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The Journal of Neuroscience, January 5, 2005, 25(1):68-77; doi:10.1523/JNEUROSCI.2823-04.2005
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Neurobiology of Disease
Temporal Dependence in Uncoupling of Blood Volume and Oxygenation during Interictal Epileptiform Events in Rat Neocortex
Minah Suh, Sonya Bahar, Ashesh D. Mehta, andTheodore H. Schwartz Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York 10021
Abstract
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Abstract
Introduction
We investigated the dynamic spatiotemporal relationships of cerebral blood volume (CBV), deoxygenated hemoglobin (Hbr), and light scatter (LS) associated with interictal epileptiform events with multiwavelength optical recording of intrinsic signals and simultaneous field potential recording. Interictal spikes (IISs) were induced with iontophoresis of bicuculline methiodide in rat neocortex. Intrinsic signal changes appeared as early as 100 msec after the IIS at all wavelengths and could be appreciated after only a single IIS. Initially, the largest signal arose from a focal increase in deoxygenation, which lasted for2 sec, consistent with an "initial dip." An equally early focal increase in CBV had a smaller amplitude than the Hbr signal until >2 sec after the IIS, when its amplitude surpassed that of the Hbr signal but also spread to a larger, less focal area. The most spatially restricted and smallest amplitude signal was produced by LS. A later hyperoxygenation, or increase in blood oxygenation level-dependent signal, was often seen in the draining veins but inconsistently seen in the IIS focus. An inverted optical signal was recorded at all wavelengths from multiple regions in the surrounding cortex within 100 msec of the IIS. We therefore conclude that the IIS induces a rapid increase in metabolic demand, which cannot be met by a rapid, initially focal but small increase in CBV that results in a prolonged increase in Hbr (epileptic dip in oxygenated hemoglobin). The inverted optical signal in the surround arises from a decrease in CBV and a decrease in Hbr, likely resulting from a combination of shunting of CBV to the focus and decreased metabolic demand resulting from decreased neuronal activity, consistent with "surround inhibition."
Key words: bicuculline; epilepsy; neocortex; rat; interictal spike; optical imaging; intrinsic signal; hemoglobin; initial dip; cerebral blood volume; BOLD; fMRI
Introduction
Interictal spikes (IISs) recorded from epileptic brain represent a population of hyperexcitable neurons (Schwartzkroin and Wyler, 1980), which are usually contiguous with the ictal onset zone, the area of the brain from which seizures arise (Engel, 1990
The basic premise behind these techniques is that neuronal activity induces an increase in cerebral metabolic rate (CMRO2), which in turn causes an increase in CBF and cerebral blood volume (CBV) as blood vessels dilate to bring oxygenated hemoglobin (HBO2) to the area (Roy and Sherrington, 1890
Previous investigations into the relationship between epileptiform events and perfusion or metabolism have demonstrated contradictory results in both animals and humans using autoradiography, PET, and fMRI, techniques with limited temporal and spatial resolution. Although an increase in perfusion is universally demonstrated, some studies find that perfusion oversupplies metabolism (Lemieux et al., 2001a
Materials and Methods
Animal preparation. Adult male Sprague Dawley rats (n = 10; 250-375 gm) were initially anesthetized with intraperitoneal ketamine (90 mg/kg) and xylazine (4.0 mg/kg) and then sustained with urethane (1.25 gm/kg), decadron (0.17 mg/kg), mannitol (0.83 gm/kg), and atropine (0.067 mg/kg). Temperature was maintained at 37°C with a heating blanket (Harvard Apparatus, Holliston, MA). Because the level of anesthesia can affect ORIS, the heart rate, pO2, and ETCO2 were carefully monitored using a small animal Capnograph (Surgivet, Waukesha, WI) and maintained stable throughout the experiment. To further ensure the consistency of ORIS resulting from the level of anesthetic, the supplementary anesthesia (0.3 gm/kg urethane) was delivered as needed, depending on the animal's reflex response to a toe pinch. The electrocardiogram was monitored between leads attached to the right hindlimb and the skin of the scalp. Rats were placed in a stereotactic frame. The skin above the skull was shaved, and the scalp was incised along the midline. The skull over one hemisphere, between lambda and bregma, was thinned using a dental drill. A small hole,Electrophysiology. A glass micropipette filled with 1% NaCl was positioned at an acute angle (20-40°) to the neocortical surface,
