Joanna E. Perthen

Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation.

Calibrated functional magnetic resonance imaging (fMRI) provides a noninvasive technique to assess functional metabolic changes associated with normal aging. We simultaneously measured both the magnitude of the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) responses in the visual cortex for separate conditions of mild hypercapnia (5% CO2) and a simple checkerboard stimulus in healthy younger (n = 10, mean: 28‐years‐old) and older (n = 10, mean: 53‐years‐old) adults. From these data we derived baseline CBF, the BOLD scaling parameter M, the fractional change in the cerebral metabolic rate of oxygen consumption (CMRO2) with activation, and the coupling ratio n of the fractional changes in CBF and CMRO2. For the functional activation paradigm, the magnitude of the BOLD response was significantly lower for the older group (0.57 ± 0.07%) compared to the younger group (0.95 ± 0.14%), despite the finding that the fractional CBF and CMRO2 changes were similar for both groups. The weaker BOLD response for the older group was due to a reduction in the parameter M, which was significantly lower for older (4.6 ± 0.4%) than younger subjects (6.5 ± 0.8%), most likely reflecting a reduction in baseline CBF for older (41.7 ± 4.8 mL/100 mL/min) compared to younger (59.6 ± 9.1 mL/100 mL/min) subjects. In addition to these primary responses, for both groups the BOLD response exhibited a post‐stimulus undershoot with no significant difference in this magnitude. However, the post‐undershoot period of the CBF response was significantly greater for older compared to younger subjects. We conclude that when comparing two populations, the BOLD response can provide misleading reflections of underlying physiological changes. A calibrated approach provides a more quantitative reflection of underlying metabolic changes than the BOLD response alone. Hum Brain Mapp 2009.

Caffeine induced uncoupling of cerebral blood flow and oxygen metabolism: A calibrated-BOLD fMRI study

Although functional MRI (fMRI) based on blood oxygenation level-dependent (BOLD) signal changes is a sensitive tool for mapping brain activation, quantitative studies of the physiological effects of pharmacological agents using fMRI alone are difficult to interpret due to the complexities inherent in the BOLD response. Hypercapnia-calibrated BOLD methodology is potentially a more powerful physiological probe of brain function, providing measures of the changes in cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO(2)). In this study, we implemented a quantitative R(2)* approach for assessing the BOLD response to improve the stability of repeated measurements, in combination with the calibrated BOLD method, to examine the CBF and CMRO(2) responses to caffeine ingestion. Ten regular caffeine consumers were imaged before and after a 200-mg caffeine dose. A dual-echo arterial spin labeling technique was used to measure CBF and BOLD responses to visual stimulation, caffeine consumption and mild hypercapnia. For a region of interest defined by CBF activation to the visual stimulus, the results were: hypercapnia increased CBF (+46.6%, +/-11.3, mean and standard error), visual stimulation increased both CBF (+47.9%, +/-2.9) and CMRO(2) (+20.7%, +/-1.4), and caffeine decreased CBF (-34.5%, +/-2.6) with a non-significant change in CMRO(2) (+5.2%, +/-6.4). The coupling between CBF and CMRO(2) was significantly different in response to visual stimulation compared to caffeine consumption. A calibrated BOLD methodology using R(2) * is a promising approach for evaluating CBF and CMRO(2) changes in response to pharmacological interventions.

Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: Implications for BOLD-fMRI

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) signal changes is a sensitive tool for mapping brain activation, but quantitative interpretation of the BOLD response is problematic. The BOLD response is primarily driven by cerebral blood flow (CBF) changes, but is moderated by M, a scaling parameter reflecting baseline deoxyhemoglobin, and n, the ratio of fractional changes in CBF to cerebral metabolic rate of oxygen consumption (CMRO(2)). We compared M and n between cortical (visual cortex, VC) and subcortical (lentiform nuclei, LN) regions using a quantitative approach based on calibrating the BOLD response with a hypercapnia experiment. Although M was similar in both regions (~5.8%), differences in n (2.21+/-0.03 in VC and 1.58+/-0.03 in LN; Cohen d=1.71) produced substantially weaker (~3.7x) subcortical than cortical BOLD responses relative to CMRO(2) changes. Because of this strong sensitivity to n, BOLD response amplitudes cannot be interpreted as a quantitative reflection of underlying metabolic changes, particularly when comparing cortical and subcortical regions.

