The effects of graded hypercapnia on the activation flow coupling response due to forepaw stimulation in α-chloralose anesthetized rats

Activation flow coupling (AFC), changes in cerebral blood flow (CBF) due to changes in neural activity with functional stimulation, provides the physiological basis of many neuroimaging techniques. Hypercapnia leads to an increase in CBF while neural activity remains unaffected. Laser Doppler (LD) flowmetry was used to measure CBF changes (LD_CBF) in the somatosensory cortex due to periodic electrical forepaw stimulation (4 s in duration) before and during graded hypercapnia (3% CO₂, 5% CO₂ and 10% CO₂). With increasing CO₂ concentrations, the baseline LD_CBF progressively increased. The peak height (PH) of the LD_CBF response, expressed as a percent change from the observed baseline for each hypercapnic state, significantly decreased (P<0.05) with increasing CO₂ concentrations. However, the absolute magnitude of the LD_CBF change was independent of CO₂ concentration. The temporal dynamics of the LD_CBF response during hypercapnia were significantly prolonged compared to baseline conditions (P<0.05).     

Changes in human regional cerebral blood flow and cerebral blood volume during visual stimulation measured by positron emission tomography.

The hemodynamic mechanism of increase in cerebral blood flow (CBF) during neural activation has not been elucidated in humans. In the current study, changes in both regional CBF and cerebral blood volume (CBV) during visual stimulation in humans were investigated. Cerebral blood flow and CBV were measured by positron emission tomography using H(2)(15)O and (11)CO, respectively, at rest and during 2-Hz and 8-Hz photic flicker stimulation in each of 10 subjects. Changes in CBF in the primary visual cortex were 16% +/- 16% and 68% +/- 20% for the visual stimulation of 2 Hz and 8 Hz, respectively. The changes in CBV were 10% +/- 13% and 21% +/- 5% for 2-Hz and 8-Hz stimulation, respectively. Significant differences between changes in CBF and CBV were observed for visual stimulation of 8 Hz. The relation between CBF and CBV values during rest and visual stimulation was CBV = 0.88CBF(0.30). This indicates that when the increase in CBF during neural activation is great, that increase is caused primarily by the increase in vascular blood velocity rather than by the increase in CBV. This observation is consistent with reported findings obtained during hypercapnia.     

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.     

MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis

BACKGROUND AND PURPOSE: The relationship between middle cerebral artery (MCA) flow velocity (CFV) and cerebral blood flow (CBF) is uncertain because of unknown vessel diameter response to physiological stimuli. The purpose of this study was to directly examine the effect of a simulated orthostatic stress (lower body negative pressure [LBNP]) as well as increased or decreased end-tidal carbon dioxide partial pressure (P(ET)CO(2)) on MCA diameter and CFV. METHODS: Twelve subjects participated in a CO(2) manipulation protocol and/or an LBNP protocol. In the CO(2) manipulation protocol, subjects breathed room air (normocapnia) or 6% inspired CO(2) (hypercapnia), or they hyperventilated to approximately 25 mm Hg P(ET)CO(2) (hypocapnia). In the LBNP protocol, subjects experienced 10 minutes each of -20 and -40 mm Hg lower body suction. CFV and diameter of the MCA were measured by transcranial Doppler and MRI, respectively, during the experimental protocols. RESULTS: Compared with normocapnia, hypercapnia produced increases in both P(ET)CO(2) (from 36+/-3 to 40+/-4 mm Hg, P<0.05) and CFV (from 63+/-4 to 80+/-6 cm/s, P<0.001) but did not change MCA diameters (from 2.9+/-0.3 to 2.8+/-0.3 mm). Hypocapnia produced decreases in both P(ET)CO(2) (24+/-2 mm Hg, P<0.005) and CFV (43+/-7 cm/s, P<0.001) compared with normocapnia, with no change in MCA diameters (from 2.9+/-0.3 to 2.9+/-0.4 mm). During -40 mm Hg LBNP, P(ET)CO(2) was not changed, but CFV (55+/-4 cm/s) was reduced from baseline (58+/-4 cm/s, P<0.05), with no change in MCA diameter. CONCLUSIONS: Under the conditions of this study, changes in MCA diameter were not detected. Therefore, we conclude that relative changes in CFV were representative of changes in CBF during the physiological stimuli of moderate LBNP or changes in P(ET)CO(2).     

