Oxygen Transport to Tissue XXXVII pp 111-120
Simulation of Preterm Neonatal Brain Metabolism During Functional Neuronal Activation Using a Computational Model
We present a computational model of metabolism in the preterm neonatal brain. The model has the capacity to mimic haemodynamic and metabolic changes during functional activation and simulate functional near-infrared spectroscopy (fNIRS) data. As an initial test of the model’s efficacy, we simulate data obtained from published studies investigating functional activity in preterm neonates. In addition we simulated recently collected data from preterm neonates during visual activation. The model is well able to predict the haemodynamic and metabolic changes from these observations. In particular, we found that changes in cerebral blood flow and blood pressure may account for the observed variability of the magnitude and sign of stimulus-evoked haemodynamic changes reported in preterm infants.
KeywordsMathematical model fNIRS Haemodynamics Autoregulation Stimulus – evoked functional response
Our research focuses on the development of a family of computational models of cerebral metabolism, primarily to investigate the effects of stimuli and physiological insults, and to inform the clinical treatment of braininjury. This work has so far centred on human adult  and piglet cerebral activity . We have recently extended our focus to the preterm neonatal brain.
A number of studies investigating functional activity in neonates using functional near infrared spectroscopy (fNIRS) have observed different haemodynamic responses. Inconsistent results have been reported in literature regarding the characteristics of stimulus-evoked changes (i.e. magnitude and sign) in oxyhaemoglobin (HbO2) and deoxyhaemoglobin (HHb). In particular, some studies report a decrease in HHb (an adult-like response) while others report the opposite. In order to research the mechanisms of these responses we have adapted an existing model of adult cerebral metabolism (BrainSignals)  to the preterm neonatal brain. In this paper, we (1) present a model of metabolism and haemodynamics in the preterm brain, (2) use the model to simulate observations of two published preterm functional response studies and (3) use the model to predict recently collected data from a stimulus-evoked haemodynamic response study in preterm neonates.
2 Modelling Functional Activation in the Developing Preterm Brain
BrainSignals parameters modified to represent the preterm neonatal brain
Normal cerebral blood flow (CBF)
ml 100 g−1 min −1
Total concentration of cytochrome-c-oxidase (CCO) in tissue
Normal fraction of oxidised CCO
Normal cerebral metabolic rate of oxygen consumption (CMRO2)
μmol 100 g−1 min −1
Pa and Pa,n
Mean arterial blood pressure
[Hbtot] and [Hbtot]n
Total concentration of haemoglobin in blood
Normal brain blood fraction
Pic and Pic,n
3 Model Simulations
Physiological characteristics of the two preterm infant subjects
Gestational age (weeks)
Actual age (weeks)
Baseline SpO2 (%)
Baseline heart rate (BPM)
The autoregulatory capacity of the preterm neonatal brain remains unclear. However, as our model simulation (Fig. 14.2a) suggests, preterm neonates may be able to maintain constant blood flow only within a very narrow range of blood pressure values. Studies have shown that the response of HHb to a functional stimulus is sometimes ‘inverted’ in preterm neonates as compared to adults. Our efforts to simulate the haemodynamic responses observed in studies performed by Kozberg et al.  and Roche-Labarbe et al.  show that the preterm model is capable of simulating the varied functional responses observed. We observed that the model predicted an HHb decrease in response to the stimulus unless we imposed vasoconstriction (as observed by Kozberg et al. ). Decreasing the radius of the blood vessel resulted in the ‘inverted’ response. The model was also able to simulate fNIRS data from the USZ study relatively well. In Neonate 1 we observed a similar response of hyperemia as observed in the Roche-Labarbe et al. study. In Neonate 2, the observed rise in ΔHHb was simulated here by a constant CBF (Fig. 14.7). However, the magnitude of ΔHbO2 and ΔHbT response was not sufficiently simulated. Neonates 1 and 2 are markedly different in both gestational and actual age (Table 14.2). The former, being older, is more likely to have a developed autoregulatory capacity although we note that both subjects showed an increased HbT response. Their differences in haematocrit and haemoglobin are also notable. Indeed it has been suggested previously that HbT may have an effect on the haemodynamic response in newborns . However, by changing baseline HbT, we did not observe an effect on the magnitude or shape of the model’s simulations.
In adapting the model to the human neonate we did not alter the normal radius of the blood vessel and other similar parameters, such as the thickness and muscular tension of the vessel wall. Our current work suggests that these baseline values do not have a significant effect on the results. However, these changes will be made in a forthcoming version of the model.
We aim to further investigate the functional response in neonates using our model. Our initial results suggest that the interaction of many variables affect this response including CBF, BP and the varied stages of development. This makes it very difficult to define a ‘normal’ functional response for all neonates.
This work was supported by a UCL-UZH neuroscience collaborative grant. TH is supported by the doctoral training centre CoMPLEX at UCL and IT by the Wellcome Trust (088429/Z/09/Z).
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