Molecular Neurobiology 1 Volume 33, 2006Molecular NeurobiologyCopyright © 2006 Humana Press Inc.All rights of any nature whatsoever reserved.ISSN 0893-7648/06/33(3): 000–000/$30.00ISSN(Online) 1559-1182Neurovascular Coupling and Oximetry During Epileptic EventsMinah Suh*, Hongtao Ma, Mingrui Zhao, Saadat Sharif, and Theodore H. SchwartzDepartment of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NYAbstractEpilepsy is an abnormal brain state in which a large population of neurons is synchronouslyactive, causing an enormous increase in metabolic demand. Recent investigations using high-resolution imaging techniques, such as optical recording of intrinsic signals and voltage-sensitive dyes, as well as measurements with oxygen-sensitive electrodes have elucidated thespatiotemporal relationship between neuronal activity, cerebral blood volume, and oximetry invivo. A focal decrease in tissue oxygenation and a focal increase in deoxygenated hemoglobinoccurs following both interictal and ictal events. This “epileptic dip” in oxygenation can persistfor the duration of an ictal event, suggesting that cerebral blood flow is inadequate to meetmetabolic demand. A rapid focal increase in cerebral blood flow and cerebral blood volume alsoaccompanies epileptic events; however, this increase in perfusion soon (>2 s) spreads to a largerarea of the cortex than the excitatory change in membrane potential. Investigations in humansduring neurosurgical operations have confirmed the laboratory data derived from animal stud-ies. These data not only have clinical implications for the interpretation of noninvasive imagingstudies such as positron emission tomography, single-photon emission tomography, and func-tional magnetic resonance imaging but also provide a mechanism for the cognitive decline inpatients with chronic epilepsy.Index Entries: Epilepsy; ictal; interictal; intrinsic signal; optical imaging; voltage-sensitive dye;oxygen-sensitive electrodes; neurovascular coupling; oximetry; initial dip; BOLD; rat; seizure;human.* Author to whom all correspondence and reprint requests should be addressed. E-mail: [email protected] August 25, 2005; Accepted ######AU:Pleaseprovideaccepteddate.IntroductionThe study of neurovascular coupling exam-ines the relationship between neuronal activity,metabolism, tissue, and blood oxygenationand blood flow. It has been generally acceptedthat increases in neuronal activity increase thecerebral metabolic rate of oxygen consumption(CMRO2), leading to an increase in cerebralblood flow (CBF) and cerebral blood volume(CBV) as the brain attempts to perfuse theactive neurons with oxygenated hemoglobin(1). It was then shown, using positron emissiontomography (PET) of glucose metabolism (atechnique with a slow temporal resolution[approximately seconds]; ref. 2) that increasesin CBF occurring 1 to 2 s after the onset of neu-ronal activity provide an oversupply of oxy-genated hemoglobin (HbO2). Therefore, CMRO2and CBF are “uncoupled,” causing relativeincreases in the concentration of HbO2 com-pared with deoxygenated hemoglobin (Hbr),which forms the basis of the blood-oxygen-level-dependent (BOLD) signal that can beimaged with functional magnetic resonanceimaging (fMRI; ref. 3). More recently, usingtechniques with higher spatial and temporalresolution, such as optical recording of intrinsicsignals (ORIS; refs. 4 and5), imaging spec-troscopy (6,7), oxygen-dependent phospheres-cence quenching (8), oxygen-sensitive electrodes(9,10), and fMRI at 1.5- and 4-Tesla (11, 12),investigators have examined changes in tissueand blood oxygenation that occur within thefirst few hundred milliseconds after neuronsbecome active. These studies have demon-strated a rapid decrease in tissue oxygenation,or an increase in Hbr, that precedes the increasein CBF. This “initial dip,” although questionedby some studies (13–15), implies that for a briefperiod of time after neurons discharge, thebrain is mildly ischemic until cerebrovascularautoregulation dilates arterioles to increaseCBF.Epilepsy is an abnormal physiological statethat, unlike normal somatosensory processing,places supranormal demands on the brain’sautoregulatory mechanisms because of anenormous increase in CMRO2(16). Therefore,the neurovascular coupling mechanisms thatapply in the normal situation may not be rele-vant. Epilepsy is a disease involving recurrentseizures that consist of the paroxysmal, syn-chronous, rhythmic firing of a population ofpathologically interconnected neurons capableof demonstrating high-frequency oscillatoryactivity (17). Between these “ictal” events, briefparoxysmal short-duration (~100 ms) eventsoccur called “interictal spikes” (18). Priorinvestigations into neurovascular couplingduring epileptic events have demonstratedcontradictory results in both animals andhumans using autoradiography, PET, andfMRI, all of which are techniques with limitedtemporal and spatial resolution (19–25).Although an increase in perfusion is univer-sally demonstrated, some studies have shownthat perfusion oversupplies metabolism(24–27), whereas others have demonstrated theopposite—namely, inadequate perfusion tomeet metabolic demand (19,21–23). Therefore,the relationship between perfusion and oxy-genation during the first few seconds after anepileptiform event has remained elusive. Thisarticle reviews recent data on neurovascularcoupling during epilepsy obtained in vivousing techniques that have high temporal andspatial resolution such as ORIS, oxygen-sensi-tive electrodes, and voltage-sensitive dyes(VSDs).Optical Recording of Intrinsic SignalsThe intrinsic optical signal (IOS) is a smallchange in the absorption (or reflection) of lightthat occurs in neuronal tissue when neuronsare activated. These changes can be recordedfrom various preparations, ranging from a sin-gle neuron preserved in vitro (28) to thehuman brain in the neurosurgical operatingroom (29). ORIS has been used extensively tomap static functional architecture such as ori-entation and ocular dominance columns invisual cortex, which has led to discoveries suchas the pinwheel organization of orientation2 Suh et al.Molecular Neurobiology Volume 33, 2006columns (30). The origins of the IOS are multi-ple because neuronal activity induces a cas-cade of events in the surrounding tissues, eachof which can influence the reflection of light.The real power of the IOS arises from the
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