On The Development of a Dynamic Contrast-Enhanced Near-Infrared Technique to Measure Cerebral Blood Flow in the Neurocritical Care Unit

A dynamic contrast-enhanced (DCE) near-infrared (NIR) method to measure cerebral blood flow (CBF) in the neurocritical care unit (NCU) is described. A primary concern in managing patients with acquired brain injury (ABI) is onset of delayed ischemic injury (DII) caused by complications during the days to weeks following the initial insult, resulting in reduced CBF and impaired oxygen delivery. The development of a safe, portable, and quantitative DCE-NIR method for measuring CBF in NCU patients is addressed by focusing on four main areas: designing a clinically compatible instrument, developing an appropriate analytical framework, creating a relevant ABI animal model, and validating the method against CT perfusion. In Chapter 2, depth-resolved continuous-wave NIR recovered values of CBF in a juvenile pig show strong correlation with CT perfusion CBF during mild ischemia and hyperemia (r=0.84, p\u3c0.001). In particular, subject-specific light propagation modeling reduces the variability caused by extracerebral layer contamination. In Chapter 3, time-resolved (TR) NIR improves the signal sensitivity to brain tissue, and a relative CBF index is be both sensitive and specific to flow changes in the brain. In particular, when compared with the change in CBF measured with CT perfusion during hypocapnia, the deconvolution-based index has an error of 0.8%, compared to 21.8% with the time-to-peak method. To enable measurement of absolute CBF, a method for characterizing the AIF is described in Chapter 4, and the theoretical basis for an advanced analytical framework—the kinetic deconvolution optical reconstruction (KDOR)—is provided in Chapter 5. Finally, a multichannel TR-NIR system is combined with KDOR to quantify CBF in an adult pig model of ischemia (Chapter 6). In this final study, measurements of CBF obtained with the DCE-NIR technique show strong agreement with CT perfusion measurements of CBF in mild and moderate ischemia (r=0.86, p\u3c0.001). The principle conclusion of this thesis is that the DCE-NIR method, combining multidistance TR instrumentation with the KDOR analytical framework, can recover CBF values that are in strong agreement with CT perfusion values of CBF. Ultimately, bedside CBF measurements could improve clinical management of ABI by detecting delayed ischemia before permanent brain damage occurs

Best practices for fNIRS publications

The application of functional near-infrared spectroscopy (fNIRS) in the neurosciences has been expanding over the last 40 years. Today, it is addressing a wide range of applications within different populations and utilizes a great variety of experimental paradigms. With the rapid growth and the diversification of research methods, some inconsistencies are appearing in the way in which methods are presented, which can make the interpretation and replication of studies unnecessarily challenging. The Society for Functional Near-Infrared Spectroscopy has thus been motivated to organize a representative (but not exhaustive) group of leaders in the field to build a consensus on the best practices for describing the methods utilized in fNIRS studies. Our paper has been designed to provide guidelines to help enhance the reliability, repeatability, and traceability of reported fNIRS studies and encourage best practices throughout the community. A checklist is provided to guide authors in the preparation of their manuscripts and to assist reviewers when evaluating fNIRS papers

An ongoing role for Wnt signaling in differentiating melanocytes in vivo.

A role for Wnt signaling in melanocyte specification from neural crest is conserved across vertebrates, but possible ongoing roles in melanocyte differentiation have received little attention. Using a systems biology approach to investigate the gene regulatory network underlying stable melanocyte differentiation in zebrafish highlighted a requirement for a positive-feedback loop involving the melanocyte master regulator Mitfa. Here, we test the hypothesis that Wnt signaling contributes to that positive feedback. We show firstly that Wnt signaling remains active in differentiating melanocytes and secondly that enhanced Wnt signaling drives elevated transcription of mitfa. We show that chemical activation of the Wnt signaling pathway at early stages of melanocyte development enhances melanocyte specification as expected, but importantly that at later (differentiation) stages, it results in altered melanocyte morphology, although melanisation is not obviously affected. Downregulation of Wnt signaling also results in altered melanocyte morphology and organization. We conclude that Wnt signaling plays a role in regulating ongoing aspects of melanocyte differentiation in zebrafish

