The blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI) depends on the evoked changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in response to changes in neural activity. This response is strongly modulated by the CBF/CMRO2 coupling relationship with activation, defined as n, the ratio of the fractional changes. The reliability of the BOLD signal as a quantitative reflection of underlying physiological changes depends on the stability of n in response to different stimuli. The effect of visual stimulus contrast on this coupling ratio was tested in 9 healthy human subjects, measuring CBF and BOLD responses to a flickering checkerboard at four visual contrast levels. The theory of the BOLD effect makes a robust prediction—independent of details of the model—that if the CBF/CMRO2 coupling ratio n remains constant, then the response ratio between the lowest and highest contrast levels should be higher for the BOLD response than the CBF response because of the ceiling effect on the BOLD response. Instead, this response ratio was significantly lower for the BOLD response (BOLD response: 0.23 ± 0.13, mean ± SD; CBF response: 0.42 ± 0.18; p = 0.0054). This data is consistent with a reduced dynamic range (strongest/weakest response ratio) of the CMRO2 response (~ 1.7-fold) compared to that of the CBF response (~ 2.4-fold) as luminance contrast increases, corresponding to an increase of n from 1.7 at the lowest contrast level to 2.3 at the highest contrast level. The implication of these results for fMRI studies is that the magnitude of the BOLD response does not accurately reflect the magnitude of underlying physiological processes.

The ratio of the changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) during brain activation is a critical determinant of the magnitude of the blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI). Cytochrome oxidase (CO), a key component of oxidative metabolism in the mitochondria, is non-uniformly distributed in visual area V1 in distinct blob and interblob regions, suggesting significant spatial variation in the capacity for oxygen metabolism. The goal of this study was to test whether CBF/CMRO2 coupling differed when these subpopulations of neurons were preferentially stimulated, using chromatic and luminance stimuli to preferentially stimulate either the blob or interblob regions. A dual-echo spiral arterial spin labeling (ASL) technique was used to measure CBF and BOLD responses simultaneously in 7 healthy human subjects. When the stimulus contrast levels were adjusted to evoke similar CBF responses (mean 65.4%±19.0% and 64.6%±19.9%, respectively for chromatic and luminance contrast), the BOLD responses were remarkably similar (1.57%±0.39% and 1.59%±0.35%) for both types of stimuli. We conclude that CBF–CMRO2 coupling is conserved for the chromatic and luminance stimuli used, suggesting a consistent coupling for blob and inter-blob neuronal populations despite the difference in CO concentration.

What is it and what can it tell us about the brain?

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.

David Eagleman’s Incognito presents the brain architecture as a “team of rivals”: a collection of neural subsystems that have overlapping functions and competing aims, creating a complex, conflict based organisation. In this framework, consciousness is analogous to the chief executive officer of a company, responsible for planning and setting goals, aware only of the headline events and representing the tip of the iceberg. This book’s title refers to the fact that much of the brain’s activity occurs outside of our control and below our levels of awareness. Thus the brain acts “incognito,” controlling most of what we do, think, and feel using neural circuits that are inaccessible …

Doctors might be able to learn something from two New York car mechanics

Although the acute stroke literature indicates that cerebral blood flow (CBF) may commonly be disordered in stroke survivors, limited research has investigated whether CBF remains aberrant in the chronic phase of stroke. A directed study of CBF in stroke is needed because reduced CBF (hypoperfusion) may occur in neural regions that appear anatomically intact and may impact cognitive functioning in stroke survivors. Hypoperfusion in neurologically-involved individuals may also affect BOLD signal in FMRI studies, complicating its interpretation with this population. The current study measured CBF in three chronic stroke survivors with ischemic infarcts (greater than 1year post-stroke) to localize regions of hypoperfusion, and most critically, examine the CBF inflow curve using a methodology that has never, to our knowledge, been reported in the chronic stroke literature. CBF data acquired with a Pulsed Arterial Spin Labeling (PASL) flow-sensitive alternating inversion recovery (FAIR) technique indicated both delayed CBF inflow curve and hypoperfusion in the stroke survivors as compared to younger and elderly control participants. Among the stroke survivors, we observed regional hypoperfusion in apparently anatomically intact neural regions that are involved in cognitive functioning. These results may have profound implications for the study of behavioral deficits in chronic stroke, and particularly for studies using neuroimaging methods that rely on CBF to draw conclusions about underlying neural activity.

