Bi-hemispheric CBF and its CO2 reactivity of TIAs and completed strokes in ICA occlusions

Bi-hemispheric cerebral blood flow (CBF) measurements during rest and hyperventilation, with intra-arterial 133Xe injection method, were investigated in 19 cases, angiographically diagnosed as unilateral internal carotid artery (ICA) occlusion, including 8 cases with TIAs and 11 cases with completed strokes as the onset. Indices of cerebral vascular resistance and CO2 reactivity with decreasing arterial PCO2 were also investigated. A significant decrease (P less than 0.05) of hemispheric mean CBF was noted in the ischemic hemisphere, but normal flow values in the unaffected hemisphere and preserved CO2 responsiveness during hyperventilation were observed in both the affected and unaffected hemispheres in patients with TIAs. Moreover, a direct relationship between CBF and blood pressure, observed in 11 cases with completed strokes, was not recognized in 8 cases with TIAs. A degree of the abnormalities of the affected hemisphere in cerebral circulation was suggested to be somewhat different between TIAs and completed strokes in ICA occlusions, and bi-hemispheric CBF measurements would be an useful method for evaluating the various indices of the CBF in ICA occlusions.     

Measurement of CBF and CMRO2 using the continuous inhalation of CO2 and O2: Experimental validation using CO2 reactivity in the anaesthetised dog

Experimental support for the steady state ¹⁵O inhalation technique, as used to measure cerebral blood flow (CBF) and oxygen utilisation (CMRO₂), was obtained by describing the response of the cerebral vasculature to variations in arterial P_CO2 in 6 anaesthetised dogs. Measurements were made using a positron emission tomograph (ECAT II) and arterial blood sampling, during the sequential constant inhalation of C¹⁵O₂ and ¹⁵O₂. Values of CBF and CMRO₂ were calculated for a mixture of white and grey matter, using the steady state tracer equations derived by Jones et al. (1976). The mean CMRO₂ was 3.58 ± 0.81 ml O₂ · 100 ml⁻¹ · min⁻¹, whilst the mean CBF and OER (oxygen extraction ratio) values (for an arterial P_CO2 of 40 mm Hg) were 39.9 ml · 100 ml⁻¹ · min⁻¹ and 0.50 ± 0.06, respectively. Arterial P_CO2 was varied between 20 and 150 mm Hg. CBF was found to correlate closely with arterial P_CO2, resulting in a mean slope (specific reactivity) of 1.52 ± 0.38 ml · 100 ml⁻¹ · min⁻¹ · mm Hg⁻¹. Pooling the flow data resulted in a linear relationship between CBF (% change) and arterial P_CO2 in the range 20–70 mm Hg, with a slope (% reactivity) of 3.2% mm Hg⁻¹ (2 P < 0.001). The oxygen extraction ratio (OER) fell with increasing values of arterial P_CO2 resulting in a stable CMRO₂ throughout each study. There was no correlation between CMRO₂ and artificially increased CBF.

These results support and give confidence in the use of the ¹⁵O inhalation technique for measuring CBF, OER and CMRO₂.     

Cerebrovascular reactivity to acetazolamide in carotid artery disease. Enhancement of side-to-side CBF asymmetry indicates critically reduced perfusion pressure

Cerebral blood flow (CBF), measured with a mobile 10 detector unit and non-invasive Xenon-133 technique, was investigated before and after cerebral vasodilation with acetazolamide (Diamox) in 78 patients prior to carotid endarterectomy. The change in side-to-side CBF asymmetry from baseline to Diamox study, the Diamox asymmetry enhancement, was compared with the intraoperatively measured cerebral perfusion pressures. Asymmetry enhancement exceeded the methodological variation in 14 patients, 13 of whom had a perfusion pressure below 65 mmHg. Insignificant asymmetry enhancement was found in 64 patients: 52 with unilateral and 12 with bilateral disease. Of these two and four patients, respectively, had perfusion pressures below 65 mmHg. Enhancement of CBF asymmetry following a potent cerebral vasodilator stimulus is a reliable predictor, in unilateral carotid artery disease, of critically reduced cerebral perfusion pressure.     