Wearable, high-density fNIRS and diffuse optical tomography technologies: a perspective

Recent progress in optoelectronics has made wearable and high-density functional near-infrared spectroscopy (fNIRS) and diffuse optical tomography (DOT) technologies possible for the first time. These technologies have the potential to open new fields of real-world neuroscience by enabling functional neuroimaging of the human cortex at a resolution comparable to fMRI in almost any environment and population. In this perspective article, we provide a brief overview of the history and the current status of wearable high-density fNIRS and DOT approaches, discuss the greatest ongoing challenges, and provide our thoughts on the future of this remarkable technology

The Potential Role of fNIRS in Evaluating Levels of Consciousness

Over the last few decades, neuroimaging techniques have transformed our understanding of the brain and the effect of neurological conditions on brain function. More recently, light-based modalities such as functional near-infrared spectroscopy have gained popularity as tools to study brain function at the bedside. A recent application is to assess residual awareness in patients with disorders of consciousness, as some patients retain awareness albeit lacking all behavioural response to commands. Functional near-infrared spectroscopy can play a vital role in identifying these patients by assessing command-driven brain activity. The goal of this review is to summarise the studies reported on this topic, to discuss the technical and ethical challenges of working with patients with disorders of consciousness, and to outline promising future directions in this field

Detecting Command-Driven Brain Activity in Patients with Disorders of Consciousness Using TR-fNIRS

Vegetative state (VS) is a disorder of consciousness often referred to as “wakefulness without awareness”. Patients in this condition experience normal sleep-wake cycles, but lack all awareness of themselves and their surroundings. Clinically, assessing consciousness relies on behavioural tests to determine a patient’s ability to follow commands. This subjective approach often leads to a high rate of misdiagnosis (~40%) where patients who retain residual awareness are misdiagnosed as being in a VS. Recently, functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI), has allowed researchers to use command-driven brain activity to infer consciousness. Although promising, the cost and accessibility of fMRI hinder its use for frequent examinations. Functional near-infrared spectroscopy (fNIRS) is an emerging optical technology that is a promising alternative to fMRI. The technology is safe, portable and inexpensive allowing for true bedside assessment of brain function. This thesis focuses on using time-resolved (TR) fNIRS, a variant of fNIRS with enhanced sensitivity to the brain, to detect brain function in healthy controls and patients with disorders of consciousness (DOC). Motor imagery (MI) was used to assess command-driven brain activity since this task has been extensively validated with fMRI. The feasibility of TR-fNIRS to detect MI activity was first assessed on healthy controls and fMRI was used for validation. The results revealed excellent agreement between the two techniques with an overall sensitivity of 93% in comparison to fMRI. Following these promising results, TR-fNIRS was used for rudimentary mental communication by using MI as affirmation to questions. Testing this approach on healthy controls revealed an overall accuracy of 76%. More interestingly, the same approach was used to communicate with a locked-in patient under intensive care. The patient had residual eye movement, which provided a unique opportunity to confirm the fNIRS results. The TR-fNIRS results were in full agreement with the eye responses, demonstrating for the first time the ability of fNIRS to communicate with a patient without prior training. Finally, this approach was used to assess awareness in DOC patients, revealing residual brain function in two patients who had also previously shown significant MI activity with fMRI

Non-invasive optical monitoring of brain haemodynamics and metabolism following acute brain injury

