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% CO(2)) 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 (CMRO(2)) with activation, and the coupling ratio n of the fractional changes in CBF and CMRO(2). 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 CMRO(2) 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.     

Comparison of unilateral and bilateral complex finger tapping-related activation in premotor and primary motor cortex

Sixteen healthy right-handed subjects performed a complex finger-tapping task that broadly activates the motor and premotor regions, including primary motor (M1), ventral premotor (PMv), and dorsal premotor (PMd) cortex. This task was performed with the right hand only, left hand only and both hands simultaneously. Behavioral performance and the possibility of mirror movements were controlled through the use of MRI-compatible gloves to monitor finger movements. Using spatially normalized ROIs from the Human Motor Area Template (HMAT), comparisons were made of the spatial extent and location of activation in the left and right motor regions between all three tasks. During unilateral right and left hand tapping, ipsilateral precentral gyrus activation occurred in all subjects, mainly in the PMv and PMd. Ipsilateral M1 activation was less consistent and shifted anteriorly within M1, towards the border of M1 and premotor cortex. Regions of ipsilateral activation were also activated during contralateral and bilateral tasks. Overall, 83%/70%/58% of the ipsilaterally activated voxels in M1/PMd/PMv were also activated during contralateral and bilateral tapping. The mean percent signal change of spatially overlapping activated voxels was similar in PMv and PMd between all three tasks. However, the mean percent signal change of spatially overlapping M1 activation was significantly less during ipsilateral tapping compared with contra- or bilateral tapping. Results suggest that the ipsilateral fMRI activation in unilateral motor tasks may not be inhibitory in nature, but rather may reflect part of a bilateral network involved in the planning and/or execution of tapping in the ipsilateral hand.     

Effects of physiological aging and cerebrovascular risk factors on the hemodynamic response to brain activation: a functional transcranial Doppler study

The influence of the vascular system on the coupling of cerebral blood flow (CBF) to focal brain activation during aging is incompletely understood. Using functional transcranial Doppler sonography and a hypercapnic challenge as a marker of intact cerebral vasoreactivity, we determined CBF velocity (CBFV) changes in response to a language and arithmetic task in a group of 43 healthy young subjects (mean age 32 ± 8.6 years), 18 healthy old subjects (mean age 64 ± 9.8 years) and 29 old subjects with risk factors for an atherosclerosis (mean age 69 ± 8.4 years). Despite a similar performance during the cognitive tasks the CBFV changes were significantly lower in the group of old subjects with vascular risk factors compared with the healthy young and old subjects. Similarly, the CBFV changes during hypercapnia were significantly lower in the group of old subjects with vascular risk factors compared with the healthy young and old subjects. In contrast, both cognitive tasks and hypercapnia produced comparable CBFV changes in the group of healthy young and old subjects. These results suggest that the hemodynamic response to neuronal activation is unaffected by aging alone, whereas the presence of cardiovascular risk factors significantly diminishes the capability of cerebral vessels to react to vasodilating stimuli.     