) was filled with a solution of bicuculline methiodide (BMI) (5 mM in 165 mM NaCl, pH 3.0; Sigma-Aldrich, St. Louis, MO) and positioned at an acute angle <1 mm from the F.P. electrode. Interictal foci were induced by iontophoresis of BMI into layers II-III, using a microiontophoresis dual current generator (World Precision Technology, Sarasota, FL). Currents used were -15 to -20 nA for retention and +50 to +500 nA for release depending on the resistance of the micropipette tip. Positive currents were maintained until stereo-typical IISs were recorded (after
Optical imaging. A CCD camera using a tandem lens (50 x 50 mm) arrangement (Ratzlaff and Grinvald, 1991
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Figure 1. Simultaneous ORIS-electrophysiology set up. Two fiber-optic light guides illuminate the exposed cortex through the thinned skull between lambda and bregma. F.P. and iontophoresis electrodes penetrate the skull and are advanced into the cortex. A time stamp for each frame acquisition with the optical imaging (OI) computer is recorded on the electrophysiology computer for later correlation with the IISs. TTL synch, Transistor-transistor logic synchronization.
Data analysis. To quantify the change in light reflectance, the series of images obtained after each IIS event was divided by the image occurring two frames before the IIS event. All quantitative analysis including mean (SD) of pixel values in a region of interest (ROI) was performed using custom image analysis software written in MATLAB. To further increase the signal-to-noise ratio of this spike-triggered image division, averaging over multiple spikes with similar amplitude and interspike intervals was performed (Schwartz and Bonhoeffer, 2001R/R (%) in an ROI. To calculate the intrinsic signal associated with the focus, an ROI was selected in the region of IIS onset. The "inverted" optical signals from the putative "inhibitory surround" were selected from multiple separate ROIs at the periphery of the area of decreased light reflectance. The mean (SD) of the pixel values within the ROI was compared before and after the onset of the IIS, and the onset latency was defined as the first frame with a statistically significant change in -
To determine the spatial extent of each IIS event, we used the "normalized threshold analysis" method developed by Chen-Bee and others (Masino et al., 1993
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Figure 8. Spatial extent of excitatory IOS as a function of time and wavelength. A, Each panel depicts a contour plot of the spatial extent of an average spike-triggered map at different wavelengths and thresholds. Although the absolute area and shape change with the threshold, the relative size remains stable. Scale bars, 1 mm. B, Time course of spatial extent at 5, 10, and 15% threshold in one animal. The temporal dependence on the relative sizes is apparent regardless of threshold. C, The average extent of spread (area) of the change in reflectance in the focus in all animals (n = 10) is both temporally and wavelength dependent. The slope of the graph in the first 1 sec demonstrates the rate of propagation of the signal.
Results
Spike-triggered image averaging of the IIS
Periodic (0.15-0.5 Hz) biphasic IISs were induced with BMI iontophoresis and recorded with an adjacent F.P. electrode (Fig. 2A). Mean (SD) amplitude of each IIS (n = 100) was -3.8 ± 0.4 mV, and mean (SD) spike width was 85 ± 18 msec. Simultaneous electrocorticography electrodes placed just outside the limits of the region of thinned bone did not record the events, indicating that horizontal propagation was limited. Each IIS induced a change in light reflection that returned near baseline depending on the interspike interval (Fig. 2B). Spike-triggered image division revealed that the amplitude of the intrinsic signal change was sufficiently large to localize a single IIS, without any image averaging, even at a temporal resolution of 100 msec (Fig. 2C). We did not find a prominent 0.1 Hz vasomotor artifact in our rat data (Mayhew et al., 1996
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Figure 2. Spike-triggered image division averaged over multiple spikes. IIS epilepsy maps can be generated using spike-triggered image division from either a single IIS or multiple IISs. A, Image obtained at 546 nm shows blood vessel pattern seen through a thin layer of skull. B, Stable, well-formed, biphasic IISs were induced at regular intervals with focal iontophoresis of BMI. Simultaneous ORIS and F.P. recordings show that each IIS induces a change in reflection of light. C, ORIS spike-triggered map at 605 nm was generated by dividing each single frame after the IIS (black bars) by the single frame (gray bar) that preceded the IIS (frame duration, 100 msec). D, To increase the signal-to-noise ratio, we averaged over multiple spikes (n = 185). Each IIS crosses a certain threshold within the first 100 msec, but the timing of the peak is variable. Frame rate and images are identical to C in the same animal. Scale bar, 1 mm.