Signal averaged laser Doppler measurements of activation–flow coupling in the rat forepaw somatosensory cortex

Regional alterations in cerebral blood flow (CBF) are widely used as a surrogate for neuronal function based on an intact coupling between changes in regional CBF and metabolism, activation–flow coupling (AFC). To further investigate parameters affecting AFC, we have implemented a rat model with electrical forepaw stimulation under α-chloralose anesthesia using laser Doppler (LD) measurements of flow parameters through thinned skull over contralateral somatosensory cortex. Signal averaging of the LD response was used to improve reproducibility. A characteristic flow response to electrical forepaw stimulation was reliably recorded from the somatosensory cortex using signal averaging. Stimulation at 5 Hz maximized the LD response, and constant current stimulation up to 1 mA did not induce changes in systemic blood pressure. The shape of the flow response consisted of an initial peak followed by a steady state plateau phase which was observed for stimulation durations longer than 4 s. When individual LD parameters of velocity, red blood cell concentration (CRBC), and cerebral blood flow (CBF) were compared, changes in LD_CBF were primarily attributable to changes in LD_velocity rather than LD_CRBC. This finding was also observed during hypercapnia. Characterization of AFC in the model provides a background for future studies of the effects of pharmacological manipulation or pathophysiological states.     

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.     

Cerebral blood flow regulation in neonatal rabbits is altered by chronic cocaine administration

Maternal cocaine abuse has several deleterious effects in the newborn, including perinatal asphyxia, hypoxia, and hypercapnia. We hypothesized that chronic cocaine exposure during development may alter cerebral blood flow (CBF) regulation. We studied 16 neonatal rabbits that had received cocaine (20 mg/kg, i.p. b.i.d.) or saline since birth. Changes in CBF were measured by laser doppler flowmetry before (baseline), and during hypercapnia (FiCO₂=7.5%), hypoxia (FiO₂=12%), and asphyxia (apnea for 1 min). During hypercapnia, CBF increased less in cocaine than in control animals (28±3% vs. 69±10%, P<0.05). During hypoxia, CBF increased similarly in both groups. During reventilation after asphyxia, CBF increased more in cocaine than in control animals (391±52% vs. 225±43%, P<0.05). Chronic cocaine exposure during brain development appears to alter CBF regulation to hypercapnia and asphyxia, which may put the drug exposed newborn at risk for neurologic injury around birth.     

Multimodality monitoring during passive tilt and Valsalva maneuver under hypercapnia.

In occlusive cerebrovascular disease cerebral blood flow (CBF) autoregulation can be impaired and constant CBF during fluctuations in blood pressure (BP) cannot be guaranteed. Therefore, an assessment of cerebral autoregulation should consider not only responsiveness to CO2 or Diamox. Passive tilting (PT) and Valsalva maneuver (VM) are established tests for cardiovascular autoregulatory function by provoking BP changes. To develop a comprehensive test for vasomotor reactivity with a potential increase of sensitivity and specificity, the authors combined these maneuvers. Blood pressure, corrected to represent arterial pressure at the level of the circle of Willis, middle cerebral artery Doppler frequencies (DF), heart rate (HR) and endtidal partial pressure of CO2 (PtCO2) were measured continuously and noninvasively in 81 healthy subjects (19-74 years). Passive tilt and Valsalva maneuver were performed under normocapnia (mean, 39 + 4 mmHg CO2) and under hypercapnia (mean, 51 + 5 mm Hg CO2). Resting BP, HR, and DF increased significantly under hypercapnia. Under normocapnia and hypercapnia, PT induced only minor, nonsignificant changes in mean BP at the level of the circle of Willis compared to baseline (normocapnia: + 2 + 15 mm Hg; hypercapnia: -3 +/- 13 mm Hg). This corresponded with a nonsignificant decrease of the mean of DF (normocapnia: -4 +/- 11%; hypercapnia -6 +/- 12%). Orthostasis reduced pulsatility of BP by a predominantly diastolic increase of BP without significant changes in pulsatility of DF. Valsalva maneuver, with its characteristic rapid changes of BP due to elevated intrathoracic pressure, showed no significant BP differences in changes to baseline between normocapnic and hypercapnic conditions. Under both conditions the decrease in BP in phase II was accompanied by significantly increased pulsatility index ratio (PIDF/PIBP). Valsalva maneuver and PT as established tests in autonomic control of circulation provoked not only changes in time-mean of BP but also in pulsatility of BP. The significant increase in pulsatility ratio and decrease of the DF/BP ratio during normocapnia and hypercapnia indicated preserved CBF autoregulation within a wide range of CO2 partial pressures. Hypercapnia did not significantly influence the autoregulatory indices during VM and PT. Physiologically submaximally dilated cerebral arterioles can guarantee unchanged dynamics of cerebral autoregulation. Combined BP and MCA-DF assessment under hypercapnia enables investigating the effect of rapid changes of blood pressure on CO2-induced predilated cerebral arterioles. Assuming no interference of hypercapnia-induced vasodilation, VM, with its rapid, distinct changes in BP, seems especially to be adequate provocation for CBF autoregulation. This combined vasomotor reactivity might provide a more sensitive diagnostic tool to detect impaired cerebral autoregulation very early.     

