Post-stimulus fMRI and EEG responses: Evidence for a neuronal origin hypothesised to be inhibitory.

Post-stimulus undershoots, negative responses following cessation of stimulation, are widely observed in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) data. However, the debate surrounding whether the origin of this response phase is neuronal or vascular, and whether it provides functionally relevant information, that is additional to what is contained in the primary response, means that undershoots are widely overlooked. We simultaneously recorded electroencephalography (EEG), BOLD and cerebral blood-flow (CBF) [obtained from arterial spin labelled (ASL) fMRI] fMRI responses to hemifield checkerboard stimulation to test the potential neural origin of the fMRI post-stimulus undershoot. The post-stimulus BOLD and CBF signal amplitudes in both contralateral and ipsilateral visual cortex depended on the post-stimulus power of the occipital 8-13Hz (alpha) EEG neuronal activity, such that trials with highest EEG power showed largest fMRI undershoots in contralateral visual cortex. This correlation in post-stimulus EEG-fMRI responses was not predicted by the primary response amplitude. In the contralateral visual cortex we observed a decrease in both cerebral rate of oxygen metabolism (CMRO2) and CBF during the post-stimulus phase. In addition, the coupling ratio (n) between CMRO2 and CBF was significantly lower during the positive contralateral primary response phase compared with the post-stimulus phase and we propose that this reflects an altered balance of excitatory and inhibitory neuronal activity. Together our data provide strong evidence that the post-stimulus phase of the BOLD response has a neural origin which reflects, at least partially, an uncoupling of the neuronal responses driving the primary and post-stimulus responses, explaining the uncoupling of the signals measured in the two response phases. We suggest our results are consistent with inhibitory processes driving the post-stimulus EEG and fMRI responses. We therefore propose that new methods are required to model the post-stimulus and primary responses independently, enabling separate investigation of response phases in cognitive function and neurological disease.

Assessing potential errors of MRI-based measurements of pulmonary blood flow using a detailed network flow model.

MRI images of pulmonary blood flow using arterial spin labeling (ASL) measure the delivery of magnetically tagged blood to an image plane during one systolic ejection period. However, the method potentially suffers from two problems, each of which may depend on the imaging plane location: 1) the inversion plane is thicker than the imaging plane, resulting in a gap that blood must cross to be detected in the image; and 2) ASL includes signal contributions from tagged blood in conduit vessels (arterial and venous). By using an in silico model of the pulmonary circulation we found the gap reduced the ASL signal to 64-74% of that in the absence of a gap in the sagittal plane and 53-84% in the coronal. The contribution of the conduit vessels varied markedly as a function of image plane ranging from ∼90% of the overall signal in image planes that encompass the central hilar vessels to <20% in peripheral image planes. A threshold cutoff removing voxels with intensities >35% of maximum reduced the conduit vessel contribution to the total ASL signal to ∼20% on average; however, planes with large contributions from conduit vessels underestimate acinar flow due to a high proportion of in-plane flow, making ASL measurements of perfusion impractical. In other image planes, perfusion dominated the resulting ASL images with good agreement between ASL and acinar flow. Similarly, heterogeneity of the ASL signal as measured by relative dispersion is a reliable measure of heterogeneity of the acinar flow distribution in the same image planes.

Rapid intravenous infusion of 20 mL/kg saline alters the distribution of perfusion in healthy supine humans.

