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Open Access Publications from the University of California

Scholarly Works (21 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2015)
Calibrated BOLD imaging, in which traditional measurements of the BOLD signal are combined with measurements of cerebral blood flow (CBF) within a BOLD biophysical model to estimate changes in oxygen metabolism (CMRO2), has been a valuable tool for untangling the physiological processes associated with neural stimulus-induced BOLD activation. However, to date this technique has largely been applied to the study of essentially steady-state physiological changes (baseline to activation) associated with block-design stimuli, and it is unclear whether this approach may be directly extended to the study of more dynamic, naturalistic experimental designs. In this study we tested an assumption underlying this technique whose validity is critical to the application of calibrated BOLD to the study of more dynamic stimuli, that information about fluctuations in venous cerebral blood volume (CBVv) can be captured indirectly by measuring fluctuations in CBF, making the independent measurement of CBVv unnecessary. To accomplish this, simultaneous arterial spin labeling and BOLD imaging were used to measure the CBF and BOLD responses to flickering checkerboards with contrasts that oscillated continuously with frequencies of ~0.02-0.16Hz. The measurements were then fit to a dynamic physiological model of the BOLD response in order to explore the range of consistent CMRO2 and CBVv responses. We found that the BOLD and CBF responses were most consistent with relatively tight dynamic coupling between CBF and CMRO2 and a CBVv response that was an order of magnitude slower than either CBF or CMRO2. This finding suggests that the assumption of tight flow-volume coupling may not be strictly valid, complicating the extension of calibrated BOLD to more naturalistic experimental designs.
    Cover page: Understanding the dynamic relationship between cerebral blood flow and the BOLD signal: Implications for quantitative functional MRI
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2019)

    The development of functional magnetic resonance imaging (fMRI) caused a paradigm shift in the study of neuroscience. However, despite the boom in research, fMRI has had a much smaller impact in the clinical setting. This is due to the complexity of the blood- oxygenation level dependent (BOLD) signal and its lack of inherent physiological meaning. Instead, cerebral blood flow (CBF) and cerebral metabolism of oxygen (CMRO2) have been proposed as physiological indicators of neural activity, and noninvasive measurement of these parameters could lead to improved applicability to clinical problems. While arterial spin labeling (ASL) techniques are well-established for measuring baseline CBF and fractional changes in CBF to a stimulus, measurements of CMRO2 are more controversial. Some methods to estimate CMRO2 involve contrast injection or administration of special gases, which could potentially prevent their use in certain patient populations.

    Here, the feasibility for quantitative measurements reflective of neural physiology is established. This is accomplished through a suite of tools to estimate specific physiological metrics that reflect baseline CBF and CMRO2 and their responses to a standard stimulus, without encumbering the patient. The techniques utilized are Velocity Selective Excitation and Arterial Nulling (VSEAN) to measure oxygen extraction fraction (OEF), which leads to the calculation of baseline CMRO2, and FLuid Attenuated Inversion Recovery-Gradient Echo Sampling of Spin Echo (FLAIR-GESSE) to calibrate baseline deoxyhemoglobin through R2', leading to fractional CMRO2 estimates. These, in combination with the latest BOLD/ASL acquisitions, form a toolbox that allows for full physiological quantification. Initial results demonstrate values of baseline CMRO2 that match previously reported results, as well as a close relationship between R2' data and widely-used gas method results. The toolbox is then applied to detecting changes in brain state induced by caffeine administration. Measurements in the pre- and post-caffeine states illustrate the ability of the toolbox to 1) reproduce known physiological changes due to caffeine and 2) significantly distinguish the change in brain state due to this intervention. These results demonstrate the use of physiological fMRI in providing a more detailed and reproducible picture of the human brain at work, paving the way for future clinical applications.

      Cover page: Establishing a foundation for physiological fMRI: How do we noninvasively quantify the human brain at work?
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2015)
      Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow-metabolism coupling (n=%ΔCBF/%ΔCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow-metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference.
        Cover page: The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2016)

        Purpose

        In pulsed arterial spin labeling (PASL) methods, arterial blood is labeled by inverting a slab with uniform thickness, resulting in different temporal widths of boluses in vessels with different flow velocities. This limits the temporal resolution and signal-to-noise ratio (SNR) efficiency gains in PASL-based methods intended for high temporal resolution and SNR efficiency, such as turbo-ASL and turbo-QUASAR.

