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1Department of Physiology and Biophysics, Georgetown University, Washington DC, 20057-1421; and 2Department of Physiology and Biophysics, College of Life Science, Peking University, Beijing, 100871, Peoples Republic of China
Submitted 2 March 2003; accepted in final form 3 October 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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; Traub et al. 1994), suggesting that intrinsic characteristics of the cortex contribute to the initiation of epileptiform activity. The interictal spike (IS) is the simplest identifiable unit of epileptiform activity in the CNS (McCormick and Contreras 2001). In several human epileptic conditions, the spontaneous IS (sIS) represents the electrographic hallmark of an active epileptic focus (Ajmone 1978; Jefferys 1990). Focal application of convulsants onto cortex in vivo can induce sISs (Federico et al. 1994; Lebovitz 1975; Schwartz and Bonhoeffer 2001), suggesting that the generation of a sIS is a local event. In vitro experiments have demonstrated that a small piece of neocortical tissue perfused with a convulsant is enough to generate sISs and organized seizure-like activities (Anderson et al. 1986; Flint and Connors 1996; Silva et al. 1991; Wong and Prince 1990). Voltage-sensitive dye and optical imaging have further shown that the initiation site for a sIS can be smaller than 0.4 x 0.4 x 0.4 mm3 in neocortical slices (Tsau et al. 1998, 1999), suggesting that generating a sIS only requires a small group of neurons. A rat neocortical slice is about 4 x 2 x 0.4 mm3 and this volume may contain tissue for approximately 50 potential initiation sites. In a slice of this size, the sISs are not generated randomly from all potential initiation sites. Instead, the majority of sISs are generated from only a few initiation sites, and one or two initiation sites may become dominant for a period of time (Tsau et al. 1998). An intact cortex in vivo may contain more potential initiation sites than a slice in vitro. It is not known, however, whether sISs are also initiated from dominant sites in vivo. In this report, we use voltage-sensitive dye (VSD) imaging to map the sIS initiation sites in vivo, in a cortical region disinhibited by bicuculline or picrotoxin. This region (5 mm diam) has the potential to host many initiation sites.
Optical imaging with VSD offers both high spatial and temporal resolutions. The VSD signal is fast enough to follow neuronal action potentials and is linearly related to the transmembrane potential (Ross et al. 1977). When imaging cortical tissue, each optical detector receives light from thousands of neurons and the VSD signal is the linear summation of the membrane potentials of these neurons (Cohen and Salzburg 1978). Volume conductance effect in the tissue does not influence this signal, so the method can be used to pinpoint the small neuronal cluster that initiates a sIS. Other methods are limited for our purpose. The spatial resolution of a field potential electrode array is limited by the volume conductance effect (Buzsáki and Traub 1997). Extracellular single-unit electrodes have good spatial and temporal resolution (Goldensohn and Salaza 1986), but it is difficult to place multiple electrodes in a small area to locate the sIS initiation site. Since the initiation of a sIS occurs within a few milliseconds (Demir et al. 1999; Tsau et al. 1998), functional MRI (fMRI), PET, single-photon emission computed tomography (SPECT), and optical imaging of intrinsic signals do not have adequate temporal resolution (Bonhoeffer and Grinvald 1996; Duncan 1997).
In vivo VSD imaging is still a difficult technique because heartbeat and blood perfusion introduce large artifacts. In this report we used a popular dye, RH-795 (Grinvald et al. 1994); the pulsation artifacts are about the same size as the sIS signal (however, new dyes may improve the signal-to-noise ratio (Shoham et al. 1999). We used ECG-triggered subtraction to eliminate the pulsation artifact. The VSD signal of sISs was large, allowing us to separate the artifact and to locate the initiation sites without averaging.