Safety of hypercapnic challenge: cardiovascular and neurologic considerations

The hemodynamic, cerebrovascular, and neurologic effects of hypercapnia with 4% and 6% CO2 were retrospectively reviewed in 217 patients referred for regional CBF (rCBF) procedures. Inhalation of CO2 significantly increased rCBF, blood pressure, and pulse from baseline. The findings suggest a higher incidence of side effects with 6% CO2 concentration and an equivalent vasoreactivity to 4%. We recommend the use of 4% CO2 for hypercapnic stimulation, and present safety guidelines for its use.     

Analysis of the effect of bilateral sympathetic stimulation of cerebral and cephalic blood flow in the dog

Unilateral stimulation of the cervical sympathetic in dogs had no effect on cerebral blood flow (CBF) measured by the venous outflow technique. Since this technique measured CBF from both cerebral hemispheres, small changes induced by unilateral stimulation could have been masked by a large constant CBF measured from the contralteral hemisphere. To test this possibility the effect of simultaneous bilateral sympathetic stimulation was studied when the dog was breathing either normal air or a gas mixture of 10%CO2. During normocapnia, no changes in CBF occurred; during hypercapnia CBF increased 19% following passively the increase in blood pressure. These data indicate that bilateral stimulation of extracranial sympathetic nerves does not exert a significant effect on CBF. We show mathematically and experimentally that unoccluded anastomses will cause CBF to appear to decrease in response to sympathetic stimulation. This may explain why others have observed changes in CBF during sympathetic stimulation.     

Haemodynamic and neural responses to hypercapnia in the awake rat

The relationship between localized changes in brain activity and metabolism, and the blood oxygenation level-dependent (BOLD) signal used in functional magnetic resonance imaging studies is not fully understood. One source of complexity is that stimulus-elicited changes in the BOLD signal arise both from changes in oxygen consumption due to increases in activity and purely 'haemodynamic' changes such as increases in cerebral blood flow. It is well established that robust cortical haemodynamic changes can be elicited by increasing the concentration of inspired CO(2) (inducing hypercapnia) and it is widely believed that these haemodynamic changes occur without significant effects upon neural activity or cortical metabolism. Hypercapnia is therefore commonly used as a calibration condition in functional magnetic resonance imaging studies to enable estimation of oxidative metabolism from subsequent stimulus-evoked functional magnetic resonance imaging BOLD signal changes. However, there is little research that has investigated in detail the effects of hypercapnia upon all components of the haemodynamic response (changes in cerebral blood flow, volume and oxygenation) in addition to recording neural activity. In awake animals, we used optical and electrophysiological techniques to measure cortical haemodynamic and field potential responses to hypercapnia (60 s, 5% CO(2)). The main findings are that firstly, in the awake rat, the temporal structure of the haemodynamic response to hypercapnia differs from that reported previously in anaesthetized preparations in that the response is more rapid. Secondly, there is evidence that hypercapnia alters ongoing neural activity in awake rats by inducing periods of cortical desynchronization and this may be associated with changes in oxidative metabolism.     

Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography.

Hypercapnia induces cerebral vasodilation and increases cerebral blood flow (CBF), and hypocapnia induces cerebral vasoconstriction and decreases CBF. The relation between changes in CBF and cerebral blood volume (CBV) during hypercapnia and hypocapnia in humans, however, is not clear. Both CBF and CBV were measured at rest and during hypercapnia and hypocapnia in nine healthy subjects by positron emission tomography. The vascular responses to hypercapnia in terms of CBF and CBV were 6.0 +/- 2.6%/mm Hg and 1.8 +/- 1.3%/mm Hg, respectively, and those to hypocapnia were -3.5 +/- 0.6%/mm Hg and -1.3 +/- 1.0%/mm Hg, respectively. The relation between CBF and CBV was CBV = 1.09 CBF0.29. The increase in CBF was greater than that in CBV during hypercapnia, indicating an increase in vascular blood velocity. The degree of decrease in CBF during hypocapnia was greater than that in CBV, indicating a decrease in vascular blood velocity. The relation between changes in CBF and CBV during hypercapnia was similar to that during neural activation; however, the relation during hypocapnia was different from that during neural deactivation observed in crossed cerebellar diaschisis. This suggests that augmentation of CBF and CBV might be governed by a similar microcirculatory mechanism between neural activation and hypercapnia, but diminution of CBF and CBV might be governed by a different mechanism between neural deactivation and hypocapnia.     