The BOLD hemodynamic response in healthy aging

Several previous studies have compared the blood oxygen level-dependent (BOLD) hemodynamic response (HDR) in healthy elderly subjects to the HDR in young subjects. Some studies have found a relative decreased amplitude in the elderly in the visual cortex, whereas other studies have found the elderly HDR amplitude in the visual cortex to be nearly identical to that in young subjects. A possible explanation for the different findings is that the peak voxel HDR is similar between the groups, but that the HDR in the group-averaged region-of-interest (ROI) is "washed out" by the inclusion of less significant voxels (due to a smaller extent of activation in the elderly) or by the inclusion of negative-peaking voxels. We tested this hypothesis using event-related functional magnetic resonance imaging (fMRI ). While undergoing fMRI, subjects performed a simple visual and motor task, pressing with their index fingers in response to visual presentation of the word tap. Data from 18 subjects, 8 young and 10 elderly, were analyzed. For each subject, a visual and a motor ROI was selected by choosing the most significant positive voxels within the anatomically defined ROI. This individual subject approach excluded both low-significance and negative-peaking voxels. Similar peaks were found for the elderly and the young subjects in both motor and visual regions and a more sustained BOLD response was found for the elderly in both regions. Additionally, as predicted, a greater percentage of voxels with a negative HDR was found for the elderly in the visual region; this finding was also replicated in our reanalysis of an independent fMRI and aging study from the fMRI Data Center. Functional neuroimaging observations of negative HDRs in visual areas have been interpreted as the effect of unconstrained processing during rest. Our results suggest that the elderly may have more unconstrained visual processing during the rest condition in the scanner. The observation that the group differences in the BOLD response are sensitive to voxel selection (e.g., inclusion of low-significance and/or negative voxels) underscores the importance of ROI selection criteria in the interpretation of fMRI studies using elderly populations.     

Impact of apomorphine on BOLD signal during movement in normals

Our group investigated modulatory effects of apomorphine on cerebral activation patterns during finger tapping movements in six healthy right-handed volunteers using an established fMRI protocol. Apomorphine application disclosed a reduction of cerebral activation to the contralateral precentral and postcentral gyrus and ipsilateral cerebellum, with a prominent net reduction of BOLD signal in cerebellar areas. These findings contradict those of similar studies performed on dopaminergic function and Parkinson's disease (PD), which predominantly found augmentation of cerebral activation patterns in normal volunteers and PD patients after dopaminergic stimulation. One conceivable explanation for our singular results would be preferred binding of apomorphine to presynaptic dopaminergic receptors, leading to inhibition of endogenous dopamine release and resultant diminished dopaminergic stimulation, reflected in diminished cerebral activation patterns. These findings warrant future consideration and further investigation of possible central inhibitory effects of dopaminergic therapy in functional imaging studies of the dopaminergic system in general and PD in particular.     

Different neuronal networks are associated with spikes and slow activity in hypsarrhythmia

PURPOSE: West syndrome is a severe epileptic encephalopathy of infancy characterized by a poor developmental outcome and hypsarrhythmia. The pathogenesis of hypsarrhythmia is insufficiently understood. METHODS: We investigated eight patients with infantile spasms and hypsarrhythmia (group I) and 8 children with complex partial seizures (group II) using simultaneous recordings of electroencephalogram (EEG) and functional MRI. Hemodynamic responses to epileptiform discharges and slow wave activity (EEG delta power) were analyzed separately. RESULTS: In group I (mean age, 7.82 +/- 2.87 months), interictal spikes within the hypsarrhythmia were associated with positive blood oxygenation level-dependent (BOLD) changes in the cerebral cortex (especially occipital areas). This was comparable with cortical positive BOLD responses in group II (mean age, 20.75 +/- 12.52 months). Slow wave activity in group I correlated significantly with BOLD signal in voxels, which were localized in brainstem, thalamus, as well as different cortical areas. There was no association between BOLD effect and EEG delta power in group II. Moreover, as revealed by group analysis, group I differed from group II according to correlations between BOLD signal and slow wave activity in putamen and brainstem. CONCLUSIONS: This study demonstrates that multifocal interictal spikes and high-amplitude slow wave activity within the hypsarrhythmia are associated with the activation of different neuronal networks. Although spikes caused a cortical activation pattern similar to that in focal epilepsies, slow wave activity produced a hypsarrhythmia-specific activation in cortex and subcortical structures such as brainstem, thalamus, and putamen.     