Rapid intravenous saline infusion, a model meant to replicate the initial changes leading to pulmonary interstitial edema, increases pulmonary arterial pressure in humans. We hypothesized that this would alter lung perfusion distribution. Six healthy subjects (29 ± 6 years) underwent magnetic resonance imaging to quantify perfusion using arterial spin labeling. Regional proton density was measured using a fast-gradient echo sequence, allowing blood delivered to the slice to be normalized for density and quantified in mL/min/g. Contributions from flow in large conduit vessels were minimized using a flow cutoff value (blood delivered > 35% maximum in mL/min/cm(3)) in order to obtain an estimate of blood delivered to the capillary bed (perfusion). Images were acquired supine at baseline, after infusion of 20 mL/kg saline, and after a short upright recovery period for a single sagittal slice in the right lung during breath-holds at functional residual capacity. Thoracic fluid content measured by impedance cardiography was elevated post-infusion by up to 13% (p<0.0001). Forced expiratory volume in 1s was reduced by 5.1% post-20 mL/kg (p=0.007). Infusion increased perfusion in nondependent lung by up to 16% (6.4 ± 1.6 mL/min/g baseline, 7.3 ± 1.8 post, 7.4 ± 1.7 recovery, p=0.03). Including conduit vessels, blood delivered in dependent lung was unchanged post-infusion; however, was increased at recovery (9.4 ± 2.7 mL/min/g baseline, 9.7 ± 2.0 post, 11.3 ± 2.2 recovery, p=0.01). After accounting for changes in conduit vessels, there were no significant changes in perfusion in dependent lung following infusion (7.8 ± 1.9 mL/min/g baseline, 7.9 ± 2.0 post, 8.5 ± 2.1 recovery, p=0.36). There were no significant changes in lung density. These data suggest that saline infusion increased perfusion to nondependent lung, consistent with an increase in intravascular pressures. Dependent lung may have been "protected" from increases in perfusion following infusion due to gravitational compression of the pulmonary vasculature.

Pulmonary perfusion heterogeneity is increased by sustained, heavy exercise in humans.

Exercise presents a considerable stress to the pulmonary system and ventilation-perfusion (Va/Q) heterogeneity increases with exercise, affecting the efficiency of gas exchange. In particular, prolonged heavy exercise and maximal exercise are known to increase Va/Q heterogeneity and these changes persist into recovery. We hypothesized that the spatial heterogeneity of pulmonary perfusion would be similarly elevated after prolonged exercise. To test this, athletic subjects (n = 6, Vo(2max) = 61 ml. kg(-1).min(-1)) with exercising Va/Q heterogeneity previously characterized by the multiple inert gas elimination technique (MIGET), performed 45 min of cycle exercise at approximately 70% Vo(2max). MRI arterial spin labeling measures of pulmonary perfusion were acquired pre- and postexercise (at 20, 40, 60 min post) to quantify the spatial distribution in isogravitational (coronal) and gravitationally dependent (sagittal) planes. Regional proton density measurements allowed perfusion to be normalized for density and quantified in milliliters per minute per gram. Mean lung density did not change significantly in either plane after exercise (P = 0.19). Density-normalized perfusion increased in the sagittal plane postexercise (P =or <0.01) but heterogeneity did not (all P >or= 0.18), likely because of perfusion redistribution and vascular recruitment. Density-normalized perfusion was unchanged in the coronal plane postexercise (P = 0.66), however, perfusion heterogeneity was significantly increased as measured by the relative dispersion [RD, pre 0.62(0.07), post 0.82(0.21), P < 0.0001] and geometric standard deviation [GSD, pre 1.74(0.14), post 2.30(0.56), P < 0.005]. These changes in heterogeneity were related to the exercise-induced changes of the log standard deviation of the ventilation distribution, an MIGET index of Va/Q heterogeneity (RD R(2) = 0.68, P < 0.05, GSD, R(2) = 0.55, P = 0.09). These data are consistent with but not proof of interstitial pulmonary edema as the mechanism underlying exercise-induced increases in both spatial perfusion heterogeneity and Va/Q heterogeneity.

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 < or =50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF < or =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.

Hypoxic pulmonary vasoconstriction does not contribute to pulmonary blood flow heterogeneity in normoxia in normal supine humans.