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. Neurology (R) 2009; 73: 702-708

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. hi 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 30:1120-1132, 2009. (C) 2008 Wiley-Liss, Inc.

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies using parallel imaging to reduce the readout window have reported a loss in temporal signal-to-noise ratio (SNR) that is less than would be expected given a purely thermal noise model. In this study, the impact of parallel imaging on the noise components and functional sensitivity of both BOLD and perfusion-based fMRI data was investigated. Dual-echo arterial spin labeling data were acquired on five subjects using sensitivity encoding (SENSE), at reduction factors (R) of 1, 2 and 3. Direct recording of cardiac and respiratory activity during data acquisition enabled the retrospective removal of physiological noise. The temporal SNR of the perfusion time series closely followed the thermal noise prediction of a √R loss in SNR as the readout window was shortened, with temporal SNR values (relative to the R=1 data) of 0.72 and 0.56 for the R=2 and R=3 data, respectively, after accounting for physiological noise. However, the BOLD temporal SNR decreased more slowly than predicted even after accounting for physiological noise, with relative temporal SNR values of 0.80 and 0.63 for the R=2 and R=3 data, respectively. Spectral analysis revealed that the BOLD trends were dominated by low-frequency fluctuations, which were not dominant in the perfusion data due to signal processing differences. The functional sensitivity, assessed using mean F values over activated regions of interest (ROIs), followed the temporal SNR trends for the BOLD data. However, results for the perfusion data were more dependent on the threshold used for ROI selection, most likely due to the inherently low SNR of functional perfusion data.

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 (CMRO2). 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 CMRO2 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.

To date, functional magnetic resonance imaging (fMRI) studies of the lateral geniculate nucleus (LGN) have primarily focused on measures of the blood oxygenation level dependent (BOLD) signal. Arterial spin labeling (ASL) is an MRI method that can provide direct measures of functional cerebral blood flow (CBF) changes. Because CBF is a well-defined physiological quantity that contributes to BOLD contrast, CBF measures can be used to improve the quantitative interpretation of fMRI studies. However, due in part to the low intrinsic signal-to-noise ratio of the ASL method, measures of functional CBF changes in the LGN are challenging and have not previously been reported. In this study, we demonstrate the feasibility of using ASL fMRI to measure the CBF response of the LGN to visual stimulation on a 3 T MRI system. The use of background suppression and physiological noise reduction techniques allowed reliable detection of LGN activation in all five subjects studied. The measured percent CBF response during activation ranged from 40 to 100%, assuming no interaction between the left and right LGN.

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 (CMRO2). In this study, we implemented a quantitative R2* 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 CMRO2 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 CMRO2 (+ 20.7%, ± 1.4), and caffeine decreased CBF (− 34.5%, ± 2.6) with a non-significant change in CMRO2 (+ 5.2%, ± 6.4). The coupling between CBF and CMRO2 was significantly different in response to visual stimulation compared to caffeine consumption. A calibrated BOLD methodology using R2∗ is a promising approach for evaluating CBF and CMRO2 changes in response to pharmacological interventions.

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.

Prior measures of the blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF) responses to a memory-encoding task within the medial temporal lobe have suggested that the coupling between functional changes in CBF and changes in the cerebral metabolic rate of oxygen (CMRO2) may be tighter in the medial temporal lobe as compared to the primary sensory areas. In this study, we used a calibrated functional magnetic resonance imaging (fMRI) approach to directly estimate memory-encoding-related changes in CMRO2 and to assess the coupling between CBF and CMRO2 in the medial temporal lobe. The CBF–CMRO2 coupling ratio was estimated using a linear fit to the flow and metabolism changes observed across subjects. In addition, we examined the effect of region-of-interest (ROI) selection on the estimates. In response to the memory-encoding task, CMRO2 increased by 23.1 ± 8.8% to 25.3 ± 5.7% (depending upon ROI), with an estimated CBF–CMRO2 coupling ratio of 1.66 ± 0.07 to 1.75 ± 0.16. There was not a significant effect of ROI selection on either the CMRO2 or coupling ratio estimates. The observed coupling ratios were significantly lower than the values (2 to 4.5) that have been reported in previous calibrated fMRI studies of the visual and motor cortices. In addition, the estimated coupling ratio was found to be less sensitive to the calibration procedure for functional responses in the medial temporal lobe as compared to the primary sensory areas.

