A model for the regulation of cerebral oxygen delivery

On the basis of the assumption that oxygen delivery across theendothelium is proportional to capillary plasmaPO₂, a model is presented that linkscerebral metabolic rate of oxygen utilization(CMR_O2) to cerebral blood flow(CBF) through an effective diffusivity for oxygen (D) of the capillarybed. On the basis of in vivo evidence that the oxygen diffusivityproperties of the capillary bed may be altered by changes in capillaryPO₂, hematocrit, and/or bloodvolume, the model allows changes in D with changes in CBF. Choice inthe model of the appropriate ratio of   (D/D)/(CBF/CBF)determines the dependence of tissue oxygen delivery on perfusion.Buxton and Frank (J. Cereb. Blood Flow. Metab. 17: 64-72, 1997) recently presented alimiting case of the present model in which  = 0. In contrast to thetrends predicted by the model of Buxton and Frank, in the current modelwhen > 0, the proportionality between changes in CBF andCMR_O2 becomes more linear, and similardegrees of proportionality can exist at different basal values ofoxygen extraction fraction. The model is able to fit the observedproportionalities between CBF and CMR_O2 for a large range ofphysiological data. Although the model does not validate any particularobserved proportionality between CBF andCMR_O2, generally values of(CMR_O2/CMR_O2)/(CBF/CBF) close to unity have been observed across ranges of graded anesthesia inrats and humans and for particular functional activations in humans.The model's capacity to fit the wide range of data indicates that theoxygen diffusivity properties of the capillary bed, which can bemodified in relation to perfusion, play an important role in regulatingcerebral oxygen delivery in vivo.

     

Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.     

Biophysical basis of brain activity: implications for neuroimaging

In vivo 13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively assessed rates of glutamate-glutamine cycle (Veye) and glucose oxidation (CMRGle(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in vivo 13C-MRS results demonstrate that glutamate recycling is a major metabolic pathway, inseparable from its actions of neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain, Veye and CMRGle(ox) are stoichiometrically related, where more than two thirds of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain measured at rest and its quantitative relation to neurotransmission reflects a sizeable activity level for the resting brain. The high activity of the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral function that leads to reinterpreting functional imaging data because the large baseline signal is commonly discarded in cognitive neuroscience paradigms. Changes in energy consumption (delta CMRO2%) can also be obtained from magnetic resonance imaging (MRI) experiments, using the blood oxygen level-dependent (BOLD) image contrast, provided that all the separate parameters contributing to the functional MRI (fMRI) signal are measured. The BOLD-derived delta CMRO2% when compared with alterations in neuronal spiking rate (delta v%) during sensory stimulation in the rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence fMRI when calibrated so as to provide delta CMRO2% can provide high spatial resolution evaluation of neuronal activity. Our studies of quantitative measurements of changes in neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary amount of activity in a localized region, rather a total level of activity is required where the increment is inversely related to the level of activity in the non-stimulated condition. These biophysical experiments have established relationships between energy consumption and neuronal activity that provide novel insights into the nature of brain function and the interpretation of fMRI data.     

Cerebral oxygen demand for short-lived and steady-state events

Because of the importance of oxidative energetics for cerebral function, extraction of oxygen consumption (CMR_O2) from blood oxygenation level-dependent (BOLD) signal using multi-modal measurements of blood flow (CBF) and volume (CBV) has become an accepted functional magnetic resonance imaging (fMRI) technique. This approach, termed calibrated fMRI, is based on a biophysical model which describes tissue oxygen extraction at steady-state. A problem encountered for calculating dynamic CMR_O2 relates to concerns whether the conventional BOLD model can be applied transiently. In particular, it is unclear whether calculation of CMR_O2 differs between short and long stimuli. Linearity was experimentally demonstrated between BOLD-related components and neural activity, thereby making it possible to use calibrated fMRI in a dynamic manner. We used multi-modal fMRI and electrophysiology, in α-chloralose anesthetized rats during forepaw stimulation to show that respective transfer functions (of BOLD, CBV, CBF) generated by deconvolution with neural activity are time invariant, for events in the millisecond to minute range. These results allowed extraction of a significant component of the BOLD signal that can be ascribed to CMR_O2 transients. We discuss the importance of minimizing residual signal, represented by the difference between modeled and raw signals, in convolution analysis of multi-modal signals.     

First Report of 'Candidatus Phytoplasma asteris' (Group 16SrI) Infecting Fruits and Vegetables in Islamabad, Pakistan

Nearby fruit and vegetable fields in Islamabad, Pakistan were surveyed for phytoplasma infection. ' Candidatus Phytoplasma asteris' (Group 16SrI) was found infecting mango, citrus, loquat, geranium, periwinkle, radish, blackberry and potato. Results suggest that a polyphagous vector may be involved in phytoplasma transmission to these plant species, which are first host records of 16SrI phytoplasma infection in Pakistan.     

Cerebral metabolism and consciousness

In vivo 13C magnetic resonance spectroscopy studies of the brain have measured rates of glutamate-glutamine cycle (Vcyc) and glucose oxidation (CMRglc(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. In both the awake human and in the anesthetized rat brains Vcyc and CMRglc(ox) are stoichiometrically related, and form a major pathway in which approximately 80% of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain at rest and its quantitative usage for neurotransmission reflect a high level of neuronal activity for the non-stimulated brain. This high activity supports a reinterpretation of functional imaging data, e.g., where the large baseline signal has commonly been discarded. Independent measurements of energy consumption (delta CMRO2%) obtained from calibrated fMRI equaled percentage changes in neuronal spiking rate (delta nu %) measured by electrodes during sensory stimulation at two depths of anesthesia. These quantitative biophysical relationships between energy consumption and neuronal activity provide novel insights into the nature of brain function. The high resting brain activity is proposed to include the global interactions constituting the subjective aspects of consciousness. Anesthesia by lowering the total firing rates correlates with the loss of consciousness. These results, which measure the localized neuronal response and distinguish inputs of peripheral neurons from inputs of neurons from other brain regions, fit comfortably into the neuronal scheme of a global workspace proposed by Dehaene and Changeux.     

Brain temperature measured by 1H-NMR in conjunction with a lanthanide complex.

In vivo data on temperature distributions in the intact brain are scarce, partly due to lack of noninvasive methods for the region of interest. NMR has been exploited for probing a variety of brain activities in vivo noninvasively within the region of interest. Here we report the use of a thulium-based thermometric sensor, infused through the blood, for monitoring absolute temperature in rat brain in vivo by (1)H-NMR and validated by direct temperature measurements with thermocouple wires. Because the (1)H chemical shifts also demonstrate pH sensitivity, detection of multiple resonances was used to measure both temperature and pH simultaneously with high sensitivity. Examination of blood plasma and cerebral spinal fluid samples removed from rats infused with the thermometric sensor suggests that the complex, despite its negative charge, crosses the blood-brain barrier to enter the extracellular milieu. In the future, the thulium-based thermometric sensor may be used for monitoring temperature (and pH) distributions throughout the entire brain, examining response to therapy and evaluating changes induced by alterations in neuronal activity.