We hypothesized that some of the heterogeneity of pulmonary blood flow present in the normal human lung in normoxia is due to hypoxic pulmonary vasoconstriction (HPV). If so, mild hyperoxia would decrease the heterogeneity of pulmonary perfusion, whereas it would be increased by mild hypoxia. To test this, six healthy nonsmoking subjects underwent magnetic resonance imaging (MRI) during 20 min of breathing different oxygen concentrations through a face mask [normoxia, inspired O(2) fraction (Fi(O(2))) = 0.21; hypoxia, Fi(O(2)) = 0.125; hyperoxia, Fi(O(2)) = 0.30] in balanced order. Data were acquired on a 1.5-T MRI scanner during a breath hold at functional residual capacity from both coronal and sagittal slices in the right lung. Arterial spin labeling was used to quantify the spatial distribution of pulmonary blood flow in milliliters per minute per cubic centimeter and fast low-angle shot to quantify the regional proton density, allowing perfusion to be expressed as density-normalized perfusion in milliliters per minute per gram. Neither mean proton density [hypoxia, 0.46(0.18) g water/cm(3); normoxia, 0.47(0.18) g water/cm(3); hyperoxia, 0.48(0.17) g water/cm(3); P = 0.28] nor mean density-normalized perfusion [hypoxia, 4.89(2.13) ml x min(-1) x g(-1); normoxia, 4.94(1.88) ml x min(-1) x g(-1); hyperoxia, 5.32(1.83) ml x min(-1) x g(-1); P = 0.72] were significantly different between conditions in either imaging plane. Similarly, perfusion heterogeneity as measured by relative dispersion [hypoxia, 0.74(0.16); normoxia, 0.74(0.10); hyperoxia, 0.76(0.18); P = 0.97], fractal dimension [hypoxia, 1.21(0.04); normoxia, 1.19(0.03); hyperoxia, 1.20(0.04); P = 0.07], log normal shape parameter [hypoxia, 0.62(0.11); normoxia, 0.72(0.11); hyperoxia, 0.70(0.13); P = 0.07], and geometric standard deviation [hypoxia, 1.88(0.20); normoxia, 2.07(0.24); hyperoxia, 2.02(0.28); P = 0.11] was also not different. We conclude that HPV does not affect pulmonary perfusion heterogeneity in normoxia in the normal supine human lung.

Quantification of regional pulmonary blood flow using ASL-FAIRER.

Pulsed arterial spin labeling (ASL) techniques have been theoretically and experimentally validated for cerebral blood flow (CBF) quantification. In this study ASL-FAIRER was used to measure regional pulmonary blood flow (rPBF) in seven healthy subjects. Two general ASL strategies were investigated: 1) a single-subtraction approach using one tag-control pair acquisition at an inversion time (TI) matched to the RR-interval, and 2) a multiple-subtraction approach using tag-control pairs acquired at various TIs. The mean rPBF averaged 1.70 +/- 0.38 ml/min/ml when measured with the multiple-subtraction approach, and was approximately 2% less when measured with the single-subtraction method (1.66 +/- 0.24 ml/min/ml). Assuming an average lung density of 0.33 g/ml, this translates into a regional perfusion of approximately 5.5 ml/g/min, which is comparable to other measures of pulmonary perfusion. As with other ASL applications, a key problem with quantitative interpretation of the results is the physical gap between the tagging region and imaged slice. Because of the high pulsatility of PBF, ASL acquisition and data analysis differ significantly between the lung and the brain. The advantages and drawbacks of the single- vs. multiple-subtraction approaches are considered within a theoretical framework tailored to PBF.

Estimation of respiration-induced noise fluctuations from undersampled multislice fMRI data.

Functional MRI time series data are known to be contaminated by highly structured noise due to physiological fluctuations. Significant components of this noise are at frequencies greater than those critically sampled in standard multislice imaging protocols and are therefore aliased into the activation spectrum, compromising the estimation of functional activations and the determination of their significance. However, in this work it is demonstrated that unaliased noise information is available in multislice data, and can be used to estimate and reduce noise due to high-frequency respiratory-related fluctuations. Magn Reson Med 45:635-644, 2001. Published 2001 Wiley-Liss, Inc.

Nonlinear temporal dynamics of the cerebral blood flow response.

The linearity of the cerebral perfusion response relative to stimulus duration is an important consideration in the characterization of the relationship between regional cerebral blood flow (CBF), cerebral metabolism, and the blood oxygenation level dependent (BOLD) signal. It is also a critical component in the design and analysis of functional neuroimaging studies. To study the linearity of the CBF response to different duration stimuli, the perfusion response in primary motor and visual cortices was measured during stimulation using an arterial spin labeling technique with magnetic resonance imaging (MRI) that allows simultaneous measurement of CBF and BOLD changes. In each study, the perfusion response was measured for stimuli lasting 2, 6, and 18 sec. The CBF response was found in general to be nonlinearly related to stimulus duration, although the strength of nonlinearity varied between the motor and visual cortices. In contrast, the BOLD response was found to be strongly nonlinear in both regions studied, in agreement with previous findings. The observed nonlinearities are consistent with a model with a nonlinear step from stimulus to neural activity, a linear step from neural activity to CBF change, and a nonlinear step from CBF change to BOLD signal change.