Because IISs occur spontaneously at irregular intervals but the images are acquired at fixed regular intervals, the peak of each IIS occurs at a slightly different time (Fig. 2D). However, according to the IIS selection algorithm, the downslope of the IIS must cross a certain threshold within the first frame. Despite this variability, in which some IISs do not peak until well into the second 100 msec frame, it is clear that a statistically significant decrease in reflection occurs within 100 msec of the onset of the IIS (Fig. 2D) (paired t test; p < 0.05). In the next set of experiments, we investigated the wavelength dependence of the latency and amplitude of the intrinsic signal change to determine the evolution of CBV, Hbr, and LS after the IIS.Optical mapping of IISs at multiple wavelengths
Spike-triggered mapping was performed at all four separate wavelengths in individual animals (n = 10). An example of such an experiment is presented in Figure 3. The optical signal at 546 nm, an in vivo isosbestic wavelength of hemoglobin (Sheth et al., 2004
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Figure 3. ORIS at multiple wavelengths. A-D, Spike-triggered image division at 546 ± 10 nm (A) (n = 208 spikes), 605 ± 10 nm (B) (n = 185 spikes), 630 ± 10 nm (C) (n = 218 spikes), and 700 ± 10 nm (D) (n = 215 spikes) demonstrate the wavelength dependence of the optical signal (see Discussion). E, Magnified example of spike-triggered image divisions at four wavelengths at 0.3 sec (early) after IISs. F, Magnified example of spike-triggered image divisions at four wavelengths at 2.5 sec (late) after IISs. G, The amplitude and time course of the intrinsic signal change was measured from a single ROI in the focus (dark blue) and multiple, symmetric ROIs in the surrounding cortex (red, orange, light blue, yellow). H, Inverted optical signals recorded from the surrounding cortex are smaller in amplitude than signals recorded from the focus, regardless of wavelength, and appear in all directions. The amplitude of the signals decreases with increasing wavelength. Scale bars, 1 mm
At 605 and 630 nm, representing the range of wavelengths used in previous studies to measure hemoglobin oxygenation (Vnek et al., 1999ORIS at 700 nm was approximately the same as at 605 or 630 nm, except the optical signals in the focus and surrounding cortex were smaller in amplitude and size (Fig. 3D,H). Quantitative analysis of this data showed that the maximal changes in light reflectance were significantly different at each wavelength [ANOVA; p < 0.001; post hoc Student-Newman-Keuls (SNK) test]. The average maximal values of -
Early versus late intrinsic signal
Because the intrinsic signal is not only sensitive to neuronal action potentials but also to subthreshold activity (Das and Gilbert, 1995
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Figure 4. Monophasic CBV signal and biphasic oxygenation signal. A-D, Multiwavelength ORIS in another animal at 546 ± 10 nm (A) (n = 134 spikes), 605 ± 10 nm (B) (n = 125 spikes), 630 ± 10 nm (C) (n = 75 spikes), and 700 ± 10 nm (D) (n = 73 spikes) highlights the reproducibility and variability of our results. Note the late inverted IOS at 605 and 630 nm begins focally and then propagates in the draining veins. E, The image at 546 nm shows a blood vessel pattern of an imaged region covered with thin skull. The blue box is an ROI in focus measured in F. Scale bars, 1 mm. Time course of superpixel in the focus measured at each wavelength. G, Magnified example of spike-triggered image divisions at four wavelengths at 0.3 sec (early) after IISs. H, Magnified example of spike-triggered image divisions at four wavelengths at 3.0 sec (late) after IISs. Scale bars, SEM.