While this paper was in preparation, Miyakawa and colleagues published a study using VSD imaging to examine the distribution of sIS initiation sites (Miyakawa et al. 2003). They have shown that the initiation sites of sISs were "neither unique nor randomly" distributed in the cortex. Here we report two observations on the distribution of the initiation sites: the suppression annulus surrounding each initiation site and the clustering of initiation sites related to the activity history. Our results suggest that the distribution of initiation sites may have unique spatiotemporal characteristics.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Adult male Sprague–Dawley rats (250–350g) were used in all the experiments. All surgical procedures were approved by the Georgetown University Animal Care and Use Committee following National Institutes of Health guidelines. The animals were initially anesthetized to surgical level with ip injections of urethane (1.25 g/kg). Additional doses (10% of initial dose) were applied by ip injection to maintain the anesthetic level when necessary. A regulated heating pad was used to maintain the body temperature at 38°C. The head was fixed in a stereotaxic frame. A craniotomy window of approximately 7 mm diam was opened over the right hemisphere. The location of the craniotomy window is shown in Fig. 1A. A well was built around the craniotomy window with dental acrylic. Dura over the window was removed and the brain was covered with artificial cerebral spinal fluid (ACSF). The ACSF contained (in mM) 132 NaCl, 3 KCl, 2 CaCl2, 2 MgSO4, 1.25 NaH2PO4, 26 NaHCO3 and 10 dextrose, bubbled with 95% O2–5% CO2 to maintain the pH at 7.4 before application to the cortex. The dye, RH-795 solution (Molecular Probes, 0.6 mg/ml in ACSF), was applied to the exposed cortex for approximately 45 min (London et al. 1989). After staining, the cortex was washed with dye-free ACSF for approximately 15 min.
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A region of cortex (5 mm diam) was imaged by a x4 macroscope onto a 464-photodiode array (WuTech Instruments, www.wutech.com, available as NeuroPlex by RedshirtImaging, www.redshirtimaging.com) (Fig. 1B). Each diode received signals from an area of 200 µm diam (Fig. 1C). A tungsten filament lamp (12 V, 100 W, Zeiss) was used for illumination. The light passed through a 530 ± 30 nm interference filter (Chroma Technology) and reflected down onto the cortex via a 580 nm dichroic mirror (Chroma Technology). Kohler illumination was achieved through the macroscope. The fluorescence of the dye (approximately 712 nm) (Takashima et al. 1999) from the stained cortex was focused by the macroscope, filtered by a 610 nm long-pass filter (RG-610, Edmund Scientific), and projected onto the fiber optic aperture of the diode array. The signals from each photodiode were individually amplified with a two-stage amplifier (50 M x 50, 0.2–400 Hz band-pass filtered). The signal was digitized and stored in a personal computer. Data were displayed and analyzed off-line by the NeuroPlex software. For additional information regarding the VSD method, see Wu and Cohen (1993) and Jin et al. (2002).
Local field potential (LFP) was recorded with a ball electrode (Ag–AgCl, approximately 150 µm diam) placed on the cortical surface (Fig. 1B). The reference electrode for the LFP was placed in a hole in the bone in front of the craniotomy window.
To reduce floor vibration, a vibration isolation table (Minus-K, www.minusk.com) was used. To reduce the pulsation artifact, in some preparations, the cortex was covered with high viscosity silicon oil (12,500 centistoke) and a cover glass during each imaging trial. The silicon oil was replaced with bicuculline solution between imaging trials.
The total recording time was limited by combined effects of dye bleaching, phototoxicity, and dye wash out (Wu and Cohen 1993; Jin et al. 2002). In one group of five animals, we divided the recording into several (no more than 8) 8-s trials (maxim 64 s of exposure time during a period of 2 h). Usually two to six sISs were recorded in each 8-s trial and 13 to 26 sISs were recorded from each animal. In another group of four animals, experiments were carried out within 40 min to reduce the dye wash out. In this group we had 40-s-long trials and 240 s of total recording time for each animal. Longer single recording trials allowed 80–120 sISs to be recorded from each animal.