Cerebral blood flow response to increases in arterial CO2 tension during alfentanil anesthesia in the rabbit.

The stability of cerebral function and blood flow (CBF), and the CBF response to changes in arterial carbon dioxide tension (CBF reactivity) during alfentanil anesthesia were examined in rabbits. This model was first shown to provide stable anesthesia, cortical function, and CBF for 4 h. CBF increased significantly to 159% [of baseline] in the left hemisphere and to 167% in the right within 5 min of an exposure to 5% CO2 (p = 0.009 on the left and p = 0.003 on the right), but then decreased to 123% on the left and to 137% on the right (not significantly different from baseline, p = 0.11 on the left and p = 0.07 on the right) while PaCO2 was still rising. Steady state reactivity levels (0.8 ml 100 g-1/min-1/mm Hg-1 CO2 on the left and 0.65 ml 100 g-1/min-1/mm Hg-1 CO2 on the right) were consistent with previous work and were reached at 20 min. These results suggest that mechanisms other than perivascular hydrogen ion concentration mediate the CBF response to changes in arterial CO2 tension during alfentanil anesthesia.     

Effects of variations in interstimulus interval on activation-flow coupling response and somatosensory evoked potentials with forepaw stimulation in the rat.

In functional neuroimaging studies, the hemodynamic response to functional activation is used as a surrogate marker for neuronal activity, typically in response to task paradigms that use periodic stimuli. With use of a model system of electrical forepaw stimulation in rats (n = 14) with laser-Doppler (LD) monitoring of cerebral blood flow (CBF) changes in the somatosensory cortex, the effects of variations in the interstimulus interval (ISI) on the hemodynamic response to periodic stimuli were examined. A characteristic peak flow response was seen for 4-second stimuli and a peak and plateau response were seen for all 8-second stimuli regardless of ISI. However, both the amplitude of the LD(CBF) response and the integrated response were significantly reduced for shorter ISIs, whereas the baseline flow was not altered. Somatosensory evoked potential responses were also recorded in some rats (n = 8) and remained unchanged for the various ISIs for a particular stimulus duration. These results suggest that the decrease in the LD(CBF) responses observed with shorter ISIs likely represents a refractoriness of the hemodynamic response and not neuronal function. These results may have important implications for the optimization and interpretation of functional activation paradigms that use periodic stimuli.     

Spatial extent of CBF response during whisker stimulation using trial averaged laser Doppler imaging

The spatial pattern of activation in response to multiple whisker stimulation was studied using high-resolution laser Doppler (LD) imaging in urethane-anesthetized rats. LD flux change representing cerebral blood flow (CBF) responses were analyzed from a single trial or after averaging a number of similar trials. CBF change in a single trial was observed predominantly over pixels having low baseline flux values (microvessels), which included diffuse circular patterns of activation 400-800 microm in diameter similar to the histological dimensions of individual barrels established in the layer IV of the rat somatosensory cortex. The overall activation pattern varied considerably between each trial (only about 9-10% overlap); however, the diffuse circular pattern of activation was reproducible in every single trial within and across all rats. With trial averaging, no significant increase was observed in the outer boundary of activation, but the number of activated pixels increased within the diffuse circular patterns of activation. Emergence of further active pixels primarily within the diffuse circular regions of activity with trial averaging indicates distinct CBF responses in the septal and barrel regions, with a lesser LD signal to noise ratio in the barrel core.     

Mitochondrial Ca2+ uniporter blockers influence activation-induced CBF response in the rat somatosensory cortex.