At each wavelength, the spatial extent of the IOS, both positive and negative, was calculated using the normalized threshold analysis technique with a threshold set 10% above and below the median, respectively (see Materials and Methods for additional details). As is clearly seen in Figure 5A, the early changes in the optical signal, which occur at 300 msec after the IIS, are much more focal than the late changes at the peak of the optical signal (>1 sec). In this particular example, at 300 msec after the IIS, the spatial extent of the positive optical signal in the focus was similar at all wavelengths (Fig. 5). At the peak of the optical signal, however, the spatial extent at 546 nm was slightly larger than the other wavelengths, and the signal clearly spreads into the draining veins at oxygen-sensitive wavelengths (Fig. 5). The inverted optical signal in the surround shows an equally dramatic temporal dependence and actually reverses at higher wavelengths when the early and late phases are compared (Fig. 5). At wavelengths sensitive to CBV, the inverted signal gradually spreads over time in the surrounding brain tissue. At oxygen-sensitive wavelengths, however, the inverted signal has two separate peaks, an earlier one in the surrounding cortex at 1.5 sec and a later one in the focus at 3 sec (Fig. 5). This animal provided a dramatic example of a late increase in oxygenated hemoglobin within the focus that might be demonstrable using conventional increase in BOLD fMRI. However, this was only observed in 2 of 10 animals. There was a nonsignificant trend toward a higher frequency of IISs in the animals without a prominent increase in BOLD signal in the focus but only in the draining veins (0.33 ± 0.08 Hz) compared with animals that did have an increase in BOLD signal within the focus (0.19 ± 0.06 Hz; p = 0.08).
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Figure 5. Spatial extent of IOS as a function of wavelength. Spatial extents were calculated by thresholding pixels as described in Materials and Methods. A, Spatial extents of both excitatory IOS in focus and inverted IOS in surround have wavelength dependence. The white area indicates pixels for which values are below (decrease in reflection of light) or above (increase in reflection of light) the threshold for excitatory and inverted signals, respectively. Early excitatory IOS was chosen 0.3 sec after the IIS, whereas late excitatory IOS was chosen at the peak of spatial extent at each wavelength. The inverted IOS was thresholded at the maximum of the early and late peaks; in this example, these peaks occurred at 1.5 and 3 sec after the IIS, respectively. The timing of images is denoted by arrows in B-E. Note the focality of the IOS in the focus recorded early and the inversion of the inverted optical signal in surround comparing early to late images. Scale bars, 1 mm. The time course of spatial extent for both excitatory (closed circle) and inverted (open circle) IOS is demonstrated at 546 nm (B), 605 nm (C), 630 nm (D), and 700 nm (E).
Average amplitude and latency of IOS
The average amplitude of IOS [-
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Figure 6. Average results of changes in reflectance as a function of time. A, Percentage of change in reflection of light in the focus as a function of time and wavelength after each IIS. The amplitude of the IOS is clearly greatest when recorded at 546 nm, followed by 605, 630, and 700 nm. B, Data are normalized to the maximum change in -
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Figure 7. Earliest significant change in light reflection. A, The earliest statistically significant change (paired t test; p < 0.05) in reflectance of light was seen at 100 msec at all wavelengths, although more commonly at wavelengths sensitive to oxygenation of hemoglobin. B, The earliest statistically significant (paired t test; p < 0.05) inverted change in reflectance of light in the surround was seen at 100 msec, regardless of the wavelength. Again, the oxygenation signal is more commonly seen at 100 msec than the CBV signal. In several cases, the inverted signal in the surrounding cortex was delayed compared with the positive signal in the focus for all wavelengths tested.