Subtraction of pulsation artifact
The dominant source of noise in our measurement was the pulsation artifact associated with the heartbeat. The excitation wavelength of RH-795 overlaps with the light absorption of hemoglobin (Shoham et al. 1999), and the illumination intensity fluctuates following each heartbeat. In our recording, this pulsation artifact had a large amplitude, similar to that of a sIS signal (Fig. 2A, Det 1-3). To eliminate this artifact, a subtraction procedure was used off-line in data analysis. An averaged pulsation artifact was obtained by a heartbeat triggered (using the peak of the QRS wave in the ECG) average. During each 8-s trial, there were about 50 heartbeats and we divided the data into about 50 sections, each starting at the time of the QRS peak (Fig. 2A). Only 2 to 6 of these approximately 50 sections contained a sIS spike. These sections were defined as the "raw signal" (Fig. 2B, thin solid trace) and were excluded from the averaging. The sections without sISs were averaged together and defined as "averaged pulsation artifact" (Fig. 2B, dashed trace). This averaging procedure was applied individually for each optical detector. The averaged pulsation artifact was subtracted from each section of raw signal. After this subtraction the processed signal had a relatively flat base line (Fig. 2B, thick solid trace).
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After the averaged pulsation artifacts were subtracted from raw VSD signals, the processed signals at different locations during each sIS were normalized to the peak of the signal (Fig. 3A). The onset time was defined as the time for the signal to reach half of the peak amplitude of an IS. The location with the earliest onset time was defined as the initiation site (Fig. 3A, detector c). Pseudocolor images were used to map the initiation site (Fig. 3B). To generate a pseudocolor image, the amplitude of the normalized IS signal (between 0 and 1) from each detector was assigned colors using a linear scale of 16 colors. With these color values from each detector at each data point, pseudocolor maps were made using the CONTOUR function provided by Interactive Display Language (IDL) (Research System, Boulder, CO) and used by NeuroPlex. The initiation site was defined as the one that reached the warm color (yellow or warmer colors) earlier than other regions. In some sISs, two neighboring detectors reached warm colors simultaneously, but the onset time had a slight difference. The one with the earlier onset time was defined as the initiation site.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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); the VSD signal strictly reflected the membrane potential changes (Ross et al. 1977; Salzberg et al. 1973) and was not affected by the current flows in the tissue.
To identify the initiation site of the sIS, we compared the onset time of the signal recorded from different locations. In Fig. 3A, signal from four detectors are shown. The distance between the two detectors was 1200 µm (Fig. 3B). The trace recorded from detector c reached its half-peak amplitude earlier than other detectors, suggesting that the sIS started near detector c and propagated to the other locations. The pseudocolor image also showed the location of the initiation site. One image (Fig. 3B) was made at the time Ti (Fig. 3A, thin line). The orange color under detector c represents greater neuron excitation than other regions, demonstrating that the region under detector c activated earlier than the other regions. All the sISs examined optically appeared to be initiated from a small initiation site (single detector) and propagated to the whole field of view (Fig. 4A), suggesting that, although the entire exposed cortex was disinhibited, the sIS starts from local interactions in a small area (approximately 200 µm). This is consistent with the observations made in neocortical slices (Tsau et al. 1998, 1999) and a recent report of in vivo observations (Miyakawa et al. 2003).
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). The initiation sites in Fig. 4B were not randomly distributed. Some sites are clustered (e.g., in areas a and b in Fig. 4B) and in other regions they are more scattered. This uneven distribution of initiation sites was further examined below. Figure 5 shows the distribution of the initiation sites from six animals. Each initiation site was marked as a dot and a line was used to connect each initiation site with its predecessor. The length of the line was referred to as "shift distance," representing the distance between two successive initiation sites. The shift distances shown in Fig. 5 appeared to be either short (<800 µm) or long (>1200 µm). Of the total 94 shift distances shown in this figure, 30 (31.9%) were short and 61 (64.9%) were long. Only 3 (3.2%) of them were between 800 and 1200 µm. It appeared that surrounding each initiation site there was a "suppression annulus" within which the likelihood of starting the next sIS was reduced.
