Non-invasive transabdominal measurement of placental oxygenation: a step toward continuous monitoring.

This study aimed to assess transabdominal placental oxygenation levels non-invasively. A wearable device was designed and tested in 12 pregnant women with an anterior placenta, 5 of whom had maternal pregnancy complications. Preliminary results revealed that the placental oxygenation level is closely related to pregnancy complications and placental pathology. Women with maternal pregnancy complications were found to have a lower placental oxygenation level (69.4% ± 6.7%) than those with uncomplicated pregnancy (75.0% ± 5.8%). This device is a step in the development of a point-of-care method designed to continuously monitor placental oxygenation and to assess maternal and fetal health.

Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue.

The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. In vivo investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.

Evaluation of the human placenta optical scattering properties using continuous wave and frequency-domain diffuse reflectance spectroscopy.

SIGNIFICANCE: Placenta is an essential organ for fetal development and successful reproduction. Placental insufficiency can lead to fetal hypoxia and, in extreme cases anoxia, leading to fetal death. Of the 145 million deliveries per year worldwide, ∼15 million neonates are small for gestational age and, therefore, at risk for antepartum and intrapartum hypoxia. Clinical methods to assess placental function largely rely on the assessment of fetal heart rate changes but do not assess placental oxygenation. Near-infrared spectroscopy (NIRS) allows non-invasive, real-time assessment of tissue oxygenation in intact organs, which can be used to assess placental oxygenation. However, tissue optical properties can affect the accuracy of methods to measure tissue oxygenation. AIM: This study was performed to estimate the scattering coefficient of the human placenta. We have computed the scattering coefficients of the human placenta for the range of 659 to 840 nm using two methods of diffuse reflectance spectroscopy (DRS). APPROACH: Measurements were performed using an in-house DRS device and a well-established frequency-domain diffuse optical spectroscopic system (DOSI). Measurements were performed in eight placentas obtained after cesarean deliveries. Placentas were perfused with normal saline to minimize the effects of absorption due to blood. Three sites per placenta were measured. Absorption and scattering coefficients were then calculated from the measured reflectance using the random walk theory for DRS and frequency-domain algorithm for DOSI. RESULTS: Average reduced scattering coefficient (µs ' ) was 0.943 ± 0.015 mm - 1 at 760 nm and 0.831 ± 0.009 mm - 1 at 840 nm, and a power function µs ' = 1.6619 (λ/500 nm) - 1.426 was derived for the human placental scattering coefficient. CONCLUSION: We report for the first time the scattering coefficient of the human placenta. This information can be used to assess baseline scattering and improve measurements of placental oxygen saturation with NIRS.

Hemodynamics of Prefrontal Cortex in Ornithine Transcarbamylase Deficiency: A Twin Case Study.

Ornithine transcarbamylase deficiency (OTCD) is the most common form of urea cycle disorder characterized by the presence of hyperammonemia (HA). In patients with OTCD, HA is known to cause impairments in domains of executive function and working memory. Monitoring OTCD progression and investigating neurocognitive biomarkers can, therefore, become critical in understanding the underlying brain function in a population with OTCD. We used functional near infrared spectroscopy (fNIRS) to examine the hemodynamics of prefrontal cortex (PFC) in a fraternal twin with and without OTCD. fNIRS is a non-invasive and wearable optical technology that can be used to assess cortical hemodynamics in a realistic clinical setting. We quantified the hemodynamic variations in total-hemoglobin as assessed by fNIRS while subjects performed the N-back working memory (WM) task. Our preliminary results showed that the sibling with OTCD had higher variation in a very low frequency band (<0.03 Hz, related to mechanism of cerebral autoregulation) compared to the control sibling. The difference between these variations was not as prominent in the higher frequency band, indicating the possible role of impaired autoregulation and cognitive function due to presence of HA. We further examined the functional connectivity in PFC, where the OTCD sibling showed lower interhemispheric functional connectivity as the task load increased. Our pilot results are the first to show the utility of fNIRS in monitoring OTCD cortical hemodynamics, indicating the possibility of inefficient neurocognitive function. This study provides a novel insight into the monitoring of OTCD focusing on the contribution of physiological process and neurocognitive function in this population.