Unlike the amplitude and latency of excitatory IOS, the amplitude and latency of the inverted optical signal in the surround did not show any clear wavelength dependence (Fig. 6C), which can also be seen when normalized to the maximal amplitude of the inverted signal (Fig. 6D). An ANOVA test showed that the peak amplitude of the inverted IOS was not significantly different at all four wavelengths (post hoc SNK test; p > 0.05). The inverted signal peaked 1 sec after the IIS for all wavelengths, which was, on average, earlier than the peak of the positive signal, although occasional exceptions were found (Fig. 3, 546 nm). Like the positive signal, the inverted signal was also recorded as early as 100 msec in 30-60% of the animals (paired t test, p < 0.05) (Fig. 7B). On average, however, the onset occurred at 225 msec (546 nm), 180 msec (605 nm), 175 msec (630 nm), and 247 msec (700 nm), which was consistently slightly delayed compared with the positive signal from the focus.Average spatial extent and propagation velocity of IOS
The calculation of an area using a thresholding technique is dependent on the chosen threshold. To ensure that our results were not biased by the arbitrariness of this choice, we investigated the relative area of the IOS at multiple thresholds and wavelengths (n = 10 animals). As we varied the threshold, the absolute size and shape of the IOS changed, but the relative area for each wavelength was stable (Fig. 8A). Depending on the latency of the measurement, the relative size of the optical signal varied dramatically between wavelengths (Fig. 8C). Within 1 sec of the IIS, the CBV signal (546 nm) was significantly smaller than the other wavelengths (Fig. 8C, Table 1). From 1-2 sec, the area was largest at oxygen-dependent wavelengths (605 and 630 nm), followed by the light scatter wavelength (700 nm) and then the CBV signal (Fig. 8C, Table 1). After 2.5 sec, the CBV signal was the largest, whereas the signal at other wavelengths began to return to baseline (Fig. 8C, Table 1). On average, the maximal area of the OIS at 546 nm was no larger than at 605 or 630 nm. In six animals (60%), however, the area of spread was significantly larger at 546 nm (ANOVA; post hoc SNK test; p < 0.05).
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Table 1. Statistical significance in the area of IOS depending on wavelength and latency
To calculate the propagation velocity, we assumed the initial IOS spread was circular and performed a linear fit to calculate the slope of the radius of its spatial extent. Over the first 1 sec, the average slopes were 0.24 ± 0.12 mm/sec (R2 = 0.94 ± 0.05) at 546 nm, 0.46 ± 0.15 mm/sec (R2 = 0.91 ± 0.08) at 605 nm, 0.44 ± 0.10 mm/sec (R2 = 0.95 ± 0.04) at 630 nm, and 0.43 ± 0.15 mm/sec (R2 = 0.94 ± 0.06) at 700 nm. The initial velocity at 546 nm was significantly slower than the one at 605, 630, and 700 nm (ANOVA; post hoc SNK test; p < 0.05), but there was no significant difference in the rate of spread between 605, 630, and 700 nm (ANOVA; post hoc SNK test; p > 0.05).
Discussion
This report marks the first optical recording of epileptiform activity at wavelengths sensitive to Hbt (CBV) and Hbr. Haglund et al. (1992The epileptic initial dip
At wavelengths sensitive to Hbr, we found a clear decrease in oxygenation in the focus, which began within 100 msec after the IIS that persisted for almost 3 sec. The most likely explanation for this event is that the increased metabolic demand of the neuronal population participating in the IIS outweighs the ability of the brain to increase perfusion to the area. The existence of this initial dip during normal somatosensory processing has been challenged based on its absence under certain experimental conditions (Silva et al., 2000Epilepsy is a pathological condition, and the metabolic demands associated with the IIS are "supranormal." We found that the IIS induces a profound dip in hemoglobin oxygenation (increase in Hbr) and, in contrast to normal physiological events, the amplitude of the initial dip was larger than the later increase in oxygenation. In fact, this late increase or BOLD effect was not often seen in the focus at all. One physiological explanation for the lack of a late hyperoxygenation is that the frequency of the interictal events was relatively high, so the metabolic rate in the focus remained supranormal, and there was insufficient time for the brain to adequately perfuse the area with oxygenated blood. This implies that the neurons in an epileptic focus may be chronically hypoxic, depending on the rate of the interictal events. In human epilepsy, however, interictal events are less frequent and less focal, so our findings may be specific to this acute disinhibition rat model. In support of this explanation, previous autoradiography studies in status epilepticus demonstrate that metabolism remains supranormal for several hours, revealing that increases in perfusion ultimately fail to match increases in metabolic demand leading to tissue injury and neuronal damage (Ingvar and Siesjo, 1983