Baseline CBF,and BOLD,CBF, and CMRO2 fMRI of visual and vibrotactile stimulations in baboons

Neurovascular coupling associated with visual and vibrotactile stimulations in baboons anesthetized sequentially with isoflurane and ketamine was evaluated using multimodal functional magnetic resonance imaging (fMRI) on a clinical 3-Tesla scanner. Basal cerebral blood flow (CBF), and combined blood-oxygenation-level-dependent (BOLD) and CBF fMRI of visual and somatosensory stimulations were measured using pseudo-continuous arterial spin labeling. Changes in stimulus-evoked cerebral metabolic rate of oxygen (CMRO₂) were estimated using calibrated fMRI. Arterial transit time for vessel, gray matter (GM), and white matter (WM) were 250, 570, and 823 ms, respectively. Gray matter and WM CBF, respectively, were 107.8±7.9 and 47.8±3.8 mL per 100 g per minute under isoflurane, and 108.8±10.3 and 48.7±4.2 mL per 100 g per minute under ketamine (mean±s.e.m., N=8 sessions, five baboons). The GM/WM CBF ratio was not statistically different between the two anesthetics, averaging 2.3±0.1. Hypercapnia evoked global BOLD and CBF increases. Blood-oxygenation-level-dependent, CBF, and CMRO₂ signal changes by visual and vibrotactile stimulations were 0.19% to 0.22%, 18% to 23%, and 4.9% to 6.7%, respectively. The CBF/CMRO₂ ratio was 2.9 to 4.7. Basal CBF and fMRI responses were not statistically different between the two anesthetics. This study establishes a multimodal fMRI protocol to probe clinically relevant functional, physiological and metabolic information in large nonhuman primates.     

Comparison of Xe-CT/CBF and quantitative ECD-SPELT

We compared stable xenon enhanced X-ray computed tomography (Xe-CT) with Technetium-99m ethylsteinate dimer single-photon emission computed tomography (ECD-SPECT) in 12 patients. We evaluated the cerebral blood flow (CBF) values in the territory of the anterior, middle and posterior cerebral artery, and in the thalamus. The CBF values were higher in ECD-SPECT than in Xe-CT except for the values of the thalamus. The posterior cerebral artery territory showed a lower correlation and the thalamus had no correlation between two methods. We discussed causes of these differences.     

Tissue PCO2 in brain ischemia related to lactate content in normo- and hypercapnic rats.

The amount of lactate formed during ischemia determines the rise in tissue PCO2 (PtCO2). Conflicting results exist on the relationship between lactate and PtCO2. The objective of this study was to settle this issue. We varied the preischemic plasma glucose concentration of normo- and hypercapnic rats, assessed tissue lactate and total CO2 contents, and determined the PCO2/lactate relationship over the lactate range 2-40 mmol kg-1. The results showed that whatever the equilibration time, the PCO2/lactate relationship was linear. The results obtained could be reproduced by a theoretical buffer system that mimics the buffering behavior of intracellular fluid. Our results bear on the question of whether compartmentation of H+ occurs during ischemia, with glial cells becoming more acid than neurons. A discontinuous PCO2/lactate relationship, with a constant PCO2 above a certain lactate content, would support this contention. Since our results demonstrate a linear relationship between lactate and PCO2 over the lactate range 2-40 mmol kg-1, they considerably weaken any argument for gross compartmentation of H+.     

Pharmacological uncoupling of activation induced increases in CBF and CMRO2

Neurovascular coupling provides the basis for many functional neuroimaging techniques. Nitric oxide (NO), adenosine, cyclooxygenase, CYP450 epoxygenase, and potassium are involved in dilating arterioles during neuronal activation. We combined inhibition of NO synthase, cyclooxygenase, adenosine receptors, CYP450 epoxygenase, and inward rectifier potassium (Kir) channels to test whether these pathways could explain the blood flow response to neuronal activation. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO₂) of the somatosensory cortex were measured during forepaw stimulation in 24 rats using a laser Doppler/spectroscopy probe through a cranial window. Combined inhibition reduced CBF responses by two-thirds, somatosensory evoked potentials and activation-induced CMRO₂ increases remained unchanged, and deoxy-hemoglobin (deoxy-Hb) response was abrogated. This shows that in the rat somatosensory cortex, one-third of the physiological blood flow increase is sufficient to prevent microcirculatory increase of deoxy-Hb concentration during neuronal activity. The large physiological CBF response is not necessary to support small changes in CMRO₂. We speculate that the CBF response safeguards substrate delivery during functional activation with a considerable ‘safety factor''. Reduction of the CBF response in pathological states may abolish the BOLD–fMRI signal, without affecting underlying neuronal activity.     