Putting spatial attention on the map: timing and localization of stimulus selection processes in striate and extrastriate visual areas.

This study investigated the cortical mechanisms of visual-spatial attention in a task where subjects discriminated patterned targets in one visual field at a time. Functional magnetic imaging (fMRI) was used to localize attention-related changes in neural activity within specific retinotopic visual areas, while recordings of event-related brain potentials (ERPs) traced the time course of these changes. The earliest ERP components enhanced by attention occurred in the time range 70-130 ms post-stimulus onset, and their neural generators were estimated to lie in the dorsal and ventral extrastriate visual cortex. The anatomical areas activated by attention corresponded closely to those showing increased neural activity during passive visual stimulation. Enhanced neural activity was also observed in the primary visual cortex (area V1) with fMRI, but ERP recordings indicated that the initial sensory response at 50-90 ms that was localized to V1 was not modulated by attention. Modeling of ERP sources over an extended time range showed that attended stimuli elicited a long-latency (160-260 ms) negativity that was attributed to the dipolar source in area V1. This finding is in line with hypotheses that V1 activity may be modulated by delayed, reentrant feedback from higher visual areas.

Detection power, estimation efficiency, and predictability in event-related fMRI.

Experimental designs for event-related functional magnetic resonance imaging can be characterized by both their detection power, a measure of the ability to detect an activation, and their estimation efficiency, a measure of the ability to estimate the shape of the hemodynamic response. Randomized designs offer maximum estimation efficiency but poor detection power, while block designs offer good detection power at the cost of minimum estimation efficiency. Periodic single-trial designs are poor by both criteria. We present here a theoretical model of the relation between estimation efficiency and detection power and show that the observed trade-off between efficiency and power is fundamental. Using the model, we explore the properties of semirandom designs that offer intermediate trade-offs between efficiency and power. These designs can simultaneously achieve the estimation efficiency of randomized designs and the detection power of block designs at the cost of increasing the length of an experiment by less than a factor of 2. Experimental designs can also be characterized by their predictability, a measure of the ability to circumvent confounds such as habituation and anticipation. We examine the relation between detection power, estimation efficiency, and predictability and show that small increases in predictability can offer significant gains in detection power with only a minor decrease in estimation efficiency.

T(1) and T(2) selective method for improved SNR in CSF-attenuated imaging: T(2)-FLAIR.

We present here a method for improving SNR in CSF-attenuated imaging relative to the standard technique of using an inversion pulse and imaging at the null point of CSF. In this new method the inversion pulse is replaced with a 90(x)-180(y)-90(x) preparation sequence that provides T(1) and T(2) selectivity. This allows the tissue magnetization to recover more rapidly, allows for the use of shorter TR values, and reduces T(1) weighting. Magn Reson Med 45:529-532, 2001.

Altered brain response to verbal learning following sleep deprivation.

The effects of sleep deprivation on the neural substrates of cognition are poorly understood. Here we used functional magnetic resonance imaging to measure the effects of 35 hours of sleep deprivation on cerebral activation during verbal learning in normal young volunteers. On the basis of a previous hypothesis, we predicted that the prefrontal cortex (PFC) would be less responsive to cognitive demands following sleep deprivation. Contrary to our expectations, however, the PFC was more responsive after one night of sleep deprivation than after normal sleep. Increased subjective sleepiness in sleep-deprived subjects correlated significantly with activation of the PFC. The temporal lobe was activated after normal sleep but not after sleep deprivation; in contrast, the parietal lobes were not activated after normal sleep but were activated after sleep deprivation. Although sleep deprivation significantly impaired free recall compared with the rested state, better free recall in sleep-deprived subjects was associated with greater parietal lobe activation. These findings show that there are dynamic, compensatory changes in cerebral activation during verbal learning after sleep deprivation and implicate the PFC and parietal lobes in this compensation.

Mapping the physiological parameters of articular cartilage with magnetic resonance imaging.