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We also used a surrogate of the observed data to further verify the existence of the suppression annulus. In the surrogate we randomized the temporal sequence of the sISs and the shift distances were measured from all possible combinations of the initiation sites in each animal (e.g., if one animal yielded 10 sites, 45 shift distances could be measured). The surrogate contained 1260 shift distances. We divided the density of the surrogate data by a factor of 2.89 (1260/436 = 2.89), so that the surrogate (Fig. 6C, thin line) could be directly compared with the observed data. In the surrogate the clustering between 0 and 400 µm was obvious but the local minimum in the range of 800–1200 µm disappeared. The difference between the observed data and the surrogate was significant in the 800-1200 µm region (t-test, P < 0.01) while not in other regions (200–800 µm and 1400–2200 µm; t-test, P > 0.05). This comparison further confirmed that the likelihood for initiating the next sIS was reduced in the suppression annulus; it also indicated that the suppression only occurred temporarily, affecting only the initiation of the next sIS.
The synaptic mechanisms of suppression annulus were tentatively explored. In the presence of high concentration of bicuculline, the calcium-activated potassium channels may be partially blocked (Strobaek et al. 2000). To eliminate this effect, picrotoxin was used instead of bicuculline. The suppression annulus still appeared in the picrotoxin bath (Fig. 7), suggesting that the suppression annulus was not a result of K+ channel blockade. GABAb antagonist CGP35348was used together with bicuculline to test whether the suppression annulus was a result of the GABAb-mediated inhibition. In the presence of CGP35348the occurrence rate of the sISs increased (approximately 1.2 Hz). However, the distribution of the initiation sites did not show any significant difference from that with bicuculline alone (Fig. 7), suggesting that GABAb inhibition was not involved.
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Again we saw a suppression annulus surrounding the initiation site. Because the pretreatment created a cluster of initiation sites near the filter paper, the suppression annulus can be seen in the results from individual animals (Fig. 8B, 1–4). Of the total of 310 sISs recorded in six animals, 135 (43.6%) initiated from the region within 800 µm from the filter paper; 11 (3.5%) initiated in the region between 800 to 1200 µm from the filter paper (suppression annulus), and 164 (52.9%) initiated from outside of the suppression annulus (>1200 µm). The distribution of the initiation sites was shown in Fig. 8C (the distance between the initiation sites and the edge of the filter paper was used as the shift distance). A local minimum between 800 and 1200 µm occurred in the distribution, indicating the existence of suppression annulus.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In this report we have observed 499 sISs from 251 sites, or each initiation site initiated about two epileptiform events. This is very different from our previous observations in brain slices where each site initiated 30–100 events (300–400 events from 3–4 sites; Tsau et al. 1998). Several factors might contribute to this difference: first, an intact cortex contains more tissue than a slice and thus contains more potential initiation sites. Second, a brain slice is only a small vertical section of the cortical network and horizontal connections are largely cut. Horizontal connections may promote interactions for sIS initiation. Third, under in vivo conditions, cortical neurons may have higher levels of spontaneous activity, which may trigger sISs. In a neocortical local network, if only a few groups of neurons have a certain level of spontaneous activity that can trigger an IS, then all the sISs would start from these few initiation sites and each initiation site would initiate many sISs. In contrast, if many neurons have high levels of spontaneous activity that can trigger an IS, then sISs would start from many possible sites and each initiation site would initiate only a few sISs, as seen in this report.
Synchronized firing of a local neuronal population may be required for the initiation of an IS (Demir et al. 1999; Jefferys 1990; Jensen and Yaari 1997). It is well known that an evoked activity from an electrical shock to a rat neocortex slice can reliably trigger an IS (Chagnac-Amitai and Connors 1989; Curtis et al. 1970; Prince 1967). In intact cortex, evoked activity by deflection of a whisker can also reliably trigger the initiation of an IS (London et al. 1989; Prince 1966). These evoked activities are all visible in LFP electrode recordings, suggesting a certain level of synchrony within the local neuronal population. Bathed in normal ACSF, in vitro slices showed no obvious spontaneous activity in LFP recordings. In contrast, EEG recordings from anesthetized rat cortex showed constant spontaneous activity, suggesting that there were more possible triggers for starting sIS in vivo.
