CURRENT REVIEW IN CLINICAL SCIENCE 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 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 f MRI 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 Neurovascular Coupling in the Brain during Normal Cortical Processing 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 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 med cornell edu Epilepsy Currents Vol 7 No 4 July August 2007 pp 91 94 Blackwell Publishing Inc C American Epilepsy Society 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 f MRI 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 f MRI 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 Neurovascular Coupling in Epilepsy 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 longstanding 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 92 Current Review in Clinical Science in tissue pO2 25 26 and tissue injury that occurred even in crease in tissue pO2 at the onset and throughout most of the the absence of cerebral anoxia 16 22 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 PET and f MRI one can find studies performed as long as 40 years ago in which More recent studies in animals using autoradiography PET oxygen sensitive electrodes were placed within the epileptic foand f MRI which have limited temporal and spatial resolucus of human cortex during chronic electrocorticographic montion have been contradictory 18 20 27 30 While an initoring These studies also showed a decrease in tissue pO2 durcrease in perfusion is universally demonstrated some studies ing focal human epilepsy 43 44 More recently similar results find that perfusion oversupplies metabolism 29 30 while othwere shown with near infrared spectroscopic NIRS data meaers demonstrate that there is inadequate perfusion to meet sured through the scalp during pediatric epileptic events 45 metabolic demand 18 20 27 28 Investigators using intericand using multiwavelength ORIS in human epileptic cortex in tal and ictal spike triggered f MRI on humans generally report the operating room 46 47 55 an increase in the BOLD signal consistent with a decrease in deoxygenated hemoglobin and adequate CBF 31 36 However most f MRI studies have been performed on interictal rather Significance than ictal events which may elicit such a brief focal increase in What is the significance of these findings First if the transient deoxygenated hemoglobin as to be undetectable without higher decrease in hemoglobin oxygenation associated with
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