Alessandro Allievi

Development of BOLD signal hemodynamic responses in the human brain

In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the Blood Oxygen Level Dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41 + 1 weeks), and 10 preterm infants (median PMA 34 + 4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brains response to stimuli across the last trimester of gestation and beyond.

Maturation of Sensori-Motor Functional Responses in the Preterm Brain

Preterm birth engenders an increased risk of conditions like cerebral palsy and therefore this time may be crucial for the brains developing sensori-motor system. However, little is known about how cortical sensori-motor function matures at this time, whether development is influenced by experience, and about its role in spontaneous motor behavior. We aimed to systematically characterize spatial and temporal maturation of sensori-motor functional brain activity across this period using functional MRI and a custom-made robotic stimulation device. We studied 57 infants aged from 30 + 2 to 43 + 2 weeks postmenstrual age. Following both induced and spontaneous right wrist movements, we saw consistent positive blood oxygen level–dependent functional responses in the contralateral (left) primary somatosensory and motor cortices. In addition, we saw a maturational trend toward faster, higher amplitude, and more spatially dispersed functional responses; and increasing integration of the ipsilateral hemisphere and sensori-motor associative areas. We also found that interhemispheric functional connectivity was significantly related to ex-utero exposure, suggesting the influence of experience-dependent mechanisms. At term equivalent age, we saw a decrease in both response amplitude and interhemispheric functional connectivity, and an increase in spatial specificity, culminating in the establishment of a sensori-motor functional response similar to that seen in adults.

The effects of hemorrhagic parenchymal infarction on the establishment of sensori-motor structural and functional connectivity in early infancy.

IntroductionThe objective of the study was to characterize alterations of structural and functional connectivity within the developing sensori-motor system in infants with focal perinatal brain injury and at high risk of cerebral palsy.MethodsFunctional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were used to study the developing functional and structural connectivity framework in six infants born prematurely at term equivalent age. This was first characterised in three infants without focal pathology, which was then compared to that derived from three infants with unilateral haemorrhagic parenchymal infarction and a subsequent focal periventricular white matter lesion who developed later haemiparesis.ResultsFunctional responses to passive hand movement were in the contralateral perirolandic cortex, regardless of focal pathology. In infants with unilateral periventricular injury, afferent thalamo-cortical tracts appeared to have developed compensatory trajectories which circumvented areas of damage. In contrast, efferent corticospinal tracts showed marked asymmetry at term equivalent age following focal brain injury. Sensori-motor network analysis suggested that inter-hemispheric functional connectivity is largely preserved despite pathology and that impairment may be associated with adverse neurodevelopmental outcome.ConclusionFollowing focal perinatal brain injury, altered structural and functional connectivity is already present and can be characterized with MRI at term equivalent age. The results of this small case series suggest that these techniques may provide valuable new information about prognosis and the pathophysiology underlying cerebral palsy.

Technology-aided assessment of sensorimotor function in early infancy.

There is a pressing need for new techniques capable of providing accurate information about sensorimotor function during the first 2 years of childhood. Here, we review current clinical methods and challenges for assessing motor function in early infancy, and discuss the potential benefits of applying technology-assisted methods. We also describe how the use of these tools with neuroimaging, and in particular functional magnetic resonance imaging (fMRI), can shed new light on the intra-cerebral processes underlying neurodevelopmental impairment. This knowledge is of particular relevance in the early infant brain, which has an increased capacity for compensatory neural plasticity. Such tools could bring a wealth of knowledge about the underlying pathophysiological processes of diseases such as cerebral palsy; act as biomarkers to monitor the effects of possible therapeutic interventions; and provide clinicians with much needed early diagnostic information.

Computer-controlled stimulation for functional magnetic resonance imaging studies of the neonatal olfactory system

Olfactory sensation is highly functional early in human neonatal life, with studies suggesting that odours can influence behaviour and infant–mother bonding. Due to its good spatial properties, blood oxygen level–dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) has the potential to rapidly advance our understanding of the neural activity which underlies the development of olfactory perception in this key period. We aimed to design an ‘olfactometer’ specifically for use with neonatal subjects for fMRI studies of odour perception.

