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Epilepsy Curr. Jul 2007; 7(4): 91–94.
PMCID: PMC1941907
Neurovascular Coupling and Epilepsy: Hemodynamic Markers for Localizing and Predicting Seizure Onset
Theodore H Schwartz, MD
Department of Neurological Surgery, Weill Medical College of Cornell University, New York
Address correspondence to Theodore H. Schwartz, MD, Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th St., Box No. 99, New York, NY 10021. E-mail: schwarh/at/med.cornell.edu
Abstract
Hemodynamic surrogates of epileptic activity are being used to map epileptic foci with PET, SPECT, and fMRI. However, there are few studies of neurovascular coupling in epilepsy. Recent data indicate that cerebral blood flow, although focally increased at the onset of a seizure, may be temporarily inadequate to meet the metabolic demands of both interictal and ictal epileptic events. Transient focal tissue hypoxia and hyperperfusion may be excellent markers for the epileptic focus and may even precede the onset of the ictal event.
In recent years, the field of brain mapping has witnessed the growth of a variety of techniques that use measurements of hemodynamic changes as surrogates for neuronal activity. This development particularly has occurred in the treatment of epilepsy, for which therapeutic decisions are often made based on the results of PET, SPECT, and fMRI scans. Hemodynamic signals, generally derived from perfusion and/or oximetry, are attractive since they often can be measured noninvasively. However, accurate interpretation of these data depends on a firm understanding of neurovascular coupling mechanisms in the brain, especially as they pertain to abnormal events such as epilepsy.
The study of neurovascular coupling examines the relationships among neuronal activity, metabolism, tissue and blood oxygenation, and blood flow. It is generally accepted that during normal cortical processing, increases in neuronal activity simultaneously increase the cerebral metabolic rate of oxygen and glucose, leading to an increase in cerebral blood flow (CBF) and cerebral blood volume (CBV), as the brain attempts to perfuse active neurons with oxygenated hemoglobin (1). PET studies of oxygen metabolism and blood flow, a technique with a slow temporal resolution, have demonstrated that increases in CBF occurring 1–2 s after the onset of neuronal activity provide an oversupply of oxygenated hemoglobin (2). Hence, the cerebral metabolic rate of oxygen and CBF are “uncoupled,” causing an increase in oxygenated hemoglobin that forms the basis of the blood oxygenation level-dependent (BOLD) signal imaged with fMRI (3). More recently, using techniques with higher spatial and temporal resolution—such as optical recording of intrinsic signals (ORIS) (4), imaging spectroscopy (5,6), oxygen-dependent phosphorescence quenching (7), oxygen-sensitive electrodes (8,9), and fMRI at 1.5 and 4 Tesla (10,11)—investigators have examined changes in tissue and blood oxygenation that occur within the first few hundred milliseconds after neurons become active. These studies demonstrated a rapid decrease in tissue oxygenation and an increase in deoxygenated hemoglobin that precedes the increase in CBF. This “initial dip,” although questioned by some studies (12,13), implies that for a brief period of time after neurons discharge, the brain is mildly ischemic until cerebrovascular autoregulation dilates arterioles to increase CBF.
Epilepsy is an abnormal physiologic state which, unlike normal somatosensory processing, places supra-normal demands on the brain's autoregulatory mechanisms as a result of an enormous increase in the metabolic rate of oxygen following both interictal and ictal events (14). Hence, neurovascular-coupling mechanisms that apply in the normal situation may not be relevant to the epileptic brain. Whether or not CBF is adequate to meet the increased metabolic demands of epilepsy has been a long-standing debate. The initial hypoxia–hypoperfusion hypothesis, derived from histologic similarities between ischemic and epileptic brain damage, proposed that the cell damage following status epilepticus was caused by cerebral anoxia (1517). Later studies refuted this theory based on findings that the relative increase in CBF was greater than the relative increase in cerebral metabolism (1820); the cellular damage associated with status epilepticus was not identical to hypoxic injury (21); seizures induced increases, rather than decreases, in venous oxygenation (17,22); the presence of oxidation in the mitochondrial transport chain, NADH, and cytochrome oxidase (23,24); increases in tissue pO2 (25,26); and tissue injury that occurred even in the absence of cerebral anoxia (16,22).
