Understanding how spatially remote brain regions interact to form functional brain networks, and how these develop during the neonatal period, provides fundamental insights into normal brain development, and how mechanisms of brain disorder and recovery may function in the immature brain. A key imaging tool in characterising functional brain networks is examination of T2*-weighted fMRI signal during rest (resting state fMRI, rs-fMRI). The majority of rs-fMRI studies have concentrated on slow signal fluctuations occurring at <0.1 Hz, even though neuronal rhythms, and haemodynamic responses to these fluctuate more rapidly, and there is emerging evidence for crucial information about functional brain connectivity occurring more rapidly than these limits. The characterisation of higher frequency components has been limited by the sampling frequency achievable with standard T2* echoplanar imaging (EPI) sequences. We describe patterns of neonatal functional brain network connectivity derived using accelerated T2*-weighted EPI MRI. We acquired whole brain rs-fMRI data, at subsecond sampling frequency, from preterm infants at term equivalent age and compared this to rs-fMRI data acquired with standard EPI acquisition protocol. We provide the first evidence that rapid rs-fMRI acquisition in neonates, and adoption of an extended frequency range for analysis, allows identification of a substantial proportion of signal power residing above 0.2 Hz. We thereby describe changes in brain connectivity associated with increasing maturity which are not evident using standard rs-fMRI protocols. Development of optimised neonatal fMRI protocols, including use of high speed acquisition sequences, is crucial for understanding the physiology and pathophysiology of the developing brain.

BackgroundFunctional magnetic resonance imaging (fMRI) in neonates has been introduced as a non-invasive method for studying sensorimotor processing in the developing brain. However, previous neonatal studies have delivered conflicting results regarding localization, lateralization, and directionality of blood oxygenation level dependent (BOLD) responses in sensorimotor cortex (SMC). Amongst the confounding factors in interpreting neonatal fMRI studies include the use of standard adult MR-coils providing insufficient signal to noise, and liberal statistical thresholds, compromising clinical interpretation at the single subject level.Patients / methodsHere, we employed a custom-designed neonatal MR-coil adapted and optimized to the head size of a newborn in order to improve robustness, reliability and validity of neonatal sensorimotor fMRI.Thirteen preterm infants with a median gestational age of 26 weeks were scanned at term-corrected age using a prototype 8-channel neonatal head coil at 3T (Achieva, Philips, Best, NL). Sensorimotor stimulation was elicited by passive extension/flexion of the elbow at 1 Hz in a block design. Analysis of temporal signal to noise ratio (tSNR) was performed on the whole brain and the SMC, and was compared to data acquired with an ‘adult’ 8 channel head coil published previously. Task-evoked activation was determined by single-subject SPM8 analyses, thresholded at p < 0.05, whole-brain FWE-corrected.ResultsUsing a custom-designed neonatal MR-coil, we found significant positive BOLD responses in contralateral SMC after unilateral passive sensorimotor stimulation in all neonates (analyses restricted to artifact-free data sets = 8/13). Improved imaging characteristics of the neonatal MR-coil were evidenced by additional phantom and in vivo tSNR measurements: phantom studies revealed a 240% global increase in tSNR; in vivo studies revealed a 73% global and a 55% local (SMC) increase in tSNR, as compared to the ‘adult’ MR-coil.ConclusionsOur findings strengthen the importance of using optimized coil settings for neonatal fMRI, yielding robust and reproducible SMC activation at the single subject level. We conclude that functional lateralization of SMC activation, as found in children and adults, is already present in the newborn period.

Preterm birth is associated with adverse neurodevelopmental outcomes. The pathological mechanisms leading to adverse outcomes involve several pathways, which are not fully understood. Current methods of assessing neurological injury associated with preterm birth have limited scope and low prognostic value. Whilst structural MRI may provide detailed anatomical information about the neonatal brain, there is imperfect mapping between structure and function. A supplementary approach is the use of functional MRI (fMRI) to infer functional connectivity (FC), evaluating integration of neural activity within the brain. There is emerging evidence that children who were born preterm show long term changes in FC, and early detection of such changes offers potential to improve understanding of pathophysiology of preterm brain injury. These functional changes may be influenced by both neonatal course and underlying susceptibilities to abnormal development, including genetic risk factors. We used resting state fMRI (rs-fMRI) at 3T to examine functional brain connectivity in 20 infants born at <32 weeks of gestation, scanned at term. Infants also had genetic testing to examine polymorphisms in the EAAT2 glutamate transporter, previously associated with variation in preterm neurodevelopmental outcomes. Using a multivariate model to examine the independent contributions of demographic, genetic and clinical characteristics of the infants to FC, we identified multiple dissociable influences on functional brain networks. This is the first report of genetic variability in cerebral glutamate homeostasis influencing neonatal brain connectivity. We discuss the impact on understanding preterm brain injury, and the potential for predicting neurodevelopmental outcome by non-invasive measurement of functional brain connectivity.