Following acute brain injury (ABI), cellular hypoxia-ischaemia (CH-I) is central to the pathophysiological cascades that lead to death and neurological disability. Thus, a key tenet of neurocritical care is the avoidance of CH-I, and a key prerequisite to doing so is the availability of a bedside clinical monitor that can identify CH-I as it occurs. This thesis describes normal cerebral physiology, how this is deranged and clinically manipulated following ABI, and the use of near infrared spectroscopy (NIRS), a non- invasive optical technique, to monitor for CH-I in a variety of clinical contexts. I then present my work investigating the use of NIRS, with an emphasis on the measurement of the oxidation state of cytochrome c oxidase (CCO), in healthy volunteers who are subjected to a variety of challenges designed to manipulate cerebral oxygen delivery with both isovolaemic and hyper/hypovolaemic challenges. Finally, I describe experiments in a cohort of a patients who have suffered from ABI, manipulating cerebral oxygen delivery by means of normobaric hyperoxia. The results suggest that the measurement of CCO with NIRS in patients with ABI provides a useful adjunct to established monitors of cerebral haemodynamics and metabolism; an in-depth discussion of the observed changes in different haemodynamic and metabolic parameters, and their relevance to normal physiology and pathophysiology of ABI is carried out

Comparison of short-channel separation and spatial domain filtering for removal of non-neural components in functional near-infrared spectroscopy signals

Significance: With the increasing popularity of functional near-infrared spectroscopy (fNIRS), the need to determine localization of the source and nature of the signals has grown. Aim: We compare strategies for removal of non-neural signals for a finger-thumb tapping task, which shows responses in contralateral motor cortex and a visual checkerboard viewing task that produces activity within the occipital lobe. Approach: We compare temporal regression strategies using short-channel separation to a spatial principal component (PC) filter that removes global signals present in all channels. For short-channel temporal regression, we compare non-neural signal removal using first and combined first and second PCs from a broad distribution of short channels to limited distribution on the forehead. Results: Temporal regression of non-neural information from broadly distributed short channels did not differ from forehead-only distribution. Spatial PC filtering provides results similar to short-channel separation using the temporal domain. Utilizing both first and second PCs from short channels removes additional non-neural information. Conclusions: We conclude that short-channel information in the temporal domain and spatial domain regression filtering methods remove similar non-neural components represented in scalp hemodynamics from fNIRS signals and that either technique is sufficient to remove non-neural components

Translação de um sistema de óptica de difusão para monitoramento de pacientes neurocríticos

