted of eight blocks. Each block consisted of six or three stimulation trials and three non-stimulation (control) trials interlaced randomly, with an intertrial interval of 20 s. During each trial, eight optical images were collected over 5.0 s and stored on a computer with VDAQ data acquisition software (Optical Imaging). For stimulation trials, the median nerve, digit I and V, or the supraorbital and mental nerves, were stimulated for 2 s from the onset of data acquisition (also see Fig. 1B). Optical reflectance images were represented by a fractional change (
R/R) to correct for uneven illumination using a data-analyzing software program, TVMix (Optical Imaging). It usually took ~15 min to obtain a functional map.
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Preoperative Magnetoencephalography (MEG) Recording
We recorded somatosensory evoked fields (SEFs) in seven patients before surgical operations using a whole-head type MEG system with 148 channel magnetometers (Magnes, Biomagnetic Technologies, San Diego, CA). We clearly detected the SEFs in six of seven patients. For four patients (cases 2, 4, 5 and 11 in Table 1), MEG was not performed because of their poor condition. Following the recording, the source current locations in three dimensions of SEFs and the equivalent current dipole (ECD) moments were calculated using a single-dipole model, assuming the brain to be a sphere. The ECDs that best explained the most dominant source were determined using data recorded from a subset of channels, and the ECDs were superimposed on a three-dimensionally reconstructed magnetic resonance (MR) image of the brain.
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Results |
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Nature of the Optical Signals in Response to Median Nerve Stimulation
Figure 1A shows a typical example of intrinsic optical images obtained from a 61 year old patient who suffered from anaplastic oligodendroglioma (case 3 in Table 1
). The left median nerve was stimulated by surface electrodes, and intrinsic optical signals (optical reflectance changes) were detected from the right parietal lobe. Before making the intrinsic optical recording, we recorded cortical SEPs in response to left median nerve stimulation to identify the central sulcus (indicated by the white line in the right panel of Fig. 1A
). The recording site is shown with black squares in a three-dimensionally reconstructed MR image and a photograph of the cortical surface (left panels of Fig.1A
). The detected reflectance signals were illustrated by a pseudo-color image, in which a decrease in light reflectance was shown in green to red (right panel of Fig. 1A
). In this image, the optical response induced by median nerve stimulation was clearly identified near the central sulcus. To check whether the optical response was definitely detected from a median nerve-related region in the somatosensory cortex, we examined the location of an equivalent current dipole (ECD) measured with MEG, which is illustrated with a green solid circle in the upper left panel in Figure 1A
. The optical response area and the ECD were located in nearly the same region of the somatosensory cortex, supporting the idea that the optical responses reflect neuronal activity evoked by median nerve stimulation (also see Discussion).
Figure 1B shows the time course of the intrinsic optical signal obtained in the response area. In this figure, a decrease in light reflectance is plotted against the recording time. The intrinsic optical signal exhibited biphasic features, and showed its maximum amplitude in the third frame (1.4 s from the onset of stimulation): no significant optical change was detected without stimulation. This time course is consistent with that reported previously using a wavelength of 605 nm (Bonhoeffer and Grinvald, 1993
; Tanaka et al., 2000
). Similar intrinsic signals with a similar time course were obtained from three other patients (cases 1, 2 and 10 in Table 1
) whose median nerves were stimulated electrically (data not shown).
Optical Responses to Digit I and V Stimulation
Figure 2A shows intrinsic optical images obtained from a 63 year old patient who suffered from a metastatic brain tumor (case 8 in Table 1
). Right digits I and V were stimulated individually by surface electrodes, and intrinsic optical signals were detected from the left somatosensory cortex. The detected area is illustrated with a black square in the right panel, which corresponded to the postcentral gyrus (primary somatosensory cortex, SI). The optical responses induced by digit I and V stimulation were clearly detected from different areas of the primary somatosensory cortex. Figure 2B
shows the optical response areas identified with three repetitive trials. In this figure, we traced the optical response area of each trial at half the normalized difference of the signal (see Materials and Methods), and three traces from three trials are superimposed for each stimulation. The response area appeared in almost the same region, and trial-to-trial variations were not significant. In Figure 2C
, ECDs are superimposed on a three-dimensional MR image. The red closed circle is the ECD to digit I stimulation, and the green closed circle is the ECD to digit V stimulation. As is the case in median nerve stimulation, the relative positions of the optical response areas and ECDs were coincident, suggesting that the optical responses induced by digit I and V stimulation clearly reflected neuronal activity in the primary somatosensory cortex.
