Simultaneous estimation of a model-derived input function for quantifying cerebral glucose metabolism with [18F]FDG PET.

BACKGROUND: Quantification of the cerebral metabolic rate of glucose (CMRGlu) by dynamic [18F]FDG PET requires invasive arterial sampling. Alternatives to using an arterial input function (AIF) include the simultaneous estimation (SIME) approach, which models the image-derived input function (IDIF) by a series of exponentials with coefficients obtained by fitting time activity curves (TACs) from multiple volumes-of-interest. A limitation of SIME is the assumption that the input function can be modelled accurately by a series of exponentials. Alternatively, we propose a SIME approach based on the two-tissue compartment model to extract a high signal-to-noise ratio (SNR) model-derived input function (MDIF) from the whole-brain TAC. The purpose of this study is to present the MDIF approach and its implementation in the analysis of animal and human data. METHODS: Simulations were performed to assess the accuracy of the MDIF approach. Animal experiments were conducted to compare derived MDIFs to measured AIFs (n = 5). Using dynamic [18F]FDG PET data from neurologically healthy volunteers (n = 18), the MDIF method was compared to the original SIME-IDIF. Lastly, the feasibility of extracting parametric images was investigated by implementing a variational Bayesian parameter estimation approach. RESULTS: Simulations demonstrated that the MDIF can be accurately extracted from a whole-brain TAC. Good agreement between MDIFs and measured AIFs was found in the animal experiments. Similarly, the MDIF-to-IDIF area-under-the-curve ratio from the human data was 1.02 ± 0.08, resulting in good agreement in grey matter CMRGlu: 24.5 ± 3.6 and 23.9 ± 3.2 mL/100 g/min for MDIF and IDIF, respectively. The MDIF method proved superior in characterizing the first pass of [18F]FDG. Groupwise parametric images obtained with the MDIF showed the expected spatial patterns. CONCLUSIONS: A model-driven SIME method was proposed to derive high SNR input functions. Its potential was demonstrated by the good agreement between MDIFs and AIFs in animal experiments. In addition, CMRGlu estimates obtained in the human study agreed to literature values. The MDIF approach requires fewer fitting parameters than the original SIME method and has the advantage that it can model the shape of any input function. In turn, the high SNR of the MDIFs has the potential to facilitate the extraction of voxelwise parameters when combined with robust parameter estimation methods such as the variational Bayesian approach.

Characterization of cerebral macro- and microvascular hemodynamics during transient hypotension.

The aim of the current study was to establish the interplay between blood flow patterns within a large cerebral artery and a downstream microvascular segment under conditions of transiently reduced mean arterial pressure (MAP). We report data from nine young, healthy participants (5 women; 26 ± 4 yr) acquired during a 15-s bout of sudden-onset lower body negative pressure (LBNP; -80 mmHg). Simultaneous changes in microvascular cerebral blood flow (CBF) and middle cerebral artery blood velocity (MCAvmean) were captured using diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound (TCD), respectively. Brachial blood pressure (finger photoplethysmography) and TCD waveforms were extracted at baseline and during the nadir blood pressure (BP) response to LBNP and analyzed using a modified Windkessel model to calculate indices of cerebrovascular resistance (Ri) and compliance (Ci). Compared with baseline, rapid-onset LBNP decreased MAP by 22 ± 16% and Ri by 14 ± 10% (both P ≤ 0.03). Ci increased (322 ± 298%; P < 0.01) but MCAvmean (-8 ± 16%; P = 0.09) and CBF (-2 ± 3%; P = 0.29) were preserved. The results provide evidence that changes in both vascular resistance and compliance preserve CBF, as indexed by no significant changes in MCAvmean or DCS microvascular flow, during transient hypotension.NEW & NOTEWORTHY To characterize the relationship between cerebrovascular patterns within the large middle cerebral artery (MCA) and a downstream microvascular segment, we used a novel combination of transcranial Doppler ultrasound of the MCA and optical monitoring of a downstream microvascular segment, respectively, under conditions of transiently reduced mean arterial pressure (i.e., lower body negative pressure, -80 mmHg). A rapid increase in vessel compliance accompanied the maintenance of MCA blood velocity and downstream microvascular flow.

Effects of Systemic Physiology on Mapping Resting-State Networks Using Functional Near-Infrared Spectroscopy.