Orientador: Rickson Coelho MesquitaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb WataghinResumo: As doenças cerebrovasculares são uma das principais causas de morte e incapacidade em todo o mundo. Em 2015, mais de 590.000 pacientes foram hospitalizados por estas doenças no Brasil, com aproximadamente 100.000 óbitos. A prevenção de danos secundários é um dos principais objetivos no tratamento de doenças cerebrovasculares graves, como o acidente vascular cerebral (AVC). No entanto, atualmente há uma falta de métodos não invasivos para monitoramento contínuo da fisiologia cerebral. Neste contexto, a espectroscopia óptica de difusão (DOS) e a espectroscopia de correlação de difusão (DCS) foram recentemente propostas como potenciais monitores não invasivos e contínuos capazes de fornecer informações neurofisiológicas em pacientes neurocríticos. Ao incidir luz infravermelha no escalpo, DCS pode medir o fluxo sanguíneo cerebral (CBF) e DOS pode medir as concentrações de oxi e desoxi-hemoglobina. A combinação de DOS e DCS foi explorada anteriormente para monitorar pacientes em vários cenários clínicos, como monitoramento neonatal, durante intervenções cerebrovasculares e para monitoramento de pacientes neurocríticos. No entanto, a confiabilidade da técnica para fornecer informações precisas em tempo real durante medições longitudinais, bem como durante alguns tipos de intervenções clínicas, permanece em grande parte não estudada. O principal objetivo desta tese foi mostrar que as técnicas de óptica de difusão podem auxiliar de maneira confiável e no monitoramento em tempo real de doenças cerebrovasculares. Para isso, desenvolvemos sistemas baseados em óptica de difusão e testamos a viabilidade destes sistemas em diferentes ambientes clínicos, envolvendo o monitoramento de pacientes dentro de uma unidade de terapia intensiva (UTI), bem como durante o tratamento endovascular de AVC. Primeiro, relatamos a construção e a translação de um sistema híbrido de óptica de difusão, combinando DOS e DCS, para o monitoramento em tempo real da fisiologia cerebral de pacientes internados em uma UTI. Mais especificamente, apresentamos dois estudos de caso, onde mostramos que os parâmetros neurofisiológicos medidos pelas técnicas de óptica de difusão são consistentes com a evolução clínica destes pacientes. Em seguida, relatamos a translação das técnicas de óptica de difusão para monitorar a hemodinâmicas cerebral durante o tratamento endovascular de dois pacientes com oclusões na artéria carótida interna. Nossos resultados identificaram um aumento induzido pela recanalização no CBF ipsilateral, com pouca ou nenhuma alteração no CBF contralateral e no fluxo sanguíneo extracerebral. Nossos resultados mostraram que a óptica de difusão tem grande potencial para monitorar os danos secundários em pacientes neurocríticos, sem interferir com práticas clínicas. Além disso, nossos resultados sugerem que o monitoramento hemodinâmico cerebral com as técnicas ópticas tem potencial para guiar terapias baseadas na fisiologia individual de pacientes. Por fim, para melhorar a confiabilidade das técnicas de ópticas de difusão, também propusemos a implementação de algoritmos aprimorados para a análise de dados. Mostramos que, usando um modelo de duas camadas para DOS/DCS, podemos melhorar a precisão na recuperação das alterações hemodinâmicas cerebraisAbstract: Cerebrovascular diseases are one of the main causes of death and disability worldwide. In 2015, there were more than 590.000 patients hospitalized due to cerebrovascular diseases in Brazil, with approximately 100.000 deaths. Prevention of secondary damage is an important goal in the treatment of severe neurological conditions, such as head trauma and stroke. However, there is currently a lack of non-invasive methods for continuous monitoring of cerebral physiology in real-time. More recently, diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) have been proposed as noninvasive and continuous bedside monitors capable of providing neurophysiology information in neurocritical patients. By shining near-infrared light from the scalp, DCS can measure microvascular cerebral blood flow (CBF), and DOS can measure oxy- and deoxy-hemoglobin concentrations. The combination of DOS and DCS has been previously explored to monitor patients in several clinical scenarios, such as neonatal monitoring, during cerebrovascular interventions, and for monitoring of neurocritical patients. However, the reliability of the technique to provide accurate real-time information during longitudinal (i.e., across multiple days) measurement as well as during a few different clinical interventions remains largely unaddressed. The main goal of this thesis was to show that diffuse optics can reliably aid in monitoring cerebrovascular diseases, in real-time. To that end, we have translated a diffuse optical system to different clinic environments: during long-term monitoring of patients inside an intensive care unit, as well as during an endovascular treatment of stroke. First, we reported the construction and translation of a hybrid diffuse optical system combining DOS and DCS for real-time monitoring of cerebral physiology in a neuro intensive care unit. By presenting two representative case-studies, we show that the neurophysiological parameters measured by diffuse optics at the bedside are consistent with the clinical evolution of the patients. Then, we reported the translation of diffuse optics to monitor frontal-lobe cerebral hemodynamic changes during endovascular treatment of two patients with ischemic stroke due to internal carotid artery occlusions. The monitoring instrument identified a recanalization-induced increase in ipsilateral CBF with little or no concurrent change in contralateral CBF and extracerebral blood flow. Taken together, our results showed that diffuse optics holds promise for monitoring secondary damage in neurocritical patients, with minimal interference with current clinical practices. Additionally, our results suggest that cerebral hemodynamic monitoring with diffuse optics has the potential to guide therapy based on the individual physiology of neurocritical patients. Last, to improve the reliability of the diffuse optical techniques, we have also proposed the implementation of improved algorithms for data analysis. We showed that by using a two-layer model for DOS/DCS, we can improve the accuracy of diffuse optics in recovering the cerebral hemodynamic changesDoutoradoFísicaDoutor em Ciências2014/25486-61504865/2015FAPESPCAPE