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Optical Responses to N V1 and N V3 Stimulation
In other regions of the primary somatosensory cortex, can we find the same functional organization? To answer this question, we applied an optical technique to the face region in the somatosensory cortex. Figure 7A illustrates intrinsic optical images obtained with supraorbital (N V1) and mental (N V3) nerve stimulation in a patient who suffered from an astrocytoma (case 7 in Table 1
). Both supraorbital and mental nerve stimulation induced optical responses in two separate areas, areas O1 and O2, and areas M1 and M2 respectively. We traced the area of the optical responses induced by the supraorbital and mental nerve stimulation at half the normalized difference. Each trace was superimposed on the vascular image of the somatosensory cortex (Fig. 7B
). The recording site is shown with a black square on a three-dimensionally reconstructed MR image in Figure 7C
. As in the case with digit I and V stimulation, supraorbital and mental nerve stimulation induced neural responses in different regions near the central sulcus (areas O1 and M1), and in the same region near the postcentral sulcus (areas O2 and M2). This result shows that, in the face region, the functional organization is the same as in the digit region.
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Discussion |
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Optical Mapping of the Human Primary Somatosensory Cortex
Intrinsic optical imaging of neuronal activity is an excellent technique to obtain functional maps of the central nervous system, and it has recently been applied to several sensory systems (Bonhoeffer and Grinvald, 1995). In the present study, we applied this technique to the human primary somatosensory cortex, and clearly detected neural responses induced by median nerve, digit I and V, and N V1 and N V3 stimulation. Although an fMRI study has shown that the primary motor cortex is systematically coactivated by tactile and proprioceptive tasks (Kurth et al., 2000
), we did not obtain intrinsic optical signals from the motor cortex. This discrepancy may be due to a difference in the stimulation paradigms. Indeed, an electrophysiological study showed that peripheral electrical stimulation preferentially activates the primary somatosensory cortex (Buchner et al., 1994
).
In the present experiment, as a first step, we tried to detect optical signals induced by median nerve stimulation in the primary somatosensory cortex. As shown in Figure 1, median nerve stimulation induced optical changes near the central sulcus, and this response area was located in a median nerve-related region measured with preoperative MEG. Generally, intrinsic optical imaging has the advantage of detecting neuronal activity from the cortical surface, whereas MEG has the advantage of detecting neuronal activity from the cortex perpendicular to the brain surface. Considering the anatomical structure of the somatosensory cortex (Brodmann, 1909
; Vogt and Vogt, 1919
; White et al., 1997
), it is reasonable to assume that the response area detected by optical imaging corresponds to Brodmann's area 1, while that detected by MEG corresponds to Brodmann's area 3b. Brodmann's areas 3b and 1 are closely situated and organized as approximate mirror images of each other (Kaas et al., 1979
; Nelson et al., 1980
; Sur et al., 1982
; Felleman et al., 1983
). Therefore, the fact that the optical signals and MEG signals were detected from nearly the same region of the somatosensory cortex suggests that the intrinsic optical responses in the present study certainly reflect neuronal activity induced by peripheral stimulation.
As shown in Figure 1B, the induced intrinsic optical signal showed a biphasic time course, which is similar to that described in experimental animals using a wavelength of 605 nm (Bonhoeffer and Grinvald, 1993
; Tanaka et al., 2000
). This result also supports the idea that the optical responses reflect neuronal activity evoked in the somatosensory cortex. In previous reports (Haglund et al., 1992
; Toga et al., 1996), optical signals with large amplitudes and a monophasic time course were demonstrated. Similar monophasic optical signals were also recorded in our experiments. As Bonhoeffer and Grinvald (Bonhoeffer and Grinvald, 1995
) pointed out, it is possible that such signals are contaminated by noise from the microvascular system. Thus, we did not analyze these signals in the present study.
As a second step, we tried to record neuronal activity separately from Brodmann's subdivisions. As shown in Figures 5 and 7, we detected optical signals from two separated areas on the crown of the postcentral gyrus with digit I and V or N V1 and N V3 stimulation. Although the human primary somatosensory cortex has been divided microstructually into four areas, namely Brodmann's area 3a, 3b, 1 and 2 (Brodmann, 1909
; Vogt and Vogt, 1919
; White et al., 1997
), the borders of these areas vary between researchers. We considered two possible interpretations concerning the origin of the optical signals.
The first interpretation is that the response area near the central sulcus corresponds to Brodmann's area 1, and that near the postcentral sulcus corresponds to Brodmann's area 2. This interpretation is based on the traditional context of the division of the somatosensory cortex (Brodmann, 1909; Vogt and Vogt, 1919
; White et al., 1997
). The second interpretation is that both the optical response areas correspond to Brodmann's area 1. This interpretation is based on a recent observation by Geyer et al. (Geyer et al., 1999
, 2000
), who identified cytoarchitectonic borders of Brodmann's subdivisions with a new observer-independent and statistically testable procedure. In their map, Brodmann's area 1 occupies the crown of the postcentral gyrus and reaches down into the postcentral sulcus.