Functional MRI near vascular anomalies: comparison of cavernoma and arteriovenous malformation

BACKGROUND AND PURPOSE: Mapping of eloquent cortex using blood-oxygen-level-dependent (BOLD) contrast functional MRI (fMRI) has rapidly gained acceptance as part of the evaluation of patients being considered for neurosurgical interventions. The BOLD signal measures local susceptibility in the blood, which can change during periods of increased neuronal activation as a result of alteration in blood flow and cerebral oxygen utilisation. Vascular anomalies could influence the BOLD signal via their effects on both blood flow and susceptibility. METHODS: In the present study we have compared the fMRI signal associated with functional activation near arteriovenous malformations and cavernomas in a group of patients referred for pre-surgical mapping of eloquent cortex. RESULTS: The magnitude of the BOLD signal was not different for the cavernoma group and the AVM group (mean percentage signal change 6.3% vs. 5.5%). For subjects with cavernoma, there was an increase in cavernoma volume on the functional images compared to T1-weighted anatomical images (mean 570%), and a BOLD signal was only detected outside the enlarged cavernoma. CONCLUSION: The findings show that susceptibility effects associated with cavernoma, most likely due to hemosiderin deposition, can result in an apparent increase in the separation between the BOLD signal and the cavernoma itself. This could lead to falsely high levels of surgical confidence during neurosurgical resection. Differential patterns of blood flow associated with cavernoma and AVM do not appear to significantly affect the BOLD signal magnitude.     

Primary motor area activation during precision-demanding versus simple finger movement

The authors used functional magnetic resonance imaging to explore whether the primary motor area (M1) serves a processing role in a finger-movement tracking task, emphasizing attention to accuracy, beyond its execution role of simple movements, with no attention to accuracy. Twenty healthy subjects performed alternating conditions: Rest, involving no finger movement; Track, involving careful control of a cursor along a target pathway with finger extension/flexion movements; and Move, involving finger extension/flexion movements without careful control. The authors compared volume of activated voxels in the M1, blood-oxygen-level-dependent (BOLD) signal intensity of activated voxels in the M1, and BOLD signal intensity of all voxels in the M1 between the Track and Move conditions. The results showed greater volume and signal intensity in both the contralateral and ipsilateral M1 during Track than during Move. Overall, the results suggest that the M1 is engaged not only in the execution of movements but also in spatial and temporal processing to produce accurately controlled movements. These findings invite further work exploring whether precision-demanding movements, such as tracking, form a more potent stimulus for promoting helpful brain reorganization in the M1 during the recovery from stroke than simple repetitive movements.     

Task demand modulation of steady-state functional connectivity to primary motor cortex

Correlations in blood oxygen level-dependent (BOLD) MRI signals from separate areas within the human brain have been used as a measure of functional connectivity. Steady-state measures of interregional correlations are particularly useful because they do not depend on the specific design of a task nor on subtracting conditions in a blocked design task. However, the conditions under which such correlations are measured may influence these indices of functional connectivity. The aim of this study was to investigate the influence of task demand on interregional correlations within the motor system. Specifically, tapping rates in audibly paced finger-tapping tasks were controlled and varied between runs in order to observe their effects on interregional correlations to contralateral primary motor cortex (PM). Regions of interest included the supplementary motor area, ipsilateral cerebellum, ipsilateral auditory cortex, and a control region. It was found that tapping rate was a significant factor in determining the mean correlation of some regions to PM, and that correlations measured during tapping in general increased relative to resting state. Furthermore, analysis of the percent of voxels in each region significantly correlated to PM suggested that changes in the mean correlation of that region to PM could be accounted for by changes in the fraction of significantly correlated voxels within a region. This provides insight into the manner in which steady-state correlations are modified in response to different task demands and further evidence that low-frequency fluctuations in BOLD signals reflect functional connectivity.     