Functional near-infrared spectroscopy in toddlers: Neural differentiation of communicative cues and relation to future language abilities.

The toddler and preschool years are a time of significant development in both expressive and receptive communication abilities. However, little is known about the neurobiological underpinnings of language development during this period, likely due to difficulties acquiring functional neuroimaging data. Functional near-infrared spectroscopy (fNIRS) is a motion-tolerant neuroimaging technique that assesses cortical brain activity and can be used in very young children. Here, we use fNIRS during perception of communicative and noncommunicative speech and gestures in typically developing 2- and 3-year-olds (Study 1, n = 15, n = 12 respectively) and in a sample of 2-year-olds with both fNIRS data collected at age 2 and language outcome data at age 3 (Study 2, n = 18). In Study 1, 2- and 3-year-olds differentiated between communicative and noncommunicative stimuli as well as between speech and gestures in the left lateral frontal region. However, 2-year-olds showed different patterns of activation from 3-year-olds in right medial frontal regions. In Study 2, which included two toddlers identified with early language delays along with 16 typically developing toddlers, neural differentiation of communicative stimuli in the right medial frontal region at age 2 predicted receptive language at age 3. Specifically, after accounting for variance related to verbal ability at age 2, increased neural activation for communicative gestures (vs. both communicative speech and noncommunicative gestures) at age 2 predicted higher receptive language scores at age 3. These results are discussed in the context of the underlying mechanisms of toddler language development and use of fNIRS in prediction of language outcomes.

Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency.

Hyperammonia due to ornithine transcarbamylase deficiency (OTCD) can cause a range of deficiencies in domains of executive function and working memory. Only a few fMRI studies have focused on neuroimaging data in a population with OTCD. Yet, there is a need for monitoring the disease progression and neurocognitive function in this population. In this study, we used a non-invasive neuroimaging technique, functional Near Infrared Spectroscopy (fNIRS), to examine the hemodynamics of prefrontal cortex (PFC) based on neural activation in an OTCD population. Using fNIRS, we measured the activation in PFC of the participants while performing the Stroop task. Behavioral assessment such as reaction time and correct response were recorded. We investigated the difference in behavioral measures as well as brain activation in left and right PFC in patients with OTCD and controls. Results revealed a distinction in left PFC activation between controls and patients with OTCD, where control subjects showed higher task related activation increase. Subjects with OTCD also exhibited bilateral increase in PFC activation. There was no significant difference in response time or correct response between the two groups. Our findings suggest the alterations in neurocognitive function of PFC in OTCD compared to the controls despite the behavioral profiles exhibiting no such differences. This is a first study using fNIRS to examine a neurocognitive function in OTCD population and can provide a novel insight into the screening of OTCD progression and examining neurocognitive changes.

Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism.

