Physiological characterization of a robust survival rodent fMRI method.

Anesthetics are commonly used in preclinical functional MRI studies. It is well-appreciated that proper choice of anesthetics is of critical importance for maintaining a physiologically normal range of autonomic functioning. A recent study, using a low dose of dexmedetomidine (active isomer of medetomidine) in combination with a low dose of isoflurane, suggested stable measurements across repeated fMRI experiments in individual animals with each session lasting up to several hours. The rat default mode network has been successfully identified using this preparation, indicating that this protocol minimally disturbs brain network functions. However, medetomidine is known to cause peripheral vasoconstriction, respiratory suppression, and bradycardia, each of which could independently confound the BOLD signal. The goal of this study was to systematically characterize physiological conditions for fMRI experiments under this anesthetic regimen. To this end, we acquired somatosensory stimulation "task-evoked" and resting-state fMRI to evaluate the integrity of neurovascular coupling and brain network function during three time windows (0-30min, 30-90min, and 90-150min) following dexmedetomidine initiation. Results demonstrate that both evoked BOLD response and resting-state fMRI signal remained stable during the 90-150min time window, while autonomic physiological parameters maintained near-normal conditions during this period. Our data suggest that using a spontaneously-inhaled, low dose of isoflurane in combination with a continuous low dose of dexmedetomidine is a viable option for longitudinal imaging studies in rats.

[1]  B. Pypendop,et al.  Pharmacokinetics of dexmedetomidine after intravenous administration of a bolus to cats. , 2014, American journal of veterinary research.

[2]  I Kanno,et al.  Modulation of evoked cerebral blood flow under excessive blood supply and hyperoxic conditions. , 2000, The Japanese journal of physiology.

[3]  Chris J. Martin,et al.  Optical imaging spectroscopy in the unanaesthetised rat , 2002, Journal of Neuroscience Methods.

[4]  Andreas Hess,et al.  Imaging of hyperalgesia in rats by functional MRI , 2007, European journal of pain.

[5]  B. Pypendop,et al.  Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats. , 2012, Journal of veterinary pharmacology and therapeutics.

[6]  A Villringer,et al.  Coupling of brain activity and cerebral blood flow: basis of functional neuroimaging. , 1995, Cerebrovascular and brain metabolism reviews.

[7]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[8]  Afonso C. Silva,et al.  Laminar specificity of functional MRI onset times during somatosensory stimulation in rat , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Xiaoping P. Hu,et al.  Comparison of alpha-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat. , 2010, Magnetic resonance imaging.

[10]  M. Raichle,et al.  Rat brains also have a default mode network , 2012, Proceedings of the National Academy of Sciences.

[11]  Dieter Jaeger,et al.  Infraslow LFP correlates to resting-state fMRI BOLD signals , 2013, NeuroImage.

[12]  Hanbing Lu,et al.  Low- but Not High-Frequency LFP Correlates with Spontaneous BOLD Fluctuations in Rat Whisker Barrel Cortex. , 2014, Cerebral cortex.

[13]  David Borsook,et al.  Utilizing brain imaging for analgesic drug development. , 2002, Current opinion in investigational drugs.

[14]  Geoffrey Schoenbaum,et al.  The Role of Orbitofrontal Cortex in Drug Addiction: A Review of Preclinical Studies , 2008, Biological Psychiatry.

[15]  Adam J. Schwarz,et al.  Anti-Correlated Cortical Networks of Intrinsic Connectivity in the Rat Brain , 2013, Brain Connect..

[16]  M. Scheinin,et al.  Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery. , 1990, Anesthesiology.

[17]  A. Guyton,et al.  Textbook of Medical Physiology , 1961 .

[18]  F. J. Neto,et al.  Effects of epidural administration of dexmedetomidine on the minimum alveolar concentration of isoflurane in dogs. , 2007 .

[19]  Feng Luo,et al.  Attenuation of brain response to heroin correlates with the reinstatement of heroin-seeking in rats by fMRI , 2004, NeuroImage.

[20]  J. Drummond,et al.  Monitoring depth of anesthesia: with emphasis on the application of the bispectral index and the middle latency auditory evoked response to the prevention of recall. , 2000, Anesthesiology.

[21]  Seong-Gi Kim,et al.  Effects of the α2‐adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex , 2013, The European journal of neuroscience.

[22]  Seong-Gi Kim,et al.  Dose‐dependent effect of isoflurane on neurovascular coupling in rat cerebral cortex , 2009, The European journal of neuroscience.

[23]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[24]  B. Pypendop,et al.  Hemodynamic effects of medetomidine in the dog: a dose titration study. , 1998, Veterinary surgery : VS.

[25]  Lei Zhou,et al.  BOLD study of stimulation-induced neural activity and resting-state connectivity in medetomidine-sedated rat , 2008, NeuroImage.

[26]  Fuqiang Zhao,et al.  fMRI of pain processing in the brain: A within-animal comparative study of BOLD vs. CBV and noxious electrical vs. noxious mechanical stimulation in rat , 2012, NeuroImage.

[27]  Bharat B. Biswal,et al.  A protocol for use of medetomidine anesthesia in rats for extended studies using task-induced BOLD contrast and resting-state functional connectivity , 2009, NeuroImage.

[28]  E. Brown,et al.  General anesthesia and altered states of arousal: a systems neuroscience analysis. , 2011, Annual review of neuroscience.

[29]  Fahmeed Hyder,et al.  Quantitative fMRI and oxidative neuroenergetics , 2012, NeuroImage.

[30]  T. Duong,et al.  Regional Cerebral Blood Flow and BOLD Responses in Conscious and Anesthetized Rats under Basal and Hypercapnic Conditions: Implications for Functional MRI Studies , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  M. Roesch,et al.  Orbitofrontal Cortex, Associative Learning, and Expectancies , 2005, Neuron.

[32]  Dirk Wiedermann,et al.  A fully noninvasive and robust experimental protocol for longitudinal fMRI studies in the rat , 2006, NeuroImage.

[33]  Reduction of the Minimum Alveolar Concentration of Isoflurane by Dexmedetomidine , 1997, Anesthesiology.

[34]  Jason Berwick,et al.  Functional MRI in conscious rats using a chronically implanted surface coil , 2013, Journal of magnetic resonance imaging : JMRI.

[35]  S. Ogawa,et al.  Oxygenation‐sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields , 1990, Magnetic resonance in medicine.

[36]  Wei Chen,et al.  Procedure for minimizing stress for fMRI studies in conscious rats , 2005, Journal of Neuroscience Methods.

[37]  F. Ye,et al.  Correction for geometric distortion and N/2 ghosting in EPI by phase labeling for additional coordinate encoding (PLACE) , 2007, Magnetic resonance in medicine.

[38]  Fuqiang Zhao,et al.  Functional imaging of olfaction by CBV fMRI in monkeys: Insight into the role of olfactory bulb in habituation , 2015, NeuroImage.

[39]  Anthony H. Dickenson,et al.  Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat , 1979, PAIN.

[40]  Ciprian Catana,et al.  Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI , 2013, Proceedings of the National Academy of Sciences.

[41]  Yihong Yang,et al.  fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history , 2012, NeuroImage.

[42]  B B Biswal,et al.  Effects of hypoxia and hypercapnia on capillary flow velocity in the rat cerebral cortex. , 1997, Microvascular research.

[43]  Yihong Yang,et al.  Registering and analyzing rat fMRI data in the stereotaxic framework by exploiting intrinsic anatomical features. , 2010, Magnetic resonance imaging.