In the human brain, Brodmann's subdivisions are considered to constitute hierarchical stages of cortical processing (Eskenasy and Clarke, 2000). In physiological and anatomical studies of non-human primates, it has also been demonstrated that there is a complete topographic representation of the body in each of the four Brodmann's areas and that these areas exhibit a hierarchy in sensory information processing (Merzenich et al., 1978
; Kaas et al., 1979
; Nelson et al., 1980
; Sur et al., 1982
; Garraghty et al., 1990
) [for a review see Kaas (Kaas, 1983
)]. In electrophysiological studies of the monkey somatosensory cortex, cutaneous thalamic inputs are relayed in parallel to Brodmann's areas 3b and 1, while kinetic information is relayed to Brodmann's areas 3a and 2 [reviewed by Gardner (Gardner, 1988
) and Jones (Jones, 1986
)]. Somatosensory inputs to the cortex originate from the ventral posterior lateral nucleus of the thalamus. Neurons in this nucleus project to all areas in the primary somatosensory cortex (SI), mainly to Brodmann's areas 3a and 3b, and also to areas 1 and 2. Neurons in areas 3a and 3b project to areas 1 and 2, while all of them project to the secondary somatosensory cortex (SII) and posterior parietal cortex. In the present study, digit I and V stimulation, or supraorbital and mental nerve stimulation, induced neural responses in different regions near the central sulcus, and also induced neural responses in the same region near the postcentral sulcus. If the first interpretation of the signal origin is the case (see above), our results suggest that neurons in Brodmann's area 2 are activated by larger peripheral inputs than those in Brodmann's area 1. Similar observations have been reported in the monkey somatosensory cortex (Gardner, 1988
; Iwamura et al., 1985a
,b
; Pons et al., 1985
). On the other hand, if the second possibility is the case, our data show that there are further functional subdivisions within Brodmann's area 1.
As shown in Figure 4, the optical responses detected near the central sulcus appeared to be evoked earlier than those detected near the postcentral sulcus. This result may reflect the hierarchical organization in the human brain, although we have not obtained direct evidence for neuronal connections from the former to the latter.
In the present study, we could not quantitatively compare the detected areas between subjects for the following reasons: (i) all subjects in the present study had brain tumors and their brains were more or less transformed; (ii) the anesthetic state was not completely the same between the subjects; and (iii) parts of the response area were located outside the detected field (e.g. cases 9 and 11 in Fig. 6). In future studies, more detailed maps of the somatosensory cortex should be obtained.
Usefulness of Intraoperative Intrinsic Optical Imaging for Neurosurgery
During neurosurgery on brain tumors, it is very important to make functional local maps of the human cortex to decide the resection area. It is self-evident that the smaller the resection area is, the better the patient's quality of life will be after the operation. Recent advances in imaging techniques, such as computerized tomography (CT) and MRI, have made it possible to detect the whole shape of the brain tumor. We can also obtain functional images using PET, fMRI and MEG prior to a neurosurgical operation. Although the resection line is usually decided with these neuroimaging examinations, we cannot neglect the possibility that the resection causes neural function deficits in patients, since the spatial resolution of these techniques is limited.
In the present study, we performed intrinsic optical imaging in brain tumor patients and could detect clear functional images in response to peripheral stimulation. The feasibility of this technique for human brain mapping has been pointed out in previous studies (Haglund et al., 1992; Shoham and Grinvald, 1994
; Cannestra et al., 1998
, 2000
; Pouratian et al., 2000
). We discussed advantages of the optical technique (Bonhoeffer and Grinvald, 1995
), and these were confirmed in the present study.
First, intraoperative intrinsic optical imaging is a highly effective imaging technique to monitor neuronal activity during neurosurgery. In the present study, we obtained clear optical images from 10 of 11 patients. The only unsuccessful case (case 4 in Table 1) was a re-operation case, and the brain was severely conglutinated.
Second, the spatial resolution is higher than with conventional brain-imaging techniques. We obtained topological information on sensory representations in the digit and face regions of Brodmann's subdivisions. The results demonstrated that the spatial resolution of the intraoperative optical imaging technique is good enough to distinguish neuronal responses in these areas. Brodmann's subdivisions are located in the same gyrus (postcentral gyrus), and it is difficult to obtain each functional image with other imaging techniques, such as MEG, cortical SEPs, PET or fMRI.
Third, we obtained topological information on sensory representation in a patient whose cortex was severely transformed (Fig. 6B, case 9). Brain tumors often transform the cerebral cortex. In such patients, the pattern of sensory representation is different from that in normal people, and it is much more difficult to decide the brain tumor resection line during the operation.
Finally, the optical imaging apparatus is small enough to set up easily in the operating room. It is difficult to use conventional imaging techniques during surgery, and we believe that, in the near future, intrinsic optical imaging will become a routine examination during neurosurgical operations.
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Notes |
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References |
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