Effect of anesthesia on CBF, MAP and fMRI-BOLD signal in response to apnea

Systemic effects of anesthesia on the dynamics of the apnea-induced Blood Oxygen Level Dependent (BOLD) signal is still not clear. In the present study, the dynamics of the fMRI-BOLD signal and blood flow using laser Doppler flowmetry (LDF) was studied in rats in response to apnea. Two anesthetics namely pentobarbital and urethane, hypothesized to have distinct effects on the mean arterial blood pressure (MAP) were used. During normoxic baseline conditions, MAP decreased in response to apnea in rats anesthetized with pentobarbital but increased with urethane. However, MAP did not change significantly in response to apnea during hyperoxic or hypercapnic baseline conditions with both anesthetics. LDF increased in response to apnea during normoxia, hyperoxia or hypercapnia and was influenced by MAP during normoxia. Apnea-induced BOLD signal dynamics was similar with both anesthetics, dominated by an alteration in arterial blood oxygenation and independent of changes in MAP. Our results suggest that anesthesia-dependent MAP change modulates the apnea-induced cerebral blood flow (CBF) response but has a minimal effect on the fMRI-BOLD signal probably due to uncoupling of CBF and oxygen consumption.     

Swallowing intentional off-state in aging and Alzheimer's disease: preliminary study

Frontal cortical activation is elicited when subjects have been instructed not to initiate a sensorimotor task. The goal of this preliminary fMRI study was to examine BOLD response to a "Do Not Swallow" instruction (an intentional "off-state") in the context of other swallowing tasks in 3 groups of participants (healthy young, healthy old, and early Alzheimer's disease (AD)). Overall, the older group had larger, bilaterally active clusters in the cortex, including the dorsomedial prefrontal cortex during the intentional swallowing off-state; this region is commonly active in response inhibition studies. Disease-related differences were evident where the AD group had significantly greater BOLD response in the insula/operculum than the old. These findings have significant clinical implications for control of swallowing across the age span and in neurodegenerative disease. Greater activation in the insula/operculum for the AD group supports previous studies where this region is associated with initiating swallowing. The AD group may have required more effort to "turn off" swallowing centers to reach the intentional swallowing off-state.     

Increasing measurement accuracy of age‐related BOLD signal change: Minimizing vascular contributions by resting‐state‐fluctuation‐of‐amplitude scaling

In this report we demonstrate a hemodynamic scaling method with resting‐state fluctuation of amplitude (RSFA) in healthy adult younger and older subject groups. We show that RSFA correlated with breath hold (BH) responses throughout the brain in groups of younger and older subjects which RSFA and BH performed comparably in accounting for age‐related hemodynamic coupling changes, and yielded more veridical estimates of age‐related differences in task‐related neural activity. BOLD data from younger and older adults performing motor and cognitive tasks were scaled using RSFA and BH related signal changes. Scaling with RSFA and BH reduced the skew of the BOLD response amplitude distribution in each subject and reduced mean BOLD amplitude and variability in both age groups. Statistically significant differences in intrasubject amplitude variation across regions of activated cortex, and intersubject amplitude variation in regions of activated cortex were observed between younger and older subject groups. Intra‐ and intersubject variability differences were mitigated after scaling. RSFA, though similar to BH in minimizing skew in the unscaled BOLD amplitude distribution, attenuated the neural activity‐related BOLD amplitude significantly less than BH. The amplitude and spatial extent of group activation were lower in the older than in the younger group before and after scaling. After accounting for vascular variability differences through scaling, age‐related decreases in activation volume were observed during the motor and cognitive tasks. The results suggest that RSFA‐scaled data yield age‐related neural activity differences during task performance with negligible effects from non‐neural (i.e., vascular) sources. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

BOLD fMRI signal increases with age in selected brain regions in children

To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9-18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Broca's, middle frontal, Wernicke's, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.     