Cerebrovascular CO2 reactivity in migraine with aura and without aura. A transcranial doppler study

Inntroduction – We studied by means of Transcranial Doppler (TCD) recordings the CO₂ cerebrovascular reactivity in migraine patients during the headache-free period. Material & methods - In three groups of subjects (15 controls, 15 suffering from migraine with aura and 15 from migraine without aura) the middle cerebral artery (MCA) mean flow velocity (MFV) was recorded under basal condition and hypocapnia induced by hyperventilation. Relative MFV, PI (Pulsatility Index) changes and Reactivity Index (RI) were calculated. Results - Reactivity Index values were: 0.019 ± 0.007 (mean ± SD) in control subjects: 0.029 ± 0.008 in migraine with aura; 0.022 ± 0.008 in migraine without aura. Statistical analysis showed a significantly (P < 0.05) increased RI in migraine with aura group. Conclusion – Cerebrovascular CO₂ reactivity is increased during the interictal period in migraine with aura patients.     

Electrocortical reactivity to emotional images and faces in middle childhood to early adolescence

The late positive potential (LPP) is an event-related potential (ERP) component that indexes sustained attention toward motivationally salient information. The LPP has been observed in children and adults, however little is known about its development from childhood into adolescence. In addition, whereas LPP studies examine responses to images from the International Affective Picture System (IAPS; Lang et al., 2008) or emotional faces, no previous studies have compared responses in youth across stimuli. To examine how emotion interacts with attention across development, the current study used an emotional-interrupt task to measure LPP and behavioral responses in 8- to 13-year-olds using unpleasant, pleasant, and neutral IAPS images, as well as sad, happy, and neutral faces. Compared to older youth, younger children exhibited enhanced LPPs over occipital sites. In addition, sad but not happy faces elicited a larger LPP than neutral faces; behavioral measures did not vary across facial expressions. Both unpleasant and pleasant IAPS images were associated with increased LPPs and behavioral interference compared to neutral images. Results suggest that there may be developmental differences in the scalp distribution of the LPP, and compared to faces, IAPS elicit more robust behavioral and electrocortical measures of attention to emotional stimuli.     

Maternal overprotection in childhood is associated with amygdala reactivity and structural connectivity in adulthood

Recently, we reported that variability in early-life caregiving experiences maps onto individual differences in threat-related brain function. Here, we extend this work to provide further evidence that subtle variability in specific features of early caregiving shapes structural and functional connectivity between the amygdala and medial prefrontal cortex (mPFC) in a cohort of 312 young adult volunteers. Multiple regression analyses revealed that participants who reported higher maternal overprotection exhibited increased amygdala reactivity to explicit signals of interpersonal threat but not implicit signals of broad environmental threat. While amygdala functional connectivity with regulatory regions of the mPFC was not significantly associated with maternal overprotection, participants who reported higher maternal overprotection exhibited relatively decreased structural integrity of the uncinate fasciculus (UF), a white matter tract connecting these same brain regions. There were no significant associations between structural or functional brain measures and either maternal or paternal care ratings. These findings suggest that an overprotective maternal parenting style during childhood is associated with later functional and structural alterations of brain regions involved in generating and regulating responses to threat.     

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.     

Cerebrovascular reactivity to acetazolamide in carotid artery disease: Enhancement of side-to-side CBF asymmetry indicates critically reduced perfusion pressure

Cerebral blood flow (CBF), measured with a mobile 10 detector unit and non-invasive Xenon-133 technique, was investigated before and after cerebral vasodilation with acetazolamide (Diamox) in 78 patients prior to carotid endarterectomy. The change in side-to-side CBF asymmetry from baseline to Diamox study, the Diamox asymmetry enhancement, was compared with the intraoperatively measured cerebral perfusion pressures. Asymmetry enhancement exceeded the methodological variation in 14 patients, 13 of whom had a perfusion pressure below 65 mmHg, Insignificant asymmetry enhancement was found in 64 patients: 52 with unilateral and 12 with bilateral disease. Of these two and four patients, respectively, had perfusion pressures below 65 mmHg. Enhancement of CBF asymmetry following a potent cerebral vasodilator stimulus is a reliable predictor, in unilateral carotid artery disease, of critically reduced cerebral perfusion pressure.     

