CURRENT REVIEW IN CLINICAL SCIENCENEUROVASCULAR COUPLING ANDEPILEPSY:HEMODYNAMIC MARKERSFORLOCALIZING ANDPREDICTINGSEIZURE ONSETTheodore H. Schwartz, MDDepartment of Neurological Surgery, Weill Medical College ofCornell University, New YorkHemodynamic surrogates of epileptic activity are being used to mapepileptic foci with PET, SPECT, and fMRI. However, there are fewstudies of neurovascular coupling in epilepsy. Recent data indicatethat cerebral blood flow, although focally increased at the onsetof a seizure, may be temporarily inadequate to meet the metabolicdemands of both interictal and ictal epileptic events. Transient focaltissue hypoxia and hyperperfusion may be excellent markers for theepileptic focus and may even precede the onset of the ictal event.In recent years, the field of brain mapping has witnessedthe growth of a variety of techniques that use measurementsof hemodynamic changes as surrogates for neuronal activity.This development particularly has occurred in the treatment ofepilepsy, for which therapeutic decisions are often made basedon the results of PET, SPECT, and f MRI scans. Hemodynamicsignals, generally derived from perfusion and/or oximetry, areattractive since they often can be measured noninvasively. How-ever, accurate interpretation of these data depends on a firm un-derstanding of neurovascular coupling mechanisms in the brain,especially as they pertain to abnormal events such as epilepsy.Neurovascular Coupling in the Brainduring Normal Cortical ProcessingThe study of neurovascular coupling examines the relation-ships among neuronal activity, metabolism, tissue and bloodoxygenation, and blood flow. It is generally accepted that dur-ing normal cortical processing, increases in neuronal activityAddress correspondence to Theodore H. Schwartz, MD, Departmentof Neurological Surgery, Weill Medical College of Cornell Univer-sity, 525 East 68th St., Box No. 99, New York, NY 10021. E-mail:[email protected] Currents, Vol. 7, No. 4 (July/August) 2007 pp. 91–94Blackwell Publishing, Inc.CAmerican Epilepsy Societysimultaneously increase the cerebral metabolic rate of oxygenand glucose, leading to an increase in cerebral blood flow (CBF)and cerebral blood volume (CBV), as the brain attempts toperfuse active neurons with oxygenated hemoglobin (1). PETstudies of oxygen metabolism and blood flow, a technique witha slow temporal resolution, have demonstrated that increases inCBF occurring 1–2 s after the onset of neuronal activity pro-vide an oversupply of oxygenated hemoglobin (2). Hence, thecerebral metabolic rate of oxygen and CBF are “uncoupled,”causing an increase in oxygenated hemoglobin that forms thebasis of the blood oxygenation level-dependent (BOLD) sig-nal imaged with f MRI (3). More recently, using techniqueswith higher spatial and temporal resolution—such as opticalrecording of intrinsic signals (ORIS) (4), imaging spectroscopy(5,6), oxygen-dependent phosphorescence quenching (7),oxygen-sensitive electrodes (8,9), and f MRI at 1.5 and 4 Tesla(10,11)—investigators have examined changes in tissue andblood oxygenation that occur within the first few hundred mil-liseconds after neurons become active. These studies demon-strated a rapid decrease in tissue oxygenation and an increasein 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 autoregulationdilates arterioles to increase CBF.Neurovascular Coupling in EpilepsyEpilepsy is an abnormal physiologic state which, unlike normalsomatosensory processing, places supra-normal demands on thebrain’s autoregulatory mechanisms as a result of an enormousincrease in the metabolic rate of oxygen following both interic-tal and ictal events (14). Hence, neurovascular-coupling mech-anisms that apply in the normal situation may not be relevantto the epileptic brain. Whether or not CBF is adequate to meetthe increased metabolic demands of epilepsy has been a long-standing debate. The initial hypoxia–hypoperfusion hypothe-sis, derived from histologic similarities between ischemic andepileptic brain damage, proposed that the cell damage followingstatus epilepticus was caused by cerebral anoxia (15–17). Laterstudies refuted this theory based on findings that the relativeincrease in CBF was greater than the relative increase in cerebralmetabolism (18–20); the cellular damage associated with statusepilepticus was not identical to hypoxic injury (21); seizuresinduced increases, rather than decreases, in venous oxygenation(17,22); the presence of oxidation in the mitochondrial trans-port chain, NADH, and cytochrome oxidase (23,24); increases92 Current Review in Clinical Sciencein tissue pO2(25,26); and tissue injury that occurred even inthe absence of cerebral anoxia (16,22).PET andfMRIMore recent studies in animals using autoradiography, PET,and f MRI, which have limited temporal and spatial resolu-tion, have been contradictory (18,20,27–30). While an in-crease in perfusion is universally demonstrated, some studiesfind that perfusion oversupplies metabolism (29,30) while oth-ers demonstrate that there is inadequate perfusion to meetmetabolic demand (18,20,27,28). Investigators using interic-tal and ictal spike-triggered f MRI on humans, generally reportan increase in the BOLD signal consistent with a decrease in de-oxygenated hemoglobin and adequate CBF (31–36). However,most f MRI studies have been performed on interictal ratherthan ictal events, which may elicit such a brief focal increase indeoxygenated hemoglobin as to be undetectable without higherstrength magnets (31–33,35). Likewise, ictal f MRI studies havebeen done either on generalized spike-and-wave events, whichmay not elicit an increase in deoxygenated hemoglobin in thecortex (34,36), or without concurrent electrical recordings, ren-dering the timing of the imaging unclear with respect to theseizure onset (37,38).Optical Spectroscopy and Oxygen-SensitiveElectrodesMore recently, studies in animals using techniques, such asORIS and oxygen-sensitive electrodes that have even higherspatial and/or temporal resolution than PET or f MRI, havebeen performed to resolve these persistent questions. Opticalspectroscopy uses ORIS at multiple wavelengths to measureblood oxygenation and CBV from large areas of cortex simul-taneously with a spatial and
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