Effects of mitochondrial calcium signaling blockade on neural activation-induced CBF response were studied in urethane-anesthetized rats. Ruthenium red (RuR), a nonspecific inhibitor of the mitochondrial calcium uniporter (MCU), and Ru360, a highly specific inhibitor of the MCU, were delivered intravenously (i.v.) or intracerebroventricularly (i.c.v.). Baseline cerebral blood flow (CBF) and cerebral hyperemic response to whisker stimulation were measured through a thinned skull over the somatosensory cortex using laser Doppler imaging (LDI). Ruthenium red or Ru360 did not alter the baseline CBF at all doses used. However, the hyperemic response, defined as the activation area and amplitude of CBF increase in response to mechanical whisker stimulation, was significantly reduced in the presence of either RuR or Ru360 delivered i.c.v. The hyperemic response reduced significantly with a dose of 14.5 nmol RuR (i.c.v.), showing a further decrease with 29 nmol RuR (i.c.v.). A comparable decrease in the hyperemic response was observed during treatment with a relatively lower dose of 4.5 and 9 nmol Ru360 (i.c.v.). Delivered intravenously, Ru360 significantly diminished the cerebral hyperemic response at doses greater than 80 microg/kg i.v., up to a dose of 320 microg/kg i.v. However, RuR (i.v.) had an opposite effect with an enhancement in the cerebral hyperemic response at all doses studied. Ruthenium red or Ru360 had no significant effect on the cerebral reactivity to hypercapnia, indicating that altered cerebral hyperemic response to whisker stimulation was predominantly neural. We conclude that mitochondrial calcium signaling through the MCU mediates neural activation-induced CBF response in vivo.     

Increases in oxygen consumption without cerebral blood volume change during visual stimulation under hypotension condition.

The magnitude of the blood oxygenation level-dependent (BOLD) signal depends on cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Thus, it is difficult to separate CMRO2 changes from CBF and CBV changes. To detect the BOLD signal changes induced only by CMRO2 responses without significant evoked CBF and CBV changes, BOLD and CBV functional magnetic resonance imaging (fMRI) responses to visual stimulation were measured under normal and hypotension conditions in isoflurane-anesthetized cats at 4.7 T. When the mean arterial blood pressure (MABP) decreased from 89+/-10 to 50+/-1 mm Hg (mean+/-standard deviation, n=5) by infusion of vasodilator sodium nitroprusside, baseline CBV in the visual cortex increased by 28.4%+/-8.3%. The neural activity-evoked CBV increase in the visual cortex was 10.8%+/-3.9% at normal MABP, but was negligible at hypotension. Positive BOLD changes of +1.8%+/-0.5% (gradient echo time=25 ms) at normal MABP condition became prolonged negative changes of -1.2%+/-0.3% at hypotension. The negative BOLD response at hypotension starts approximately 1 sec earlier than positive BOLD response, but similar to CBV change at normal MABP condition. Our finding shows that the negative BOLD signals in an absence of CBV changes are indicative of an increase in CMRO2. The vasodilator-induced hypotension model simplifies the physiological source of the BOLD fMRI signals, providing an insight into spatial and temporal CMRO2 changes.     

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.     

Functional, perfusion and diffusion MRI of acute focal ischemic brain injury.

Combined functional, perfusion and diffusion magnetic resonance imaging (MRI) with a temporal resolution of 30 mins was performed on permanent and transient focal ischemic brain injury in rats during the acute phase. The apparent diffusion coefficient (ADC), baseline cerebral blood flow (CBF), and functional MRI (fMRI) blood-oxygen-level-dependent (BOLD), CBF, and CMRO(2) responses associated with CO(2) challenge and forepaw stimulation were measured. An automated cluster analysis of ADC and CBF data was used to track the spatial and temporal progression of different tissue types (e.g., normal, 'at risk,' and ischemic core) on a pixel-by-pixel basis. With permanent ischemia (n=11), forepaw stimulation fMRI response in the primary somatosensory cortices was lost, although vascular coupling (CO(2) response) was intact in some animals. Control experiments in which the right common carotid artery was ligated without causing a stroke (n=8) showed that the delayed transit time had negligible effect on the fMRI responses in the primary somatosensory cortices. With temporary (15-mins, n=8) ischemia, transient CBF and/or ADC declines were observed after reperfusion. However, no T(2) or TTC lesions were observed at 24 h except in two animals, which showed very small subcortical lesions. Vascular coupling and forepaw fMRI response also remained intact. Finally, comparison of the relative and absolute fMRI signal changes suggest caution when interpreting percent changes in disease states in which the baseline signals are physiologically altered; quantitative CBF fMRI are more appropriate measures. This approach provides valuable information regarding ischemic tissue viability, vascular coupling, and functional integrity associated with ischemic injury and could have potential clinical applications.     

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.