        Theory and methods

        A novel wedge-shaped (WS) adiabatic inversion pulse is developed by adding in-plane gradient pulses to a slice-selective (SS) adiabatic inversion pulse to linearly modulate the inversion thicknesses at different locations while maintaining the adiabatic properties of the original pulse. A hyperbolic secant (HS)-based WS inversion pulse was implemented. Its performance was tested in simulations and in phantom and human experiments and compared with an SS HS inversion pulse.

        Results

        Compared with the SS inversion pulse, the WS inversion pulse was capable of inducing different inversion thicknesses at different locations. It could be adjusted to generate a uniform temporal width of boluses in arteries at locations with different flow velocities.

        Conclusion

        The WS inversion pulse can be used to control the temporal widths of labeled boluses in PASL experiments. This should benefit PASL experiments by maximizing labeling duty cycle and improving temporal resolution and SNR efficiency. Magn Reson Med 76:838-847, 2016. © 2015 Wiley Periodicals, Inc.
          Cover page: Wedge‐shaped slice‐selective adiabatic inversion pulse for controlling temporal width of bolus in pulsed arterial spin labeling
          • Article
          • Peer Reviewed
          UC Riverside Previously Published Works (2016)

          Purpose

          In pulsed arterial spin labeling (PASL) methods, arterial blood is labeled by inverting a slab with uniform thickness, resulting in different temporal widths of boluses in vessels with different flow velocities. This limits the temporal resolution and signal-to-noise ratio (SNR) efficiency gains in PASL-based methods intended for high temporal resolution and SNR efficiency, such as turbo-ASL and turbo-QUASAR.

          Theory and methods

          A novel wedge-shaped (WS) adiabatic inversion pulse is developed by adding in-plane gradient pulses to a slice-selective (SS) adiabatic inversion pulse to linearly modulate the inversion thicknesses at different locations while maintaining the adiabatic properties of the original pulse. A hyperbolic secant (HS)-based WS inversion pulse was implemented. Its performance was tested in simulations and in phantom and human experiments and compared with an SS HS inversion pulse.

          Results

          Compared with the SS inversion pulse, the WS inversion pulse was capable of inducing different inversion thicknesses at different locations. It could be adjusted to generate a uniform temporal width of boluses in arteries at locations with different flow velocities.