Many inborn errors of metabolism and genetic disorders affect the brain. The brain biochemistry may differ from that in the periphery and is not accessible by simple blood and urine sampling. Therefore, neuroimaging has proven to be a valuable tool to not only evaluate the brain structure, but also biochemistry, blood flow and function. Neuroimaging in patients with inborn errors of metabolism can include additional sequences in addition to T1 and T2-weighted imaging because in early stages, there may be no significant findings on the routine sequnces due to the lack of sensitivity or the evolution of abnormalities lags behind the ability of the imaging to detect it. In addition, findings on T1 and T2-weighted imaging of several inborn errors of metabolism may be non-specific and be seen in other non-genetic conditions. Therefore, additional neuroimaging modalities that have been employed including diffusion tensor imaging (DTI), magnetic resonance spectroscopy, functional MRI (fMRI), functional near infrared spectroscopy (fNIRS), or positron emission tomography (PET) imaging may further inform underlying changes in myelination, biochemistry, and functional connectivity. The use of Magnetic Resonance Spectroscopy in certain disorders may add a level of specificity depending upon the metabolite levels that are abnormal, as well as provide information about the process of brain injury (i.e., white matter, gray matter, energy deficiency, toxic buildup or depletion of key metabolites). It is even more challenging to understand how genetic or metabolic disorders contribute to short and/or long term changes in cognition which represent the downstream effects of IEMs. In order to image "cognition" or the downstream effects of a metabolic disorder on domains of brain function, more advanced techniques are required to analyze underlying fiber tracts or alternatively, methods such as fMRI enable generation of brain activation maps after both task based and resting state conditions. DTI can be used to look at changes in white matter tracks. Each imaging modality can explore an important aspect of the anatomy, physiology or biochemisty of the central nervous system. Their properties, pros and cons are discussed in this article. These imaging modalities will be discussed in the context of several inborn errors of metabolism including Galactosemia, Phenylketonruia, Maple syrup urine disease, Methylmalonic acidemia, Niemann-Pick Disease, type C1, Krabbe Disease, Ornithine transcarbamylase deficiency, Sjogren Larsson syndrome, Pelizeaus-Merzbacher disease, Pyruvate dehydrogenase deficiency, Nonketotic Hyperglycinemia and Fabry disease. Space constraints do not allow mention of all the disorders in which one of these modalities has been investigated, or where it would add value to diagnosis or disease progression.

The role of prefrontal cortex in a moral judgment task using functional near-infrared spectroscopy.

BACKGROUND: Understanding the neural basis of moral judgment (MJ) and human decision-making has been the subject of numerous studies because of their impact on daily life activities and social norms. Here, we aimed to investigate the neural process of MJ using functional near-infrared spectroscopy (fNIRS), a noninvasive, portable, and affordable neuroimaging modality. METHODS: We examined prefrontal cortex (PFC) activation in 33 healthy participants engaging in MJ exercises. We hypothesized that participants presented with personal (emotionally salient) and impersonal (less emotional) dilemmas would exhibit different brain activation observable through fNIRS. We also investigated the effects of utilitarian and nonutilitarian responses to MJ scenarios on PFC activation. Utilitarian responses are those that favor the greatest good while nonutilitarian responses favor moral actions. Mixed effect models were applied to model the cerebral hemodynamic changes that occurred during MJ dilemmas. RESULTS AND CONCLUSIONS: Our analysis found significant differences in PFC activation during personal versus impersonal dilemmas. Specifically, the left dorsolateral PFC was highly activated during impersonal MJ when a nonutilitarian decision was made. This is consistent with the majority of relevant fMRI studies, and demonstrates the feasibility of using fNIRS, with its portable and motion tolerant capacities, to investigate the neural basis of MJ dilemmas.

Exploring the role of task performance and learning style on prefrontal hemodynamics during a working memory task.

Existing literature outlines the quality and location of activation in the prefrontal cortex (PFC) during working memory (WM) tasks. However, the effects of individual differences on the underlying neural process of WM tasks are still unclear. In this functional near infrared spectroscopy study, we administered a visual and auditory n-back task to examine activation in the PFC while considering the influences of task performance, and preferred learning strategy (VARK score). While controlling for age, results indicated that high performance (HP) subjects (accuracy > 90%) showed task dependent lower activation compared to normal performance subjects in PFC region Specifically HP groups showed lower activation in left dorsolateral PFC (DLPFC) region during performance of auditory task whereas during visual task they showed lower activation in the right DLPFC. After accounting for learning style, we found a correlation between visual and aural VARK score and level of activation in the PFC. Subjects with higher visual VARK scores displayed lower activation during auditory task in left DLPFC, while those with higher visual scores exhibited higher activation during visual task in bilateral DLPFC. During performance of auditory task, HP subjects had higher visual VARK scores compared to NP subjects indicating an effect of learning style on the task performance and activation. The results of this study show that learning style and task performance can influence PFC activation, with applications toward neurological implications of learning style and populations with deficits in auditory or visual processing.

Prefrontal Hemodynamics in Toddlers at Rest: A Pilot Study of Developmental Variability.

