5BOLD Signal ChangeBaseline SignalTEActivation Signal
6Hemoglobin and Field Inhomogeneities Oxygen binds to the iron atoms to form oxyhemoglobin HbO2Release of O2 to tissue results in deoxyhemoglobin dHBO2B0Field MapsMore dHBLess dHB
7Signal Decay Some dHB, Some dephasing TE timeTESome dHB, Some dephasingMore dHB, More dephasing, Decrease in MR signal
8BOLD Signal Equation Cerebral Blood Volume Large vessels Linear =1 Ogawa et al, 1993Large vesselsLinear =1Cerebral Blood VolumeDiffusion around small vesselsQuadratic =2Simulations suggest 1.5 is a reasonable valueOgawa et al, 1993; Boxerman et al 1995, Hoge et al. 1999
9Blood Flow and Oxygen Metabolism Cerebral Blood Flow (CBF) measures delivery of blood to brain tissue (units of ml/(g-min))Cerebral Metabolic Rate of (CMRO2) is the rate of oxygen consumption (units of mol/(g-min))CBF [O2]arterialOxygen extraction fraction (E)CMRO2CMRO2= E CBF [O2]arterial
15Interpreting BOLDMost fMRI studies assume that the BOLD signal is is proportional to brain activity.This is a reasonable assumption for basic studies of healthy young unmedicated subjects.However, the assumption is less valid for studies where disease, medication, and age may be a factor.Boynton et al, 1996
16Variability in BOLD amplitude Data courtesy of J. Liau
23ASL measures of regional baseline CBF Response to Breathhold or CO2; Resting-state FluctuationsCerebralBlood VolumedeoxyHbNeuralActivityCerebralBlood FlowMetabolism(CMRO2)BOLDSignalTrust MRI Measures of whole brain venous oxygenation
24BOLD and Venous Oxygenation Inter-subject Differences in M can lead to inter-subject differences in BOLDTRUST MRI (Lu et al 2007): Measures of whole brain venous oxygenation saturation.Yv[dHB]venousBOLD
28BOLD variability and Baseline CBF M appears to be independent of CBF -- effects of increased CBF and decreased [dHb] appear to cancel outVariability in the BOLD response across subjects appears to be driven by inter-subject differences in the CBF response.Liau et al, Abstract 854, ISMRM 2008
33Scaling with Resting-State Fluctuations Wise et al 2004;
34Scaling with Resting-State Fluctuations Birn et al 2006;
35Scaling with Resting-State Fluctuations Kannapurti and Biswal 2008; also Abstract 750
36Summary of Normalization Approaches Additional measures can account for BOLD variability due to variations in baseline blood flow, volume, oxygenation, field strength, etc.Measures of venous oxygenation, cerebral blood flow, and resting fluctuations have the advantage of not requiring the subject to perform additional tasks.These approaches offer some insight into the factors that can affect the BOLD response between subjects, groups, and conditions.
41Calibrated fMRI of HIVAnces et al, in preparation
42Effect of age on CBF and BOLD Young OldNormalized CMRO2Young Old%CMRO2Restom et al, NIMG 2007
43Calibrated fMRICan provide insights that BOLD measures alone cannot provide.Can be difficult to apply to cognitive tasks and special populations, due to low sensitivity of ASL.The need for breathhold or hypercapnia can also be an issue. Hyperoxia-based method may be an alternative.
44ConclusionsThe BOLD signal is a complex function of the baseline state and changes in blood flow, volume, and metabolism.Differences in the BOLD signal do NOT always reflect differences in neural activity.Instead they may reflect differences in the baseline vascular or metabolic state.Normalization methods can help to reduce inter-subject variability.Calibrated fMRI can provide additional insights into differences in brain activity, especially in the presence of disease, medication, and age.
45Acknowledgements Beau Ances Yashar Behzadi Rick Buxton David Dubowitz Joy LiauOleg LeontievJoanna PerthenKhaled RestomEric Wong