          Conclusion

          The WS inversion pulse can be used to control the temporal widths of labeled boluses in PASL experiments. This should benefit PASL experiments by maximizing labeling duty cycle and improving temporal resolution and SNR efficiency. Magn Reson Med 76:838-847, 2016. © 2015 Wiley Periodicals, Inc.
            Cover page: Wedge-shaped slice-selective adiabatic inversion pulse for controlling temporal width of bolus in pulsed arterial spin labeling.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2019)
            Cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) signal measurements make it possible to estimate steady-state changes in the cerebral metabolic rate of oxygen (CMRO2) with a calibrated BOLD method. However, extending this approach to measure the dynamics of CMRO2 requires an additional assumption: that deoxygenated cerebral blood volume (CBVdHb) follows CBF in a predictable way. A test-case for this assumption is the BOLD post-stimulus undershoot, for which one proposed explanation is a strong uncoupling of flow and blood volume with an elevated level of CBVdHb during the post-stimulus period compared to baseline due to slow blood volume recovery (Balloon Model). A challenge in testing this model is that CBVdHb differs from total blood volume, which can be measured with other techniques. In this study, the basic hypothesis of elevated CBVdHb during the undershoot was tested, based on the idea that the BOLD signal change when a subject switches from breathing a normoxic gas to breathing a hyperoxic gas is proportional to the absolute CBVdHb. In 19 subjects (8F), dual-echo BOLD responses were measured in primary visual cortex during a flickering radial checkerboard stimulus in normoxia, and the identical experiment was repeated in hyperoxia (50% O2/balance N2). The BOLD signal differences between normoxia and hyperoxia for the pre-stimulus baseline, stimulus, and post-stimulus periods were compared using an equivalent BOLD signal calculated from measured R2* changes to eliminate signal drifts. Relative to the pre-stimulus baseline, the average BOLD signal change from normoxia to hyperoxia was negative during the undershoot period (p = 0.0251), consistent with a reduction of CBVdHb and contrary to the prediction of the Balloon Model. Based on these results, the BOLD post-stimulus undershoot does not represent a case of strong uncoupling of CBVdHb and CBF, supporting the extension of current calibrated BOLD methods to estimate the dynamics of CMRO2.
              Cover page: Cerebral blood volume changes during the BOLD post-stimulus undershoot measured with a combined normoxia/hyperoxia method
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2015)
              The calibrated BOLD (blood oxygen level dependent) technique was developed to quantify the BOLD signal in terms of changes in oxygen metabolism. In order to achieve this a calibration experiment must be performed, which typically requires a hypercapnic gas mixture to be administered to the participant. However, an emerging technique seeks to perform this calibration without administering gases using a refocussing based calibration. Whilst hypercapnia calibration seeks to emulate the physical removal of deoxyhaemoglobin from the blood, the aim of refocussing based calibration is to refocus the dephasing effect of deoxyhaemoglobin on the MR signal using a spin echo. However, it is not possible to refocus all of the effects that contribute to the BOLD signal and a scale factor is required to estimate the BOLD scaling parameter M. In this study the feasibility of a refocussing based calibration was investigated. The scale factor relating the refocussing calibration to M was predicted by simulations to be approximately linear and empirically measured to be 0.88±0.36 for the visual cortex and 0.93±0.32 for a grey matter region of interest (mean±standard deviation). Refocussing based calibration is a promising approach for greatly simplifying the calibrated BOLD methodology by eliminating the need for the subject to breathe special gas mixtures, and potentially provides the basis for a wider implementation of quantitative functional MRI.
                Cover page: Calibrating the BOLD response without administering gases: Comparison of hypercapnia calibration with calibration using an asymmetric spin echo
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2014)
                Recent studies from our group and others using quantitative fMRI methods have found that variations of the coupling ratio of blood flow (CBF) and oxygen metabolism (CMRO2) responses to a stimulus have a strong effect on the BOLD response. Across a number of studies an empirical pattern is emerging in the way CBF and CMRO2 changes are coupled to neural activation: if the stimulus is modulated to create a stronger response (e.g., increasing stimulus contrast), CBF is modulated more than CMRO2; on the other hand, if the brain state is altered such that the response to the same stimulus is increased (e.g., modulating attention, adaptation, or excitability), CMRO2 is modulated more than CBF. Because CBF and CMRO2 changes conflict in producing BOLD signal changes, this finding has an important implication for conventional BOLD-fMRI studies: the BOLD response exaggerates the effects of stimulus variation but is only weakly sensitive to modulations of the brain state that alter the response to a standard stimulus. A speculative hypothesis is that variability of the coupling ratio of the CBF and CMRO2 responses reflects different proportions of inhibitory and excitatory evoked activity, potentially providing a new window on neural activity in the human brain.
                  Cover page: Variability of the coupling of blood flow and oxygen metabolism responses in the brain: a problem for interpreting BOLD studies but potentially a new window on the underlying neural activity
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2013)
                  Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimation, we could significantly improve the precision of our estimates of the hemodynamic response to a visual stimulus and, under the conditions of a calibrated BOLD experiment, accurately determine the ratio of the oxygen metabolic response to the hemodynamic response. Importantly we were able to accomplish this without utilizing a priori knowledge of the temporal nature of the neural stimulus, suggesting that BOLD Constrained Perfusion estimation may make it feasible to quantitatively study the cerebral metabolic and hemodynamic responses to more natural stimuli that cannot be easily repeated or averaged.
                    Cover page: A Novel Method of Combining Blood Oxygenation and Blood Flow Sensitive Magnetic Resonance Imaging Techniques to Measure the Cerebral Blood Flow and Oxygen Metabolism Responses to an Unknown Neural Stimulus
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2019)
                      Cover page: The potential for gas-free measurements of absolute oxygen metabolism during both baseline and activation states in the human brain
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