The ability of magnetic resonance imaging (MRI) to visualize the spatial distribution of parameters related to the physiological and structural properties of tissues makes it an ideal tool for the study of articular cartilage. A variety of ingenious MRI methods have been devised to probe the complex composition and biochemistry of normal and degenerate articular cartilage. In this article we review the current status of this research and pose some questions concerning the future directions of articular cartilage research and clinical applications.

Dynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling.

MR images acquired by using an arterial spin-labeling technique showed spatial and temporal variations of perfusion in the skeletal muscle of exercising humans. Perfusion measurements made during plantar flexion exercise in normal volunteers were consistent with those obtained by traditional techniques reported in the literature. Spatial heterogeneity of perfusion values clearly delineated the various muscle groups within the lower leg. These results are interpreted in terms of a quantitative model for the perfusion signal in muscle. This method can provide a useful tool in the study of muscle physiology. Magn Reson Med 42:258-267, 1999. Published 1999 Wiley-Liss, Inc.

Brain activation and pupil response during covert performance of the Stroop Color Word task.

Patterns of brain activation associated with covert performance of the Stroop Color-Word task were studied in young, healthy, adult volunteers using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Comparisons of the incongruous Stroop condition were made with both color naming and word reading baselines. Areas of the left and right anterior cingulate, the right precuneus, and the left pars opercularis displayed larger BOLD signal responses during the incongruous Stroop condition than during baseline conditions. Activation of BOLD signals in these areas was highly repeatable. In a second experiment, pupil diameter was used to assess cognitive load in 7 individuals studied during overt and covert performance of both Stroop and color naming conditions. Cognitive load was similar in overt and covert response conditions. Results from the BOLD study indicate that brain regions participating in selective visual attention and in the selection of motor programs involved in speech were activated more by the Stroop task than by the baseline tasks. The neural substrate involved in the resolution of the perceptual and motor conflicts elicited by the Stroop Color-Word task does not appear to be a single brain region. Rather, a network of brain regions is implicated, with separate regions within this system supporting distinct functions.

Quantitative perfusion imaging using arterial spin labeling.

Arterial spine labeling (ASL) techniques have matured to the point that they can provide robust quantitative multislice measurements of cerebral blood flow (CBF) under most circumstances. These techniques provide better spatial and temporal resolution than positron-emission tomography (PET) and are entirely noninvasive, requiring no injections or radiation. The most obvious clinical application is in the evaluation of acute stroke, in which the primary pathology is a lack of CBF, precisely the quantity that is measured directly by ASL. The one major technical challenge that currently prevents more general application in the brain is the sensitivity to abnormally long transit delays.

Involvement of striate and extrastriate visual cortical areas in spatial attention.

We investigated the cortical mechanisms of visual-spatial attention while subjects discriminated patterned targets within distractor arrays. Functional magnetic resonance imaging (fMRI) was used to map the boundaries of retinotopic visual areas and to localize attention-related changes in neural activity within several of those areas, including primary visual (striate) cortex. Event-related potentials (ERPs) and modeling of their neural sources, however, indicated that the initial sensory input to striate cortex at 50-55 milliseconds after the stimulus was not modulated by attention. The earliest facilitation of attended signals was observed in extrastriate visual areas, at 70-75 milliseconds. We hypothesize that the striate cortex modulation found with fMRI may represent a delayed, re-entrant feedback from higher visual areas or a sustained biasing of striate cortical neurons during attention. ERP recordings provide critical temporal information for analyzing the functional neuroanatomy of visual attention.

Sleep deprivation-induced reduction in cortical functional response to serial subtraction.

Thirteen normal volunteers were studied with fMRI during arithmetic performance after a normal night of sleep and following sleep deprivation (SD). Aims included determining whether the prefrontal cortex (PFC) and the parietal lobe arithmetic areas are vulnerable to the effects of SD. After a normal night of sleep, activation localized to the bilateral PFC, parietal lobes and premotor areas. Following SD, activity in these regions decreased markedly, especially in the PFC. Performance also dropped. Data from the serial subtraction task are consistent with Horne's PFC vulnerability hypothesis but, based on this and other studies, we suggest the localized, functional effects of SD in the brain may vary, in part, with the specific cognitive task.