Negative blood oxygen level dependence in the rat: a model for investigating the role of suppression in neurovascular coupling

Modern neuroimaging techniques rely on neurovascular coupling to show regions of increased brain activation. However, little is known of the neurovascular coupling relationships that exist for inhibitory signals. To address this issue directly we developed a preparation to investigate the signal sources of one of these proposed inhibitory neurovascular signals, the negative blood oxygen level-dependent (BOLD) response (NBR), in rat somatosensory cortex. We found a reliable NBR measured in rat somatosensory cortex in response to unilateral electrical whisker stimulation, which was located in deeper cortical layers relative to the positive BOLD response. Separate optical measurements (two-dimensional optical imaging spectroscopy and laser Doppler flowmetry) revealed that the NBR was a result of decreased blood volume and flow and increased levels of deoxyhemoglobin. Neural activity in the NBR region, measured by multichannel electrodes, varied considerably as a function of cortical depth. There was a decrease in neuronal activity in deep cortical laminae. After cessation of whisker stimulation there was a large increase in neural activity above baseline. Both the decrease in neuronal activity and increase above baseline after stimulation cessation correlated well with the simultaneous measurement of blood flow suggesting that the NBR is related to decreases in neural activity in deep cortical layers. Interestingly, the magnitude of the neural decrease was largest in regions showing stimulus-evoked positive BOLD responses. Since a similar type of neural suppression in surround regions was associated with a negative BOLD signal, the increased levels of suppression in positive BOLD regions could importantly moderate the size of the observed BOLD response.

A model of the hemodynamic response and oxygen delivery to brain

A recent nonlinear system by Friston et al. (2000. NeuroImage 12: 466–477) links the changes in BOLD response to changes in neural activity. The system consists of five subsystems, linking: (1) neural activity to flow changes; (2) flow changes to oxygen delivery to tissue; (3) flow changes to changes in blood volume and venous outflow; (4) changes in flow, volume, and oxygen extraction fraction to deoxyhemoglobin changes; and finally (5) volume and deoxyhemoglobin changes to the BOLD response. Friston et al. exploit, in subsystem 2, a model by Buxton and Frank coupling flow changes to changes in oxygen metabolism which assumes tissue oxygen concentration to be close to zero. We describe below a model of the coupling between flow and oxygen delivery which takes into account the modulatory effect of changes in tissue oxygen concentration. The major development has been to extend the original Buxton and Frank model for oxygen transport to a full dynamic capillary model making the model applicable to both transient and steady state conditions. Furthermore our modification enables us to determine the time series of CMRO2 changes under different conditions, including CO2 challenges. We compare the differences in the performance of the “Friston system” using the original model of Buxton and Frank and that of our model. We also compare the data predicted by our model (with appropriate parameters) to data from a series of OIS studies. The qualitative differences in the behaviour of the models are exposed by different experimental simulations and by comparison with the results of OIS data from brief and extended stimulation protocols and from experiments using hypercapnia.