Global ischemia in dogs: cerebrovascular CO2 reactivity and autoregulation.

One hypothesis on the pathogenesis of post-ischemic-anoxic encephalopathy is impaired cerebral perfusion or the no-reflow phenomenon. Therapies aimed at preventing the development of this phenomenon are increased cerebral perfusion pressure (CPP) and hyperventilation or hypercapnia. Using a dog model in which we have described the progressive development of post-ischemic (PI) cerebral hypoperfusion after 15 minutes of global ischemia induced by aortic and vena cavae clamping, our aims in this study were to determine during the PI cerebral hypoperfusion period: (1) cerebrovascular reactivity to CO2, and (2) cerebral blood (CBF) autoregulation. Post-ischemic cerebral hypoperfusion to about 50% of normal was not accompanied by raised intracranial pressure (ICP) but cerebrovascular CO2 reactivity was markedly attenuated while maintaining some kind of autoregulatory phenomenon. Cerebral uptake of oxygen was not significantly affected by changing PACO2 from 20 to 60 torr at constant CPP or by changing CPP from 64 to 104 torr at constant PaCO2. These results suggest that increasing both CPP and hypocapnia/hypercapnia would not significantly attenuate PI neurological deficit after global cerebral ischemia. However, in two dogs inadvertently hemodiluted in the PI period, increasing CPP from 50 to 200 torr increased CBF by 200%, suggesting that hemodilution plus increased CPP may be effective therapy for amelioration of post-ischemic-anoxic encephalopathy. The significance of our findings on cerebrovascular CO2 reactivity and autoregulation with respect to the mechanism of the no-reflow phenomenon is discussed.     

Delayed postanoxic encephalopathy after strangulation. Serial neuroradiological and neurochemical studies

A 13-year-old boy was the victim of attempted strangulation. His condition had returned to normal by the sixth day after the assault; however, from the seventh day, choreoathetosis, dystonia, and marked pseudobulbar paralysis developed in the boy. The computed tomographic scans and T2-weighted magnetic resonance images that were obtained at this time revealed low-density and high-signal intensities in the region of the bilateral putamen and caudate nucleus. These symptoms and the changes in his computed tomographic scans and magnetic resonance images subsided gradually during a 2-month period. Sequential analysis of the cerebrospinal fluid for gamma-aminobutyric acid and dopamine concentrations during his illness revealed reciprocal changes with normal recovery. Because of the delayed onset of neurological changes and the cerebrospinal fluid showing reversible symptoms, the delayed encephalopathy after strangulation had been related to the biochemical alterations that followed anoxia in the vulnerable basal ganglia.     

The reactivity of canine cerebral arteries to O2 and CO2 in vitro.

The responses of canine middle cerebral arteries to changes in pCO2 and pO2 were tested in vitro. It was found that there was no response to changes in pCO2 from 38.1 mm. Hg to 26.6 mm. Hg, but there was some constriction of the vessels with lowering of the pCO2 below 26.6 mm. Hg and there was minimal dilatation of the vessels when the pCO2 was increased from 38.1 mm. Hg to 87.2 mm. Hg. There was no response to changes in pO2 from more than 55 mm. Hg to 59.6 mm. Hg, but when pO2 was lowered below 50 mm. Hg there was a sudden, massive constriction of the arteries tested. It is postulated that this constriction is due to build-up of a substance (substances) during a period of hypoxia (pO2 less than 50 mm. Hg). The significance of the results obtained are discussed.     

Pattern of CBF in the rehabilitation of visuospatial neglect.

The CBF was assessed in seven patients before and after rehabilitation for visuospatial neglect. Two months of treatment produced an increased perfusion both in the right posterior and left anterior areas of the brain. However, only the left anterior CBF increase was correlated with the neglect disorders. The left anterior improvement in CBF was inversely correlated with right-left cerebellum asymmetry in pre- and post-treatment. The present data suggest the role of the frontal eye-fields in the mechanism of recovery of visual exploration in patients with severe neglect.