More recent studies in animals using autoradiography, PET, and fMRI, which have limited temporal and spatial resolution, have been contradictory (18,20,2730). While an increase in perfusion is universally demonstrated, some studies find that perfusion oversupplies metabolism (29,30) while others demonstrate that there is inadequate perfusion to meet metabolic demand (18,20,27,28). Investigators using interictal and ictal spike-triggered fMRI on humans, generally report an increase in the BOLD signal consistent with a decrease in deoxygenated hemoglobin and adequate CBF (3136). However, most fMRI studies have been performed on interictal rather than ictal events, which may elicit such a brief focal increase in deoxygenated hemoglobin as to be undetectable without higher strength magnets (3133,35). Likewise, ictal fMRI studies have been done either on generalized spike-and-wave events, which may not elicit an increase in deoxygenated hemoglobin in the cortex (34,36), or without concurrent electrical recordings, rendering the timing of the imaging unclear with respect to the seizure onset (37,38).
More recently, studies in animals using techniques, such as ORIS and oxygen-sensitive electrodes that have even higher spatial and/or temporal resolution than PET or fMRI, have been performed to resolve these persistent questions. Optical spectroscopy uses ORIS at multiple wavelengths to measure blood oxygenation and CBV from large areas of cortex simultaneously with a spatial and temporal resolution that is limited by the specifications of the camera acquiring the data and by the evolution of the signal (~33 milliseconds and <200 μm). This technique is based on variations in the light absorption spectrum of hemoglobin in the oxygenated and deoxygenated state (4). Measurements of deoxygenated hemoglobin and CBV with ORIS have demonstrated a clear increase in deoxygenated hemoglobin, in spite of an increase in CBV, during both interictal and ictal events in animal models of focal epilepsy, indicating that for a variable period of time at the onset of a epileptic event CBF is not adequate to meet metabolic demand (3942). For interictal events, hemoglobin oxygenation drops for ~3 s, whereas at the beginning of a seizure, the drop in oxygenation can last for tens of seconds. Once the dip ends, there is a dramatic increase in oxygenated hemoglobin, which explains the increase in BOLD signal found with fMRI. Confirmation of this finding was achieved by directly measuring tissue pO2 using oxygen-sensitive electrodes, which demonstrated a decrease in tissue pO2 at the onset and throughout most of the duration of focal seizures followed by an increase in pO2 (39).
Whether animal data are relevant to human epilepsy is unclear. However, taking a look back in order to look forward, one can find studies performed as long as 40 years ago in which oxygen-sensitive electrodes were placed within the epileptic focus of human cortex during chronic electrocorticographic monitoring. These studies also showed a decrease in tissue pO2 during focal human epilepsy (43,44). More recently, similar results were shown with near infrared spectroscopic (NIRS) data measured through the scalp during pediatric epileptic events (45) and using multiwavelength ORIS in human epileptic cortex in the operating room (46,47,55).
What is the significance of these findings? First, if the transient decrease in hemoglobin oxygenation associated with interictal and ictal events is more focal than the subsequent increase, then imaging techniques that measure the later increase, such as BOLD fMRI, may mistakenly localize the epileptic focus or demonstrate a larger area than the onset zone. Higher resolution magnets that concentrate on the earlier decrease in hemoglobin oxygenation may have better localizing value. Second, a decrease in tissue oxygen during epileptic events again raises the possibility of hypoxia-induced tissue damage during prolonged ictal or high-frequency interictal events. Therapeutic intervention to restore cortical oxygenation may prove efficacious. Finally, there is increasing evidence that hemodynamic events may be useful not only for localizing but also for predicting the onset of seizures. This concept was proposed as early as 1933 (48). More recent studies using transcranial Doppler have demonstrated increases in lobar perfusion 20 min before focal as well as generalized spike-and-wave events (4951). Likewise, both increases (36,45,52) and decreases (53) in tissue oxygenation have been found tens of seconds before seizure onset using fMRI and NIRS. ORIS data also have shown focal preictal changes in light reflection in both animal and human models (46,55). These findings raise the intriguing possibility that hemodynamic changes may be useful in predicting seizure onset and triggering a variety of “closed-loop” therapies, such as cortical stimulation, focal drug perfusion, or cooling.
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