Cerebral blood flow and BOLD responses to a memory encoding task: A comparison between healthy young and elderly adults

Functional magnetic resonance imaging (fMRI) studies of the medial temporal lobe have primarily made use of the blood oxygenation level dependent (BOLD) response to neural activity. The interpretation of the BOLD signal as a measure of medial temporal lobe function can be complicated, however, by changes in the cerebrovascular system that can occur with both normal aging and age-related diseases, such as Alzheimers disease. Quantitative measures of the functional cerebral blood flow (CBF) response offer a useful complement to BOLD measures and have been shown to aid in the interpretation of fMRI studies. Despite these potential advantages, the application of ASL to fMRI studies of cognitive tasks and at-risk populations has been limited. In this study, we demonstrate the application of ASL fMRI to obtain measures of the CBF and BOLD responses to the encoding of natural scenes in healthy young (mean 25 years) and elderly (mean 74 years) adults. The percent CBF increase in the medial temporal lobe was significantly higher in the older adults, whereas the CBF levels during baseline and task conditions and during a separate resting-state scan were significantly lower in the older group. The older adults also showed slightly higher values for the BOLD response amplitude and the absolute change in CBF, but the age group differences were not significant. The percent CBF and BOLD responses are consistent with an age-related increase in the cerebral metabolic rate of oxygen metabolism (CMRO(2)) response to memory encoding.

Resting cerebral blood flow: a potential biomarker of the effects of HIV in the brain.

Objective: HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC). Methods: This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV− subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated. Results: rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV− subjects. A 2-tiered CART approach using either LN rCBF ≤50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF ≤37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV− controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects. Conclusion: Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment.

Prospects for quantitative fMRI: Investigating the effects of caffeine on baseline oxygen metabolism and the response to a visual stimulus in humans

Functional magnetic resonance imaging (fMRI) provides an indirect reflection of neural activity change in the working brain through detection of blood oxygenation level dependent (BOLD) signal changes. Although widely used to map patterns of brain activation, fMRI has not yet met its potential for clinical and pharmacological studies due to difficulties in quantitatively interpreting the BOLD signal. This difficulty is due to the BOLD response being strongly modulated by two physiological factors in addition to the level of neural activity: the amount of deoxyhemoglobin present in the baseline state and the coupling ratio, n, of evoked changes in blood flow and oxygen metabolism. In this study, we used a quantitative fMRI approach with dual measurement of blood flow and BOLD responses to overcome these limitations and show that these two sources of modulation work in opposite directions following caffeine administration in healthy human subjects. A strong 27% reduction in baseline blood flow and a 22% increase in baseline oxygen metabolism after caffeine consumption led to a decrease in baseline blood oxygenation and were expected to increase the subsequent BOLD response to the visual stimulus. Opposing this, caffeine reduced n through a strong 61% increase in the evoked oxygen metabolism response to the visual stimulus. The combined effect was that BOLD responses pre- and post-caffeine were similar despite large underlying physiological changes, indicating that the magnitude of the BOLD response alone should not be interpreted as a direct measure of underlying neurophysiological changes. Instead, a quantitative methodology based on dual-echo measurement of blood flow and BOLD responses is a promising tool for applying fMRI to disease and drug studies in which both baseline conditions and the coupling of blood flow and oxygen metabolism responses to a stimulus may be altered.

Caffeine reduces the activation extent and contrast-to-noise ratio of the functional cerebral blood flow response but not the BOLD response

Measures of the spatial extent of functional activation are important for a number of functional magnetic resonance imaging (fMRI) applications, such as pre-surgical planning and longitudinal tracking of changes in brain activation with disease progression and drug treatment. The interpretation of the data from these applications can be complicated by inter-subject or inter-session variability in the measured fMRI signals. Prior studies have shown that modulation of baseline cerebral blood flow (CBF) can directly alter the functional CBF and blood oxygenation level dependent (BOLD) responses, suggesting that the spatial extents of functional activation maps based on these signals may also depend on baseline CBF. In this study, we used a caffeine dose (200 mg) to decrease baseline CBF and found significant (p<0.05) reductions in both the CBF activation extent and contrast-to-noise ratio (CNR) but no significant changes in the BOLD activation extent and CNR. In contrast, caffeine significantly changed the temporal dynamics of the BOLD response but not the CBF response. The decreases in the CBF activation extent and CNR were consistent with a significant caffeine-induced decrease in the absolute CBF change accompanied by no significant change in the residual noise. Measures of baseline CBF also accounted for a significant portion of the inter-subject variability in the CBF activation map area and CNR. Factors that can modulate baseline CBF, such as age, medication, and disease, should therefore be carefully considered in the interpretation of studies that use functional CBF activation maps.

A Primer on Functional Magnetic Resonance Imaging

In this manuscript, basic principles of functional magnetic resonance imaging (fMRI) are reviewed. In the first section, two intrinsic mechanisms of magnetic resonance image contrast related to the longitudinal and transverse components of relaxing spins and their relaxation rates, T1 and T2, are described. In the second section, the biophysical mechanisms that alter the apparent transverse relaxation time,

Bayesian inference of hemodynamic changes in functional arterial spin labeling data.

T_2^*