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.

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 (15–17). Later studies refuted this theory based on findings that the relative increase in CBF was greater than the relative increase in cerebral metabolism (18–20); 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 (18,20,27–30). 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 (31–36). 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 (31–33,35). 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).

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 (49–51). 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.