The inverted optical signal
The significance of the inverted optical signal surrounding the epileptic focus has been debated. It was first described by Haglund et al. (1992This is the first report of an inverted optical signal surrounding an epileptic focus in the rat. Using high temporal resolution ORIS, we investigated the spatiotemporal dynamics of the inverted optical signal and describe an early and a late component at wavelengths >600 nm. The early inverted signal in the surrounding brain appears within 100 msec of the interictal event both symmetrically within the parenchyma of the surrounding brain as well as in the draining veins and lasts
We also report a novel finding that an inverted optical signal is also apparent in the surrounding brain at 546 nm, implying a ring of decreased CBV around the focus. Such a decrease likely represents shunting of blood to the adjacent active focus. How can we explain an early decrease in Hbr and a decrease in CBV in the surrounding brain immediately after the IIS? One explanation is that the metabolic rate of the neurons decreases out of proportion with the movement of blood into the focus. In other words, Hbt decreases but Hbr decreases even more, which could be explained by a decrease in neuronal activity, or "surround inhibition." Hence, even in the surround, where neurons are inhibited, there is an uncoupling of neuronal CMRO2 and hemoglobin oxygenation, because Hbr decreases out of proportion with demand.
ORIS of epileptiform events: the influence of wavelength and timing on focality
The spatial correlation between intrinsic signal changes and neuronal activity has been well investigated after sensory processing, particularly in cat visual and rodent barrel cortex (Frostig et al., 1990Our data show that during the initial stages of its evolution, when the IOS is most focal, the amplitude is larger at wavelengths sensitive to the oxygenation state of hemoglobin. Thus, although focal maps can be obtained at all wavelengths, the most reliable epilepsy maps were obtained from the initial dip. In contrast, when the temporal evolution of the signal is ignored, the signal recorded at 700 nm, which presumably arises mostly from LS, is clearly the most focal. The origins of this signal are multifactorial and have been attributed to the movement of sodium and potassium ions in and out of both neurons and glia associated fluid shifts and increases and decreases in the volume of the extracellular space as well as the morphology of the vasculature (Hill and Keynes, 1949
In conclusion, we found that the intrinsic signal changes associated with interictal epileptiform events occur more rapidly than previously thought, regardless of wavelength. This increases its utility in mapping the onset of fast events such as interictal spikes. Although the CBV signal is focal in the first 2 sec after the IIS, the amplitude of the initial deoxygenation-related signal is larger, making this signal potentially more useful in mapping the onset of the event in clinical situations such as spike-triggered fMRI and intraoperative ORIS. This extended dip in oxygenation in which metabolic demand and hemoglobin oxygenation are uncoupled is more profound than after normal sensory activation, which is likely a result of the high metabolic rate of the epileptic neurons. We find an inverted optical signal surrounding the focus that has a distinct temporal signature, an early wavelength-independent phase that may be related to neuronal inhibition and a later wavelength-dependent phase, where the signal transitions to the draining veins at wavelengths sensitive to hemoglobin oxygenation like the BOLD signal recorded with fMRI.
Footnotes
Received March 26, 2004; revised October 1, 2004; accepted October 1, 2004.T.H.S. was supported by the Epilepsy Foundation Junior Investigator Award, American Association of Neurological Surgeons Young Clinician Investigator Award, Citizens United for Research in Epilepsy, and by National Institute of Neurological Disorders and Stroke Grant K08 NS43799. We thank Koon Ho (Danny) Wong for technical assistance and Dr. Jonathan Victor for help with this manuscript.
Correspondence should be addressed to Dr. Minah Suh, Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, NY 10021. E-mail: mis2032{at}med.cornell.edu.
Copyright © 2005 Society for Neuroscience 0270-6474/05/250068-10$15.00/0
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