Michela Groppo

Emergence of resting state networks in the preterm human brain

The functions of the resting state networks (RSNs) revealed by functional MRI remain unclear, but it has seemed possible that networks emerge in parallel with the development of related cognitive functions. We tested the alternative hypothesis: that the full repertoire of resting state dynamics emerges during the period of rapid neural growth before the normal time of birth at term (around 40 wk of gestation). We used a series of independent analytical techniques to map in detail the development of different networks in 70 infants born between 29 and 43 wk of postmenstrual age (PMA). We characterized and charted the development of RSNs from recognizable but often fragmentary elements at 30 wk of PMA to full facsimiles of adult patterns at term. Visual, auditory, somatosensory, motor, default mode, frontoparietal, and executive control networks developed at different rates; however, by term, complete networks were present, several of which were integrated with thalamic activity. These results place the emergence of RSNs largely during the period of rapid neural growth in the third trimester of gestation, suggesting that they are formed before the acquisition of cognitive competencies in later childhood.

Magnetic resonance imaging of white matter diseases of prematurity

Periventricular leucomalacia (PVL) and parenchymal venous infarction complicating germinal matrix/intraventricular haemorrhage have long been recognised as the two significant white matter diseases responsible for the majority of cases of cerebral palsy in survivors of preterm birth. However, more recent studies using magnetic resonance imaging to assess the preterm brain have documented two new appearances, adding to the spectrum of white matter disease of prematurity: punctate white matter lesions, and diffuse excessive high signal intensity (DEHSI). These appear to be more common than PVL but less significant in terms of their impact on individual neurodevelopment. They may, however, be associated with later cognitive and behavioural disorders known to be common following preterm birth. It remains unclear whether PVL, punctate lesions, and DEHSI represent a continuum of disorders occurring as a result of a similar injurious process to the developing white matter. This review discusses the role of MR imaging in investigating these three disorders in terms of aetiology, pathology, and outcome.

Somatosensory cortical activation identified by functional MRI in preterm and term infants

Functional MRI (fMRI) has not previously been used systematically to investigate brain function in preterm infants. We here describe statistically robust and reproducible fMRI results in this challenging subject group using a programmable somatosensory stimulus synchronized with MR image acquisition which induced well-localized positive blood oxygen level dependent (BOLD) responses contralateral to the side of the stimulation in: 11 preterm infants (median post menstrual age 33 weeks and 4 days, range 29+1 to 35+3); 6 control infants born at term gestational age; and 18 infants born preterm (median gestational age at birth 30 weeks and 5 days, range 25+4 to 36+0) but studied at term corrected gestational age. Bilateral signals were identified in 8 of the ex-preterm infants at term age. Anatomical confirmation of appropriate activations was provided with diffusion tensor imaging (DTI) based tractography which identified connecting pathways from the regions of activation through the ipsilateral corticospinal tracts and posterior limb of the internal capsule. These results demonstrate that it is possible to reliably identify positive BOLD signals in the infant brain and that fMRI techniques can also be applied in the study of preterm infants.

Magnetic resonance imaging assessment of brain maturation in preterm neonates with punctate white matter lesions

IntroductionEarly white matter (WM) injury affects brain maturation in preterm infants as revealed by diffusion tensor imaging and volumetric magnetic resonance (MR) imaging at term postmenstrual age (PMA). The aim of the study was to assess quantitatively brain maturation in preterm infants with and without milder forms of WM damage (punctate WM lesions, PWML) using conventional MRI.MethodsBrain development was quantitatively assessed using a previously validated scoring system (total maturation score, TMS) which utilizes four parameters (progressive myelination and cortical infolding, progressive involution of glial cell migration bands and germinal matrix tissue). PWML were defined as foci of increased signal on T1-weighted images and decreased signal on T2-weighted images with no evidence of cystic degeneration. A group of 22 preterm infants with PWML at term PMA (PWML group) were compared with 22 matched controls with a normal MR appearance.ResultsThe two groups were comparable concerning gestational age, birth weight and PMA. TMS was significantly lower in the PWML group than in the control group (mean TMS 12.44 ± 2.31 vs 14.00 ± 1.44; P = 0.011). Myelination (mean 2.76 ± 0.42 PWML group vs 3.32 ± 0.55 control group, P = 0.003) and cortical folding (3.64 ± 0.79 vs 4.09 ± 0.43, P = 0.027) appeared to be significantly delayed in babies with PWML.ConclusionConventional MRI appears able to quantify morphological changes in brain maturation of preterm babies with PWML; delayed myelination and reduced cortical infolding seem to be the most significant aspects.

Normal thrombin generation in neonates in spite of prolonged conventional coagulation tests

Findings of this study reinforce the concept that the coagulation balance in neonates, usually regarded as perturbed because of the deficiency of procoagulants, might be restored by the concomitant deficiency of the naturally-occurring anticoagulants. Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin generation in neonates, because they do not allow full activation of the reduced levels of protein C. Therefore, they do not reflect the action of pro- and anti-coagulants as does the endogenous thrombin potential assessed in the presence of thrombomodulin. Endogenous thrombin potential measured without thrombomodulin was greater than the lower-limit of the adult reference interval in 30% of 109 full-term and 49% of 55 pre-term neonates, a finding consistent with the reduced levels of procoagulants in this setting. When the test was modified adding thrombomodulin, endogenous thrombin potential reverted into the adult reference interval in 97% and 100% full-term and pre-term neonates. In conclusion, the coagulation balance in neonates is restored by the concomitant reduction of pro- and anticoagulants. The restored balance can be shown in vitro by the endogenous thrombin potential test that includes thrombomodulin, but not by conventional coagulation tests.

A patient care system for early 3.0 Tesla magnetic resonance imaging of very low birth weight infants.