Adaptations in maximal motor unit discharge rate to strength training in young and older adults

Six young (mean = 23 years) and 6 older (mean = 76 years) adults participated in isometric resistance training 5 days/week for 6 weeks. The task involved isometric fifth finger abduction. Maximal motor unit discharge rates (MUDRs) were obtained from the abductor digiti minimi of each hand at 0, 2, 14, and 42 days of training using a quadrifilar needle electrode and automatic spike recognition software. In agreement with previous findings, maximal MUDR at baseline was significantly lower in older adults (P < 0.001), averaging 51.5 (+/-17.13) HZ in young and 43.3 (+/-14.88) HZ in older adults. In response to resistance training, maximal voluntary force increased 25% in young and 33% in older subjects (P < 0.001). Maximal MUDR increased significantly (11% young, 23% older) on day 2 [F(3,36) = 2.58, P < 0.05], but in older subjects returned to baseline levels thereafter. These adaptations in abductor digiti minimi MUDR suggest a two-part response to strengthening fifth finger abduction: early disinhibition followed by altered MU activation.Copyright 2001 John Wiley & Sons, Inc.     

Effect of pentobarbital on visual processing in man

To investigate the effect of sedative agents on visual processing in humans, we analysed the BOLD contrast signal response to a visual stimulation paradigm in 15 healthy, adult volunteers using functional magnetic resonance imaging. The subjects were tested during alert state and under sedation following intravenous administration of pentobarbital. The injection of pentobarbital not only significantly reduced the response signal strength but the reduction in BOLD contrast signal was related to the ratio of amount of sedative administered and the subject's body weight. The three subjects with the highest relative sedative dosage even displayed an inverted (negative) BOLD contrast signal. A significant reduction in the number of positively correlating pixels was found 15 min after administration of pentobarbital. All measured parameters returned to near pre-sedative levels by the end of the experimental session. The relative dosage dependence of the strength of the BOLD signal the negative BOLD signal in the three subjects with the highest relative sedative dosage indicates that pentobarbital had a more pronounced effect on cerebral blood flow than on cerebral oxidative metabolism.     

Macrovascular contribution in activation patterns of working memory.

Brain activation maps of blood oxygenation level dependent (BOLD) signals during functional magnetic resonance imaging (fMRI) are sensitive to unwanted contributions from large vessels. Most BOLD-fMRI studies are based on a stimulus-correlated modulation of the MRI signal amplitude that is sensitive to desired microvascular effects and unwanted macrovascular effects. Aiming to suppress macrovascular effects in activation patterns, this BOLD-fMRI study evaluates brain activation during a verbal working memory task (2-back) in healthy volunteers (n=18) using the amplitude and phase components of the MRI signal. The use of the first time point as a phase reference allowed us to eliminate phase wrapping artifacts and increase the statistical power of 'phase' activation, and this information was used to filter out voxels with significant macrovascular (i.e., draining and pial veins) contribution in 'amplitude' activation patterns. Across subjects, the task produced large modulations of the relative phase in the occipital, dorsolateral prefrontal, and parietal cortices, suggesting a common distribution of draining veins in these regions across subjects, and in the rostral frontal cortex, probably associated to stimulus-correlated motion of the head. The phase filtering method partially suppressed BOLD responses in the superior and lateral prefrontal, parietal, and occipital cortices; therefore the commonly reported brain activation in these cortices during working memory tasks may include significant macrovascular contributions. This study suggests that the phase information embedded in the MRI signal can be used to suppress unwanted macrovascular contributions in fMRI studies.     

A pilot study of somatotopic mapping after cortical infarct

BACKGROUND AND PURPOSE: Animal studies have described remodeling of sensory and motor representational maps after cortical infarct. These changes may contribute to return of function after stroke. METHODS: Functional MRI was used to compare sensory and motor maps obtained in 35 normal control subjects with results from 2 patients with good recovery 6 months after a cortical stroke. RESULTS: During finger tapping in controls, precentral gyrus activation exceeded or matched postcentral gyrus activation in 40 of 42 cases. Patient 1 had a small infarct limited to precentral gyrus. Finger tapping activated only postcentral gyrus, a pattern not seen in any control subject. During tactile stimulation of a finger or hand in controls, postcentral gyrus activation exceeded or matched precentral gyrus activation in 11 of 14 cases. Patient 2 had a small infarct limited to postcentral gyrus and superior parietal lobule. Tactile stimulation of the finger activated only precentral gyrus, a pattern not seen in any control. In both patients, activation during pectoralis contraction was medial to the site activated during finger tapping. CONCLUSIONS: Results during finger tapping (patient 1) and finger stimulation (patient 2) may reflect amplification of a preserved component of normal sensorimotor function, a shift in the cortical site of finger representation, or both. Cortical map reorganization along the infarct rim may be an important contributor to recovery of motor and sensory function after stroke. Functional MRI is useful for assessing motor and sensory representational maps.     

