Response

Abstract

We agree with Uludaǧ and Buxton that a decrease in basal CMRO2 is one possible explanation for the discrepancy between the measured effect of indomethacin on the MR signal, BOLDph, and the predicted value (see Appendix A in our original paper (1)). Their interpretation regarding the consistent coupling between CBF and CMRO2 (i.e., during drug injection and activation) is certainly intriguing, and we have no fundamental disagreement. However, a more detailed review of the literature would perhaps better clarify the possible effects of indomethacin on CMRO2. Uludaǧ and Buxton cited one study reporting that indomethacin significantly reduced CBF and CMRO2 in hypotensive piglets (2). In that study, the reduction in CMRO2 might be attributed to two factors. First, a large pharmacological dose of indomethacin was administered (5.0 mg/kg); second, the measurements were obtained in newborn piglets. With regard to the first point, Coyle et al. (3) observed in newborn piglets that while CMRO2 was reduced following administration of a large dose (5.0 mg/kg) of indomethacin, CMRO2 was not affected by a lower, more clinically relevant dose (0.3 mg/kg). In a recent study using a novel near-infrared spectroscopy technique to measure CMRO2, a dose of 0.2 mg/kg (which is the same dose used in our study) was found to have no effect on CMRO2 in newborn piglets, although it did reduce CBF and increase oxygen extraction (4). With regard to the second point, prostaglandins are believed to contribute to the regulation of CBF and CMRO2 in the developing brain, but not in the mature brain (5). This may explain why indomethacin, which is a potent prostaglandin inhibitor, has been shown at pharmacological doses to decrease CMRO2 in piglets, but has no effect on CMRO2 in the adult brain. This has been demonstrated in baboons (at a dose of ∼20 mg/kg) (6, 7), rats (5–10 mg/kg) (8), pigs (2 mg/kg) (9), and humans (single dose of 100 mg) (10, 11). Interestingly, although Wennmalm et al. (10) reported the same decrease in global CBF (35%) as we measured in the primary motor cortex, they found no decrease in global CMRO2 (see Table 1 in Ref. 10). If CMRO2 and CBF were coupled, a corresponding reduction in CMRO2 (∼18%) should have been observed. It is important to note that this apparent uncoupling of CBF and CMRO2 during indomethacin infusion is not unique to this drug, since alterations in the arterial blood gases (PaCO2 and PaO2) are known to change CBF independently of CMRO2 (12). Uludaǧ and Buxton have presented a novel interpretation of our data, and we agree with their conclusion that more studies are needed to clarify how CBF/CMRO2 coupling is potentially altered by indomethacin. This is a very relevant question considering the increasing number of studies using fMRI techniques to investigate potential effects of pharmacological agents on brain function (see our original paper (1) for references). K.S. St. Lawrence Ph.D kstlaw@lri.sjhc.london.on.ca*, F.Q. Ye Ph.D , J.A. Frank M.D*, A.C. McLaughlin Ph.D , * Laboratory of Diagnostic Radiology Research, Clinical Center, National Institutes of Health, Bethesda, Maryland, Functional MRI Facility, DIRP, NIMH, National Institutes of Health, Bethesda, Maryland, Laboratory of Clinical Studies, NIAAA, National Institutes of Health, Bethesda, Maryland.