BACKGROUND Very low birth weight (VLBW) infants (weight <1500 g) are increasingly cared for without prolonged periods of positive pressure ventilation (PPV). AIMS To develop a system for 3.0 T magnetic resonance (MR) image acquisition from VLBW infants who are not receiving PPV, and to test the clinical stability of a consecutive cohort of such infants. DESIGN Seventy VLBW infants whose median weight at image acquisition was 940 g (590-1490) underwent brain MR imaging with the developed care system as participants in research. Twenty infants (29%) received nasal continuous positive airway pressure (nCPAP), 28 (40%) received supplemental oxygen by nasal cannulae, and 22 (31%) breathed spontaneously in air during the MR examination. RESULTS There were no significant adverse events. Seventy-six percent had none or transient self-correcting oxygen desaturations. Desaturations that required interruption of the scan for assessment were less common among infants receiving nCPAP (2/20) or breathing spontaneously in air (2/22), compared with those receiving nasal cannulae oxygen (13/28), p=0.003. Sixty-four (91%) infants had an axillary temperature > or =36 degrees C at completion of the scan (lowest 35.7 degrees C), There was no relationship between weight (p=0.167) or use of nCPAP (p=0.453) and axillary temperature <36 degrees C. No infant became hyperthermic. CONCLUSION VLBW infants who do not require ventilation by endotracheal tube can be imaged successfully and safely at 3.0 T, including those receiving nCPAP from a customised system.

Germinal Matrix Hemorrhage: Intraventricular Hemorrhage in Very-Low-Birth-Weight Infants: The Independent Role of Inherited Thrombophilia

Background and Purpose— The etiology of germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is multifactorial and the role of genetic polymorphisms is unclear. The aim of this prospective study was to evaluate prothrombotic genetic mutations as independent risk factors for the development of all grades of GMH-IVH in very-low-birth-weight infants. Methods— The presence of both factor V Leiden and prothrombin gain-of-function gene mutations were prospectively assessed in 106 very-low-birth-weight infants. Infants with GMH-IVH were compared to those without GMH-IVH according to genetic and clinical characteristics. Results— Twenty-two out of 106 infants had GMH-IVH develop (20.7%). Infants with GMH-IVH had significantly lower gestational ages and birth weights. In the multivariate Poisson regression model, the prevalence of GMH-IVH appeared to be inversely related to gestational age, with a risk ratio of 0.83 (95% CI, 0.72–0.97; P=0.02) per week. Risk ratio of GMH-IVH for carriers of either prothrombotic mutation was 2.65 (95% CI, 1.23–5.72; P=0.01), similar to the risk ratio associated with need for resuscitation at birth (2.30; 95% CI, 1.02–5.18; P=0.04). Conclusions— Very-low-birth-weight infants who are carriers for either prothrombotic mutations are at increased risk for development of GMH-IVH. Genetic factors act as independent risk factors of the same magnitude as other known risk factors.

Visual performance and brain structures in the developing brain of pre-term infants

The presence of abnormal visual function has been related to overt lesions in the thalami, peritrigonal white matter (such as cavitational-necrotic periventricular leucomalacia) and optic radiations, and also to the extent of occipital cortex involvement. The normal development of visual function seems to depend on the integrity of a network that includes not only optic radiations and the primary visual cortex but also other cortical and subcortical areas, such as the frontal or temporal lobes or basal ganglia, which have been found to play a topical role in the development of vision. Therefore, the complex functions and functional connectivity of the developing brain of premature infants can be studied only with highly sophisticated techniques such as diffusion tensor tractography. The combined use of visual tests and neonatal structural and functional neuroimaging, which have become available for newborn infants, provides a better understanding of the correlation between structure and function from early life. This appears to be particularly relevant considering the essential role of early visual function in cognitive development. The identification of early visual impairment is also important, as it allows for early enrolment in intervention programmes. The association of clinical and functional studies to newer imaging techniques, which are being increasingly used also in neonates, are likely to provide further information on early aspects of vision and the mechanisms underlying brain plasticity, which are still not fully understood. Early exposure to a difficult postnatal environment together with early and unexpected removal from a protective milieu are exclusive and peculiar factors of prematurity that interfere with the normal development of the visual system in pre-term babies. The problem is further compounded by the influence of different perinatal brain lesions affecting the developing brain of premature babies. Nevertheless, in the last few decades, there have been considerable advances in our understanding of the development of vision in pre-term infants during early infancy. This has mainly been due to the development of age-specific tests assessing various aspects of visual function, from ophthalmological examination to more cortical aspects of vision, such as the ability to process orientation or different aspects of visual attention [1-7]. Improvements in understanding very early and specific neurological impairments in neurological functions have been reported in pre-term infants, known to be at risk of developing visual and visual-perceptual impairment. These impairments are due not only to retinopathy, a common finding in premature infants, but also to cerebral (central) visual impairment, secondary to brain lesions affecting the central visual pathway.

Brain maturation of preterm newborn babies: new insights.

Preterm birth still results in a high number of neurodevelopmental sequelae, although major forms of brain lesions—such as periventricular leukomalacia and intraventricular hemorrhage—are significantly reduced in this population of babies compared with a few years ago. This paper focuses on the possible reasons for this phenomenon. Some brain lesions, such as those affecting the periventricular white matter and the cerebellum, may be underestimated if magnetic resonance imaging is not used. In addition, a functional neurological consequence is not necessarily due to a recognized brain lesion, but may simply derive from an abnormally or suboptimally developed brain structure. The quality of nutrition given to a preterm baby could play a crucial role in such cases. In fact, nutrition is known to affect brain function; a case in point is the improvement in visual function resulting from dietary essential fatty acids. Finally, research in this area should aim at both reducing potential hazards and improving the quality of perinatal care, including the quality of nutrition.