Calibration of BOLD fMRI using breath holding reduces group variance during a cognitive task

The proportionality of blood oxygen level-dependent (BOLD) response during a cognitive task and that from a hypercapnic challenge was investigated in cortical structures involved in working memory (WM). Breath holding (BH) following inspiration was used to induce a BOLD response characteristic of regional vasomotor reactivity but devoid of metabolic changes. BOLD effects measured during BH were used to normalize individual subject activations during WM, which effectively reduced the confounding influence of individual- and region-specific differences in hemodynamic responsivity common to both tasks. In a study of seven subjects, the BH calibration reduced intersubject variability in WM effect amplitude by 24.8% (P < 0.03). Reduced intersubject variability resulted in a 23.7% increase in group WM activation voxel extent significant at P < 0.001, with further increases at more stringent thresholds. Because the BH task does not require CO(2) inhalation or other invasive manipulations and is broadly applicable across cortical regions, the proposed approach is simple to implement and may be beneficial for use not only in quantitative group fMRI analyses, but also for multicenter and longitudinal studies.     

Atypical motor and sensory cortex activation in attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study of simple sequential finger tapping.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has been shown to be associated with anomalous motor development, including excessive overflow movements. The neurological basis of these deficits has not been established. Functional magnetic resonance imaging (fMRI) was used to determine whether differences in brain activation during sequential finger tapping are present in children with ADHD compared with typically developing control subjects. METHODS: Twenty-two right-handed children between 8 and 12 years old, 11 with ADHD and 11 typically developing control subjects closely matched for age and gender, performed self-paced sequential finger tapping during fMRI acquisition. RESULTS: There were no significant between-group differences in speed of sequential finger tapping. The between-group whole-brain comparison showed greater magnitude of activation for control subjects than children with ADHD in the right superior parietal lobe during both right-handed and left-handed finger tapping. The region-of-interest analysis within Brodmann Area 4 revealed that children with ADHD showed a significantly smaller extent of fMRI activation in the primary motor cortex contralateral to the finger-sequencing hand. CONCLUSIONS: Despite similar speed of sequential finger tapping, children with ADHD showed decreased contralateral motor cortex and right parietal cortex activation during both right-handed finger sequencing (RHFS) and left-handed finger sequencing (LHFS). The fMRI findings suggest that children with ADHD have anomalous development of cortical systems necessary for execution of patterned movements.     

Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fMRI response.

The effect of the basal cerebral blood flow (CBF) on both the magnitude and dynamics of the functional hemodynamic response in humans has not been fully investigated. Thus, the hemodynamic response to visual stimulation was measured using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in human subjects in a 7-T magnetic field under different basal conditions: hypocapnia, normocapnia, and hypercapnia. Hypercapnia was induced by inhalation of a 5% carbon dioxide gas mixture and hypocapnia was produced by hyperventilation. As the fMRI baseline signal increased linearly with expired CO2 from hypocapnic to hypercapnic levels, the magnitude of the BOLD response to visual stimulation decreased linearly. Measures of the dynamics of the visually evoked BOLD response (onset time, full-width-at-half-maximum, and time-to-peak) increased linearly with the basal fMRI signal and the end-tidal CO2 level. The basal CBF level, modulated by the arterial partial pressure of CO2, significantly affects both the magnitude and dynamics of the BOLD response induced by neural activity. These results suggest that caution should be exercised when comparing stimulus-induced fMRI responses under different physiologic or pharmacologic states.