An fMRI Compatible Wrist Robotic Interface to Study Brain Development in Neonates

A comprehensive understanding of the mechanisms that underlie brain development in premature infants and newborns is crucial for the identification of interventional therapies and rehabilitative strategies. fMRI has the potential to identify such mechanisms, but standard techniques used in adults cannot be implemented in infant studies in a straightforward manner. We have developed an MR safe wrist stimulating robot to systematically investigate the functional brain activity related to both spontaneous and induced wrist movements in premature babies using fMRI. We present the technical aspects of this development and the results of validation experiments. Using the device, the cortical activity associated with both active and passive finger movements were reliably identified in a healthy adult subject. In two preterm infants, passive wrist movements induced a well localized positive BOLD response in the contralateral somatosensory cortex. Furthermore, in a single preterm infant, spontaneous wrist movements were found to be associated with an adjacent cluster of activity, at the level of the infant’s primary motor cortex. The described device will allow detailed and objective fMRI studies of somatosensory and motor system development during early human life and following neonatal brain injury.

An exploration of task based fMRI in neonates using echo-shifting to allow acquisition at longer TE without loss of temporal efficiency

Optimal contrast to noise ratio of the BOLD signal in neonatal and foetal fMRI has been hard to achieve because of the much longer T2(⁎) values in developing brain tissue in comparison to those in the mature adult brain. The conventional approach of optimizing fMRI sequences would suggest matching the echo time (TE) and the T2(⁎) of the neonatal and foetal brain. However, the use of a long echo time would typically increase the minimum repetition time (TR) resulting in inefficient sampling. Here we apply the concept of echo shifting to task based neonatal fMRI in order to achieve an improved contrast to noise ratio and efficient data sampling at the same time. Echo shifted EPI (es-EPI) is a modification of a standard 2D-EPI sequence which enables echo times longer than the time between consecutive excitations (TE>TS=TRNS, where NS is the number of acquired slices and TS the inter-slice repetition time). The proposed method was tested on neonatal subjects using a passive sensori-motor task paradigm. Dual echo EPI datasets with an identical readout structure to es-EPI were also acquired and used as control data to assess BOLD activation. From the results of the latter analysis, an average increase of 78±41% in contrast to noise ratio was observable when comparing late to short echoes. Furthermore, es-EPI allowed the acquisition of data with an identical contrast to the late echo, but more efficiently since a higher number of slices could be acquired in the same amount of time.

A Simple fMRI Compatible Robotic Stimulator to Study the Neural Mechanisms of Touch and Pain

This paper presents a simple device for the investigation of the human somatosensory system with functional magnetic imaging (fMRI). PC-controlled pneumatic actuation is employed to produce innocuous or noxious mechanical stimulation of the skin. Stimulation patterns are synchronized with fMRI and other relevant physiological measurements like electroencephalographic activity and vital physiological parameters. The system allows adjustable regulation of stimulation parameters and provides consistent patterns of stimulation. A validation experiment demonstrates that the system safely and reliably identifies clusters of functional activity in brain regions involved in the processing of pain. This new device is inexpensive, portable, easy-to-assemble and customizable to suit different experimental requirements. It provides robust and consistent somatosensory stimulation, which is of crucial importance to investigating the mechanisms of pain and its strong connection with the sense of touch.

Somatotopic Mapping of the Developing Sensorimotor Cortex in the Preterm Human Brain

Abstract In the mature mammalian brain, the primary somatosensory and motor cortices are known to be spatially organized such that neural activity relating to specific body parts can be somatopically mapped onto an anatomical “homunculus”. This organization creates an internal body representation which is fundamental for precise motor control, spatial awareness and social interaction. Although it is unknown when this organization develops in humans, animal studies suggest that it may emerge even before the time of normal birth. We therefore characterized the somatotopic organization of the primary sensorimotor cortices using functional MRI and a set of custom-made robotic tools in 35 healthy preterm infants aged from 31 + 6 to 36 + 3 weeks postmenstrual age. Functional responses induced by somatosensory stimulation of the wrists, ankles, and mouth had a distinct spatial organization as seen in the characteristic mature homunculus map. In comparison to the ankle, activation related to wrist stimulation was significantly larger and more commonly involved additional areas including the supplementary motor area and ipsilateral sensorimotor cortex. These results are in keeping with early intrinsic determination of a somatotopic map within the primary sensorimotor cortices. This may explain why acquired brain injury in this region during the preterm period cannot be compensated for by cortical reorganization and therefore can lead to long-lasting motor and sensory impairment.

Functional and Structural mapping of the somatosensory homunculus in the newborn brain

The human body’s representation within the primary somatosensory cortex of the brain is highly organized, and can be topographically mapped as a “homunculus”. Specific areas of the body are represented in particular regions (the upper body infero-laterally, and the lower body supero-medially) and others are seemingly over-represented due to their rich neural innervation in comparison to their actual physical size (such as the lips and tongue). How and when this representation emerges in early human brain development has not been explored, although animal models suggest both activity-dependent and genetic factors are involved during a critical period equivalent to the second and third trimester [1].