Functional neuromonitoring in neonates

Proposed title of the dissertation: Functional neuromonitoring in neonates Proposed outline of the dissertation: Over the last 10 years there is an increase in neuromonitoring in the neonatal intensive care unit, mainly using EEG and Near-Infrared Spectroscopy (NIRS). This gives more information regarding diagnosis, brain maturity, pharmacodynamics effects and prognosis. However, the currents neuromonitoring does not imply any functional testing of the patient. Two new techniques will be used to study neurovascular coupling in term infants with encephalopathy and in preterm infants. 1. fUSi : functional ultrasound imaging has a high temporal and spatial resolution and has been successfully used for preclinical imaging of somatosensory and olfactory responses, epileptic seizures, resting state connectivity and spatial representation in small animal studies. (1) This technique is only once described in neonates (2). In IMEC, the group of Alan Urban currently developed a new neonatal probe that makes this technique available for research of the neonatal brain.. 2. Neurovascular coupling measured with EEG and NIRS. Neurovascular coupling can also be measured by using the EEG (neuronal activity) and NIRS (blood flow) signals. Recently new algorithms were developed by the group of Prof Van Huffel to describe neurovascular coupling (3-5). The aim of this PhD thesis is to apply these new technologies for the study of the neonate with hypoxic ischemic encephalopathy (HIE) to better define the type of brain lesion and in the preterm infant to better define the maturity of the brain and neurodevelopmental outcome Tentative bibliography of most relevant sources: 1. Urban A, Dussaux C, Martel G, Brunner C, Mace E, Montaldo G. Real-time imaging of brain activity in freely moving rats using functional ultrasound. Nat Methods. 2015;12(9):873-8. 2. Demene C, Pernot M, Biran V, Alison M, Fink M, Baud O, et al. Ultrafast Doppler reveals the mapping of cerebral vascular resistivity in neonates. J Cereb Blood Flow Metab. 2014;34(6):1009-17. 3. Hendrikx D, Smits A, Lavanga M, De Wel O, Thewissen L, Jansen K, et al. Measurement of Neurovascular Coupling in Neonates. Front Physiol. 2019;10:65. 4. Hendrikx D, Thewissen L, Smits A, Naulaers G, Allegaert K, Van Huffel S, et al. Nonlinear Transfer Entropy to Assess the Neurovascular Coupling in Premature Infants. Adv Exp Med Biol. 2018;to appear. 5. Hendrikx D, Thewissen L, Smits A, Naulaers G, Allegaert K, Van Huffel S, et al. Using Graph Theory to Assess the Interaction between Cerebral Function, Brain Hemodynamics, and Systemic Variables in Premature Infants. Complexity. 2018 Provisional description of the objective(s) of the doctoral dissertation (research plan), the methodology, timing and any previously accomplished research related to the present proposal. Objectives : To describe new parameters of neurovascular coupling using two different techniques (fUSi and EEG/NIRS) in three patient groups : a) normal infants during polysomnography (where measurement of EEG and NIRS is standard) b) patients with hypoxic ischemic encephalopathy (where EEG and NIRS are routinely part of neuromonitoring in the NICU) , where we aim for a better diagnosis of the brain damage. c) preterm infants (postmenstrual age less than 34 weeks), where this technique will be used to predict brain maturity and neurodevelopmental outcome. Methods : During the measurements somatosensory and auditory stimuli will be elicited to design an activity map and connectivity map with fUSi. This will first be performed in healthy newborns. In the patients with HIE and in preterm infants, we will compare the activity and connectivity map with the normal values in order to find correlations with outcome for these specific patient groups. Neurovascular coupling will also be studied in the same patients using other techniques to link EEG and NIRS like the graph theory (5). Timing : Year 1 : -literature study and review of neurovascular coupling in neonates - literature study and review of the use and technique of fUSi. - first measurements with fUSi in healthy neonates and standardization of measurements - calculating neurovascular coupling in term infants with HIE using the database of patients where NIRS and EEG were measured. -set up for measurement in the three patient groups Year 2 : -start up study in patients with polysomnography -start up study in patients with HIE Year 3 : -start up study in preterm infants -results of patients with polysomnography Year 4 : results of patients with HIE and preterm infants. Previous Results : This PhD will be performed in collaboration with experienced research teams : Prof G. Naulaers, Neonatology UZ Leuven, has a longstanding experience in research in NIRS, cerebral autoregulation and EEG in collaboration with Prof S. Van Huffel, Stadius ESAT, which resulted in 6 successful PhD’s and 4 ongoing PhD’s in this subject. Recently neurovascular coupling was started as a new research item resulting in 3 international papers. Prof Urban is a worldwide expert in fUSi and will further develop a new neonatal system in IMEC. The collaboration of the different groups is already settled and a good structure formed for the research work. The clinical work will be in collaboration with UZ Brussels and UCL, where Kate Carkeek will also work clinically.