Resting-state functional connectivity (rsFC) has gained popularity mainly due to its simplicity and potential for providing insights into various brain disorders. In this vein, functional near-infrared spectroscopy (fNIRS) is an attractive choice due to its portability, flexibility, and low cost, allowing for bedside imaging of brain function. While promising, fNIRS suffers from non-neural signal contaminations (i.e., systemic physiological noise), which can increase correlation across fNIRS channels, leading to spurious rsFC networks. In the present work, we hypothesized that additional measurements with short channels, heart rate, mean arterial pressure, and end-tidal CO2 could provide a better understanding of the effects of systemic physiology on fNIRS-based resting-state networks. To test our hypothesis, we acquired 12 min of resting-state data from 10 healthy participants. Unlike previous studies, we investigated the efficacy of different pre-processing approaches in extracting resting-state networks. Our results are in agreement with previous studies and reinforce the fact that systemic physiology can overestimate rsFC. We expanded on previous work by showing that removal of systemic physiology decreases intra- and inter-subject variability, increasing the ability to detect neural changes in rsFC across groups and over longitudinal studies. Our results show that by removing systemic physiology, fNIRS can reproduce resting-state networks often reported with functional magnetic resonance imaging (fMRI). Finally, the present work details the effects of systemic physiology and outlines how to remove (or at least ameliorate) their contributions to fNIRS signals acquired at rest.

Improving Diagnosis and Prognosis in Acute Severe Brain Injury: A Multimodal Imaging Protocol.

Multi-modal neuroimaging techniques have the potential to dramatically improve the diagnosis of the level consciousness and prognostication of neurological outcome for patients with severe brain injury in the intensive care unit (ICU). This protocol describes a study that will utilize functional Magnetic Resonance Imaging (fMRI), electroencephalography (EEG), and functional Near Infrared Spectroscopy (fNIRS) to measure and map the brain activity of acute critically ill patients. Our goal is to investigate whether these modalities can provide objective and quantifiable indicators of good neurological outcome and reliably detect conscious awareness. To this end, we will conduct a prospective longitudinal cohort study to validate the prognostic and diagnostic utility of neuroimaging techniques in the ICU. We will recruit 350 individuals from two ICUs over the course of 7 years. Participants will undergo fMRI, EEG, and fNIRS testing several times over the first 10 days of care to assess for residual cognitive function and evidence of covert awareness. Patients who regain behavioral awareness will be asked to complete web-based neurocognitive tests for 1 year, as well as return for follow up neuroimaging to determine which acute imaging features are most predictive of cognitive and functional recovery. Ultimately, multi-modal neuroimaging techniques may improve the clinical assessments of patients' level of consciousness, aid in the prediction of outcome, and facilitate efforts to find interventional methods that improve recovery and quality of life.

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.

Multimodal Measurements of Brain Tissue Metabolism and Perfusion in a Neonatal Model of Hypoxic-Ischaemic Injury.

This is the first multimodal study of cerebral tissue metabolism and perfusion post-hypoxic-ischaemic (HI) brain injury using broadband near-infrared spectroscopy (bNIRS), diffuse correlation spectroscopy (DCS), positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). In seven piglet preclinical models of neonatal HI, we measured cerebral tissue saturation (StO2), cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), changes in the mitochondrial oxidation state of cytochrome c oxidase (oxCCO), cerebral glucose metabolism (CMRglc) and tissue biochemistry (Lac+Thr/tNAA). At baseline, the parameters measured in the piglets that experience HI (not controls) were 64 ± 6% StO2, 35 ± 11 ml/100 g/min CBF and 2.0 ± 0.4 µmol/100 g/min CMRO2. After HI, the parameters measured were 68 ± 6% StO2, 35 ± 6 ml/100 g/min CBF, 1.3 ± 0.1 µmol/100 g/min CMRO2, 0.4 ± 0.2 Lac+Thr/tNAA and 9.5 ± 2.0 CMRglc. This study demonstrates the capacity of a multimodal set-up to interrogate the pathophysiology of HIE using a combination of optical methods, MRS, and PET.

Dynamic tracking of microvascular hemoglobin content for continuous perfusion monitoring in the intensive care unit: pilot feasibility study.

PURPOSE: There is a need for bedside methods to monitor oxygen delivery in the microcirculation. Near-infrared spectroscopy commonly measures tissue oxygen saturation, but does not reflect the time-dependent variability of microvascular hemoglobin content (MHC) that attempts to match oxygen supply with demand. The objective of this study is to determine the feasibility of MHC monitoring in critically ill patients using high-resolution near-infrared spectroscopy to assess perfusion in the peripheral microcirculation. METHODS: Prospective observational cohort of 36 patients admitted within 48 h at a tertiary intensive care unit. Perfusion was measured on the quadriceps, biceps, and/or deltoid, using the temporal change in optical density at the isosbestic wavelength of hemoglobin (798 nm). Continuous wavelet transform was applied to the hemoglobin signal to delineate frequency ranges corresponding to physiological oscillations in the cardiovascular system. RESULTS: 31/36 patients had adequate signal quality for analysis, most commonly affected by motion artifacts. MHC signal demonstrates inter-subject heterogeneity in the cohort, indicated by different patterns of variability and frequency composition. Signal characteristics were concordant between muscle groups in the same patient, and correlated with systemic hemoglobin levels and oxygen saturation. Signal power was lower for patients receiving vasopressors, but not correlated with mean arterial pressure. Mechanical ventilation directly impacts MHC in peripheral tissue. CONCLUSION: MHC can be measured continuously in the ICU with high-resolution near-infrared spectroscopy, and reflects the dynamic variability of hemoglobin distribution in the microcirculation. Results suggest this novel hemodynamic metric should be further evaluated for diagnosing microvascular dysfunction and monitoring peripheral perfusion.

Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia.

Fibromyalgia (FM) syndrome is characterized by chronic widespread pain, muscle tenderness and emotional distress. Previous studies found reduced endogenous pain modulation in FM. This deficiency of pain modulation may be related to the attributes of chronic pain and other clinical symptoms experienced in patients with FM. Thus, we tested whether there is a link between the clinical symptoms of FM and functional connectivity (FC) of the periaqueductal gray (PAG), a key node of pain modulation. We acquired resting state 3T functional MRI (rsfMRI) data from 23 female patients with FM and 16 age- and sex- matched healthy controls (HC) and assessed FM symptoms with the Brief Pain Inventory (BPI), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS) and Pain Catastrophizing Scale (PCS). We found that patients with FM exhibit statistically significant disruptions in PAG FC, particularly with brain regions implicated in negative affect, self-awareness and saliency. Specifically, we found that, compared to HCs, the FM patients had stronger PAG FC with the lingual gyrus and hippocampus but weaker PAG FC with regions associated with motor/executive functions, the salience (SN) and default mode networks (DMN). The attenuated PAG FC was also negatively correlated with FIQ scores, and positively correlated with the magnification subscale of the PCS. These alterations were correlated with emotional and behavioral symptoms of FM. Our study implicates the PAG as a site of dysfunction contributing to the clinical manifestations and pain in FM.

Quantification of blood-brain barrier permeability by dynamic contrast-enhanced NIRS.

The blood-brain barrier (BBB) is integral to maintaining a suitable microenvironment for neurons to function properly. Despite its importance, there are no bedside methods of assessing BBB disruption to help guide management of critical-care patients. The aim of this study was to demonstrate that dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) can quantify the permeability surface-area product (PS) of the BBB. Experiments were conducted in rats in which the BBB was opened by image-guided focused ultrasound. DCE-NIRS data were acquired with two dyes of different molecular weight, indocyanine green (ICG, 67 kDa) and 800CW carboxylate (IRDye, 1166 Da), and PS maps were generated by DCE computer tomography (CT) for comparison. Both dyes showed a strong correlation between measured PS values and sonication power (R2 = 0.95 and 0.92 for ICG and IRDye respectively), and the PS values for IRDye were in good agreement with CT values obtained with a contrast agent of similar molecular weight. These proof-of-principle experiments demonstrate that DCE NIRS can quantify BBB permeability. The next step in translating this method to critical care practice will be to adapt depth sensitive methods to minimize the effects of scalp contamination on NIRS PS values.

Prolonged In Vivo Retention of a Cathepsin D Targeted Optical Contrast Agent in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer's disease (AD). We have previously developed a Targeted contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model. OBJECTIVE: The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA. METHODS: Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic AD mice were studied using a small animal imaging system at five and twelve months of age using our novel Targeted CA, or two different control CAs; a Non-Targeted (lacking the CatD cleavage site) and a Non-Penetrating (lacking the CPP). Following intravenous CA administration, the optical signal was recorded within the brain and uptake and washout curves were measured and fitted to a one-phase exponential decay curve. RESULTS: In all wild-type and 5XFAD mice, the washout of the Targeted CA that included a CPP domain was significantly slower than the washout of the Non-Penetrating and Non-Targeted CA. Furthermore, the washout of the CatD Targeted CA was significantly slower in the 5XFAD mice compared to the age matched wild-type controls (p <  0.05) at 5 and 12 months of age. Control CAs showed no differences in washout. CONCLUSIONS: The prolonged retention of the CatD targeted CA in 5XFAD mice suggests this agent may be useful for AD detection.

Functional imaging for interpretation of pain pathways: current clinical application/relevance and future initiatives.

Functional imaging of the central nervous system has been utilized since the 1970s focusing on the concept that neural functioning is coupled to regional cerebral blood flow. This has allowed for extensive mapping of the neural pathways associated with pain, the "pain-matrix." The study of the functional anatomy utilizes positron electron tomography and 2 magnetic resonance imaging techniques known as arterial spin labeling and blood oxygen dependent imaging. This area of study has greatly improved in recent years in being able to assist in the diagnosis of conditions and support in the creation of targeted therapies. The goal of this review is to educate the reader on the evolution of functional imaging and its application to the study of pain and furthermore to highlight the advances in this field that may allow for further clinical applications of this modality.