A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI Alessandro Gozzi a, 4 , Laura Ceolin a , Adam Schwarz a , Torsten Reese a , Simone Bertani b , Valerio Crestan b , Angelo Bifone a a Department of Neuroimaging, Centre of Excellence for Drug Discovery, Psychiatry, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy b Laboratory Animal Science, Centre of Excellence for Drug Discovery, Psychiatry, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy Accepted 11 January 2007 Abstract Pharmacological MRI (phMRI) methods have been widely applied to assess the central hemodynamic response to pharmacological intervention as a surrogate for changes in the underlying neuronal activity. However, many psychoactive drugs can also affect cardiovascular parameters, including arterial blood pressure (BP). Abrupt changes in BP or the anesthetic agents used in preclinical phMRI may impair cerebral blood flow (CBF) autoregulation mechanisms, potentially introducing confounds in the phMRI response. Moreover, relative cerebral blood volume (rCBV), often measured in small-animal phMRI studies, may be sensitive to BP changes even in the presence of intact autoregulation. We applied laser Doppler flowmetry and MRI to measure changes in CBF and microvascular CBV induced by increasing doses of intravenous norepinephrine (NE) challenge in the halothane-anesthetized rat. NE is a potent vasopressor that does not cross the blood–brain barrier and mimics the rapid BP changes typically observed with acute drug challenges. We found that CBF autoregulation was maintained over a BP range of 60–120 mmHg. Under these conditions, no significant central rCBV responses were observed, suggesting that microvascular rCBV changes in response to abrupt changes in perfusion pressure are negligible within the autoregulatory range. Larger BP responses were accompanied by significant changes in both CBV and CBF that might confound the interpretation of phMRI results. D 2007 Elsevier Inc. All rights reserved. Keywords: phMRI; CBF; CBV; Autoregulation; Rat; Blood pressure 1. Introduction Pharmacological MRI (phMRI) methods can be applied to assess the effects of acute drug challenge on cerebral hemodynamics as a surrogate for changes in the underlying neuronal activity. This approach has been widely applied to study central effects of drugs on the central nervous system (CNS) in humans and animal models [1,2]. However, many of these drugs can also induce significant peripheral effects, including severe alterations of cardiovascular parameters. Under physiological conditions, mechanisms of autoregula- tion keep cerebral blood flow (CBF) relatively constant in the presence of changes in mean arterial blood pressure (MABP). However, general anesthetics, widely used in preclinical phMRI studies to avoid head motion and to better control animal physiology, may affect the central vasoadaptive response to peripheral MABP changes, thus making it difficult to predict the influence of systemic vasopressive effects on cerebral hemodynamics. Moreover, large and rapid changes in MABP may cause a breakdown in the autoregulatory mechanisms that control brain microcirculation, thus introducing potential confounds in the interpretation of phMRI data. While blood-oxygen-level-dependent (BOLD) signals are most often measured in humans, relative cerebral blood volume (rCBV) has been widely used in phMRI studies in small laboratory animals due to the increased sensitivity afforded by rCBV measurements with intravascular contrast agents over BOLD [3]. However, dilation and constriction of cerebral blood vessels are thought to modulate vascular resistance in order to maintain CBF relatively constant in the presence of changes in perfusion pressure [4]. As a consequence, CBV might be sensitive to MABP changes even in the presence of intact autoregulation. Several attempts to correlate the magnitude of sys- temic MABP changes with the central hemodynamic res- 0730-725X/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.mri.2007.03.003 4 Corresponding author. Tel.: +39 0458219233; fax: +39 0458218073. E-mail address: alessandro.2.gozzi@gsk.com (A. Gozzi). Magnetic Resonance Imaging 25 (2007) 826 – 833