Individuals susceptible to high altitude pulmonary edema show altered pulmonary vascular responses within minutes of exposure to hypoxia. We hypothesized that a similar acute-phase vulnerability to hypoxia may exist in the brain of individuals susceptible to acute mountain sickness (AMS). In established AMS and high altitude cerebral edema, there is a propensity for vasogenic white matter edema.We therefore hypothesized that increased cerebral blood flow (CBF) during acute hypoxia would also be disproportionately greater in white matter (WM) than grey matter (GM) in AMS-susceptible subjects. We quantified regional CBF using arterial spin labeling MRI during 30 min hypoxia (F1O2 = 0. 125) in two groups: AMS-susceptible (AMS-S, n = 6) who invariably experienced AMS at altitude, and AMS-resistant (AMS-R, n = 6) who never experienced AMS despite multiple rapid ascents to high altitude.SaO(2) during hypoxia did not differ between groups (AMS-S = 87 +/- 4%, AMS-R = 89 +/- 3%, p = 0.3). Steady-state whole-brain CBF increased in hypoxia (p < 0.005), but did not differ between groups (normoxia: AMS-S = 42.7 +/- 14.0 ml/(100 g min), AMS-R = 41.7 +/- 10.1 ml/(100 g min); hypoxia: AMS-S = 47.8 +/- 19.5 ml/(100 g min), AMS-R = 48.2 +/- 10.1 ml/(100 g min), p = 0.65), and cerebral oxygen delivery remained constant. The percent change in CBF did not differ between brain regions or between groups (although absolute CBF change was greater in GM): (GM: AMS-S = 6.1 +/- 7.7 ml/(100 g min) (10 +/- 11 %), AMS-R = 8.3 +/- 5.7 ml/(100 g min) (17 :L 11 %), p = 0.57; WM: AMS-S = 4.3 5.1 ml/(100 g min) (12 +/- 15%), AMS-R = 4.8 +/- 2.9 ml/(100 g min) (16 9%), p = 0.82).Conclusion: CBF increases in acute hypoxia, but is not different between WM and GM, irrespective of AMS susceptibility. Acute phase differences in regional CBF during acute hypoxia are not a primary feature of susceptibility to AMS. (C) 2007 Elsevier B.V. All rights reserved.

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, T(1) and T(2), are described. In the second section, the biophysical mechanisms that alter the apparent transverse relaxation time, T(2*), in blood oxygenation level dependent (BOLD) studies and the creation of BOLD activation maps are discussed. The physiological complexity of the BOLD signal is emphasized. In the third section, arterial spin labeling (ASL) measures of cerebral blood flow are presented. Arterial spin labeling inverts or saturates the magnetization of flowing spins to measure the rate of delivery of blood to capillaries. In the fourth section, calibrated fMRI, which uses BOLD and ASL to infer alterations of oxygen utilization during behavioral activation, is reviewed. The discussion concludes with challenges confronting studies of individual cases.

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 Alzheimer's 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 (CMRO2) response to memory encoding.

Sensitivity encoding (SENSE) is a magnetic resonance technique that unifies gradient and receive coil encoding. SENSE reconstructs the image by solving a large, ill-conditioned inverse problem, which generally requires regularization and preconditioning. The present study suggests a simple heuristic for determining the regularization parameter. Also discussed are the use of density weighting and intensity correction as preconditioners and the role that coil sensitivity estimation has in regularization. A modification to the intensity correction is proposed for use with a phase constraint.