Number of initiation sites
Our observation of the spatial distribution of the initiation sites did not agree with Miyakawa et al. (2003). They observed only 2 to 4 initiation sites in each animal (Fig. 6 of Miyakawa et al. 2003). This was significantly fewer than our observations of 7–35 initiation sites per animal but somewhat similar to that observed in brain slices (Tsau et al. 1998).
We postulated that different ways of defining initiation sites might contribute to this discrepancy. In the two methods used in this report (Fig. 3), both defined an initiation site as a location where the signal first reached half of normalized peak amplitude. In contrast, Miyakawa et al. (2003) defined the initiation site as a position in which the signal first reached a threshold (of S/N > 2). With their method, a location with higher signal amplitude (also higher signal-to-noise ratio) may reach the threshold earlier, even though its onset time was later than other locations (e.g., Fig. 3C, top, detector 2). Since signal size may be related to the staining and other imaging factors, the location of the initiation site might also be biased.
Suppression annulus
The suppression annulus was not in the immediate surrounding region of each initiation site. Rather, it started some distance (approximately 800 µm) away from an initiation site (Fig. 6C, 7). Thus the area immediately surrounding the initiation center may host initiation sites for the next sIS, creating a cluster effect. This clustering effect was more obvious when the preparation was pretreated with a local application of bicuculline (Fig. 8, B and C). The pretreatment of applying bicuculline locally promotes multiple initiation sites in a small area and the suppression annulus for the clustered initiation sites may overlap and was, therefore, visible in individual preparations.
The mechanism that might underlie the suppression annulus was only tentatively explored. A possible involvement of GABAb inhibition was excluded. However, the occurring rate of sIS increased in the presence of GABAb antagonist, suggesting that GABAb inhibition contributes to the regulation of the sISs occurring rate. The underlying mechanisms of the temporal suppression will be further investigated.
sIS is an all-or-none event and it propagates over the entire cortical area that is exposed to bicuculline or picrotoxin. Thus one might think that the location of the initiation site should not affect the activity in other areas. Timing would be the only difference between the activity at the initiation site and the rest of the regions. It is, therefore, difficult to speculate about a network mechanism that would explain the phenomenon of the suppression annulus. In addition, the suppression annulus occurred only briefly (within a few seconds) after each sIS, adding difficulties for further study.
The existence of an "inhibitory surround" in the cortex adjacent to an acute artificial epilepsy focus has been previously suggested by a number of authors. An electrophysiological inhibitory surround was demonstrated with a single-unit recording from the cortex adjacent to acute experimental foci (Goldensohn and Salazar 1986; Prince and Wilder 1967). Negative signals were also recorded with interictal PET, fMRI, SPECT, and optical recordings based on intrinsic signals (Federico et al. 1994; Schwartz and Bonhoeffer 2001). The inhibitory surround mentioned by these authors was induced with locally applied convulsants. Within the area of inhibitory surround the GABAa inhibition was not suppressed. In this report, bicuculline is applied to the entire explored cortex and in the suppression annulus the GABAa inhibition was blocked. These suggest that the inhibitory surround and suppression annulus are two different phenomena; additional experiments are required to examine their correlations. In addition the suppression annulus in this report did not block propagation of sISs. It only reduced the chance for initiating the next sIS in the annulus. The inhibitory surround, in contrast, blocks the IS propagation.
