Periodic Reporting for period 3 - TinyBrains (BIO-PHOTONIC IMAGING OF THE INFANT BRAIN, THE MISSING LINK BETWEEN THE CELLULAR BRAIN DAMAGE AND THE NEUROVASCULAR UNIT DURING ACUTE ILLNESS)
Période du rapport: 2024-01-01 au 2025-06-30
The brain of the newborn is very different from the adult posing a major problem in assessing the origins of its injuries and in developing therapeutics. This is further complicated when the newborn was born prematurely or its in utero development has been compromised where the interplay between contributing factors cannot be understood with current tools since they are technically and ethically difficult to employ widely. The overall objective of the TinyBrains project was to build a neuroimaging platform for research that would allow the study of neurovascular coupling (NVC), cerebral autoregulation and potential episodes ischemia and hypoxia as a means to link macro (hemodynamic, electrophysiology) measurements to microscopic origins of injury in infants born with severe congenital heart defects (CHD) requiring complex heart surgery. CHD is the most prevalent congenital malformation with about a million births worldwide annually. Advances in surgical techniques and perioperative management have dramatically reduced mortality rates with more than 85% surviving to adulthood. However, significant neurodevelopmental problems are observed in about 50% due to brain injury. TinyBrains chose CHD as its target to provide a research platform to improve the understanding of the cellular origin of the brain injury by enabling the assessment of the link between energy demand and oxygen supply. As a research and innovation action, the project focused on high-risk yet high-gain technology development combining hybrid near-infrared spectroscopies with electroencephalography (EEG). The original goal was to achieve this by the first-ever built and clinically deployed combined photonics based high-density diffuse correlation tomography (DCT) and diffuse optical tomography (DOT) with EEG. The long-term goal can be described by the project motto “the quality of life resides in the brain” and we posit that new scientific knowledge will aid in the development of strategies for avoiding brain injury.
After the project onset, it was rapidly acknowledged that the changing clinical scenario – where the brain is now monitored by clinical cerebral oximeters and amplitude integrated EEG, and, other changes in infrastructure, as well as the immediate post COVID-19 pandemic shortages of components, led us to deploy risk-mitigation strategies result in the deployment of two different classes of prototypes including the originally planned hybrid high-density optical tomography platform (x2) and three, more complex but more precise and accurate monitoring prototypes. This allowed us to measure a relatively large cohort of infants pre-, intra- and post-surgery as well as a very large cohort of pre-clinical animal models. We were able to demonstrate that hybrid diffuse optics can accurately image NVC in response to auditory stimuli in this complex clinical scenario, characterize spontaneous events of NVC during surgery, relate hemodynamic changes during model heart surgery in animal models to outcome, characterize cerebral autoregulation and, overall, present a new, tri-modal device for the study of neurodevelopment in neurosciences.
The project had multiple fronts; (a) device development, assembly, validation and deployment for in vivo studies along with new methods for standardization, (b) algorithm development for multi-modal tomography, spontaneous NVC coupling, (c) data acquisition from clinical cohorts of infants born with CHD, (d) development , implementation and experimental studies of complex heart surgery in piglet models, (e) studies of markets, development of exploitation plans, and (f) dissemination of project results. We have (within the submitted and approved amendments) achieved all the main project goals, updating them as needed to meet the new realities that emerged as is the case with such clinical scenarios and explored new scientific concepts as they arose.
The project had multiple fronts; (a) device development, assembly, validation and deployment for in vivo studies along with new methods for standardization, (b) algorithm development for multi-modal tomography, spontaneous NVC coupling, (c) data acquisition from clinical cohorts of infants born with CHD, (d) development , implementation and experimental studies of complex heart surgery in piglet models, (e) studies of markets, development of exploitation plans, and (f) dissemination of project results. We have (within the submitted and approved amendments) achieved all the main project goals, updating them as needed to meet the new realities that emerged as is the case with such clinical scenarios and explored new scientific concepts as they arose.
The project was motivated because infants who were born with congenital malformations, in particular, those born with CHD, face significant morbidities. Until recent years, the focus has been on their survival but as the clinical practice has improved and the number of survivors has significantly increased, there is an increased amount of attention to the reduction of morbidity. In TinyBrains project we aimed to introduce a new, novel research tool to focus on cutting-edge research and development in the prevention of brain injury in the new born and the infant.
This complex undertaking required a trans-disciplinary collaboration with inter-linked objectives. As described above, the implementation required a more complex approach using two classes of research platforms, x2 imagers and x3 neuro-monitors. We were successful in developing, building, validating, standardizing and implementing them and they have provided important data and knowledge, which after the project will be further analyzed and interpreted towards the original goal to exploit its strong potential for both indirect (through the knowledge gained) and direct (by using an adapted version as a bed-side imager and neuro-monitor during surgery) social-impact. Paraphrasing the original proposal, the optimization of the early care of CHD and other critically ill infants/neonates with potential cerebral issues with appropriate neuro monitoring to detect and mitigate the profound burden of neurological injury has the potential to provide life-long improvements in academic achievement and quality of life. These conditions have a high prevalence and their long-term effects lead to a significant socio-economic health issue worldwide, so even modest improvements in outcome have a high potential for ground-breaking social impact. Our findings to date demonstrate that the original hypotheses, i.e. that such a platform could be utilized in the clinical setting and that it would have sensitivity to the cerebral well-being of the infant are still valid and we have taken important steps towards their validation. We have moved the state-of-the-art in both instrumentation, probes, algorithms and user-interfaces, and, in scientific knowledge providing a very rich and extensive data-set. We have also identified a clear path forward with future pre-clinical and clinical studies to bring this knowledge closer to clinical relevance.
This complex undertaking required a trans-disciplinary collaboration with inter-linked objectives. As described above, the implementation required a more complex approach using two classes of research platforms, x2 imagers and x3 neuro-monitors. We were successful in developing, building, validating, standardizing and implementing them and they have provided important data and knowledge, which after the project will be further analyzed and interpreted towards the original goal to exploit its strong potential for both indirect (through the knowledge gained) and direct (by using an adapted version as a bed-side imager and neuro-monitor during surgery) social-impact. Paraphrasing the original proposal, the optimization of the early care of CHD and other critically ill infants/neonates with potential cerebral issues with appropriate neuro monitoring to detect and mitigate the profound burden of neurological injury has the potential to provide life-long improvements in academic achievement and quality of life. These conditions have a high prevalence and their long-term effects lead to a significant socio-economic health issue worldwide, so even modest improvements in outcome have a high potential for ground-breaking social impact. Our findings to date demonstrate that the original hypotheses, i.e. that such a platform could be utilized in the clinical setting and that it would have sensitivity to the cerebral well-being of the infant are still valid and we have taken important steps towards their validation. We have moved the state-of-the-art in both instrumentation, probes, algorithms and user-interfaces, and, in scientific knowledge providing a very rich and extensive data-set. We have also identified a clear path forward with future pre-clinical and clinical studies to bring this knowledge closer to clinical relevance.