We estimated that the width of the suppression annulus was about 400 µm (Fig. 6C). At least two factors could affect the accuracy of this estimation. The first was the spatial resolution of our imaging setup, which was about 200 µm. The second was the individual variability. The local minimum in Fig. 6C was an average of our entire data set. Using the current methods we were unable to detect the actual size of the suppression annulus surrounding each individual initiation site. Despite the inaccuracy, the existence of the suppression annulus must be real, because the probability of sISs initiation was significantly lower in the annulus than its neighboring areas. This local minimum of the curve could not be eliminated when the grouping of the initiation sites was varied (e.g., from groups of 600–800, 800–1000, and 1000–1200... to groups of 500–700, 700–900, and 900–1100 µm... etc.; data not shown).
We speculate that the size of the suppression annulus might be related to the geometry of arborizations of dendrites and axons of cortical neurons. Although the long-range inhibitory connections (e.g., by large basket cells, Somogyi et al. 1983; Kisvarday et al. 1986) are greatly reduced when the GABAa inhibition is blocked, other short and long range connections might be related (e.g., the clustering and long range corticcortical projections of infragranular pyramidal cells, Martin and Whitteridge 1984; Szentágothai 1987). Additional studies are needed to explore the correlation between the boundaries of the suppression annulus (800–1200 µm) and anatomical connectivity.
Clustering of initiation sites and activity history
A cluster of sIS initiation sites can be created by locally applying bicuculline to the cortex before disinhibiting a large area (Fig. 8). The bicuculline concentration at the local area was the same as that later applied to the entire craniotomy window. The local area was exposed to bicuculline approximately 45 min earlier than the rest of the cortical area. During the period of local bicuculline pretreatment, about 1000 sISs occurred in that area. These activities may modify the cortical network in that small region and the modification may play a role in promoting the initiation sites. In six different animals we applied the pretreatment on different cortical regions but the cluster was always formed around the filter paper, suggesting that the cluster was linked to the pretreatment and unlikely to be associated any particular cortical areas. However, cortex is not a homogenous tissue and we expect the heterogeneity in the local network would also contribute to the formation of clustering and suppression annulus. A future direction would be to examine the distribution of clusters due to heterogeneity and how the altered local activity would modify the "intrinsic" distribution.
VSD method
VSD imaging provided a convenient way to map the initiation of epileptiform activity in the cortex. The dye signal of epileptiform activity is large (Demir et al. 1999; London et al. 1989; Jin et al. 2002), yielding a high signal-to-noise ratio without averaging. Seeing activity without averaging is important for examining the variant initiation and spatial–temporal dynamics of epileptiform activities.
A major drawback of the dye RH-795 is the large heartbeat artifact in the optical recordings, due to the excitation wavelength of the dye overlapping with the absorption band of hemoglobin (Shoham et al. 1999). Our method for subtracting the cardiovascular artifact was not perfect, because each individual heartbeat varies and subtracting the average left residuals. However, since the IS signal is large, the subtraction method seems adequate. A new generation of VSDs is being developed (Shoham et al. 1999). These dyes have an excitation wavelength that does not overlap with the hemoglobin absorption (the "blue dyes"). The heartbeat artifact is thus significantly reduced (Shoham et al. 1999).
In conclusion, we found that the distribution of sIS initiation sites in the intact cortex is different from that found in cortical slices; there are multiple initiation sites in the intact cortex and each site initiates only a few sISs. The initiation sites are not evenly distributed. Increased local activity may create a cluster of initiation sites. Around each initiation site there appears to be a temporal suppression annulus, where the chance of initiating the next sIS was reduced. However, we did not examine the correlation between the cellular architecture and the location of the clusters. Also our pharmacological manipulations did not verify the existence of a suppression annulus. Additional experiments are needed to work in these directions.
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ACKNOWLEDGMENTS |
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GRANTS
This work was supported by National Institute of Neurological Disorders and Stroke Grant NS-36477 and a Whitehall Foundation Grant.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J.-Y. Wu, Georgetown University, Rm 247 Basic Science Building, 3900 Reservoir Rd. NW. Washington, DC 20057 (E-mail: wuj{at}georgetown.edu).
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