Functional near infrared spectroscopy (fNIRS) is a non-invasive functional neuroimaging modality. Although, it is amenable to use in infants and young children, there is a lack of fNIRS research within the toddler age range. In this study, we used fNIRS to measure cerebral hemodynamics in the prefrontal cortex (PFC) in 18-36 months old toddlers (n = 29) as part of a longitudinal study that enrolled typically-developing toddlers as well as those "at risk" for language and other delays based on presence of early language delays. In these toddlers, we explored two hemodynamic response indices during periods of rest during which time audiovisual children's programming was presented. First, we investigate Lateralization Index, based on differences in oxy-hemoglobin saturation from left and right prefrontal cortex. Then, we measure oxygenation variability (OV) index, based on variability in oxygen saturation at frequencies attributed to cerebral autoregulation. Preliminary findings show that lower cognitive (including language) abilities are associated with fNIRS measures of both lower OV index and more extreme Lateralization index values. These preliminary findings show the feasibility of using fNIRS in toddlers, including those at risk for developmental delay, and lay the groundwork for future studies.

Prefrontal Activation During Executive Tasks Emerges Over Early Childhood: Evidence From Functional Near Infrared Spectroscopy.

Functional Near Infrared Spectroscopy (fNIRS) is a brain imaging technique that is well-suited for use in young children, making it particularly useful for investigating the neural bases of the development of executive functions. In the present study, children (ages 4-10) underwent fNIRS while completing response inhibition and working memory tasks. While both tasks were associated with increases in oxyhemoglobin and decreases in deoxyhemoglobin, we found that strength of activation increased with age and with improvements in task performance. These findings support the relation between emerging executive functions and maturation of the prefrontal cortex.

A machine learning approach to identify functional biomarkers in human prefrontal cortex for individuals with traumatic brain injury using functional near-infrared spectroscopy.

BACKGROUND: We have explored the potential prefrontal hemodynamic biomarkers to characterize subjects with Traumatic Brain Injury (TBI) by employing the multivariate machine learning approach and introducing a novel task-related hemodynamic response detection followed by a heuristic search for optimum set of hemodynamic features. To achieve this goal, the hemodynamic response from a group of 31 healthy controls and 30 chronic TBI subjects were recorded as they performed a complexity task. METHODS: To determine the optimum hemodynamic features, we considered 11 features and their combinations in characterizing TBI subjects. We investigated the significance of the features by utilizing a machine learning classification algorithm to score all the possible combinations of features according to their predictive power. RESULTS AND CONCLUSIONS: The identified optimum feature elements resulted in classification accuracy, sensitivity, and specificity of 85%, 85%, and 84%, respectively. Classification improvement was achieved for TBI subject classification through feature combination. It signified the major advantage of the multivariate analysis over the commonly used univariate analysis suggesting that the features that are individually irrelevant in characterizing the data may become relevant when used in combination. We also conducted a spatio-temporal classification to identify regions within the prefrontal cortex (PFC) that contribute in distinguishing between TBI and healthy subjects. As expected, Brodmann areas (BA) 10 within the PFC were isolated as the region that healthy subjects (unlike subjects with TBI), showed major hemodynamic activity in response to the High Complexity task. Overall, our results indicate that identified temporal and spatio-temporal features from PFC's hemodynamic activity are promising biomarkers in classifying subjects with TBI.

Facial Plethora: Modern Technology for Quantifying an Ancient Clinical Sign and Its Use in Cushing Syndrome.

CONTEXT: Facial plethora is a clinical sign described since ancient times for a variety of diseases. In the 19th century, it was linked to increased blood volume or flow, but this has never been proven. Facial plethora is also one of the earliest described clinical features of Cushing's syndrome (CS). OBJECTIVE: This study aimed to quantify facial plethora changes in CS as an early assessment of cure after surgery using noninvasive near-infrared multispectral imaging (MSI). DESIGN: The longitudinal cohort study was initiated in August 2012 and completed in August 2014. SETTING: Clinical research hospital, National Institutes of Health. PATIENTS: Thirty-four of the 38 patients who received surgical treatment for CS under protocol 97CH0076 during this period were included. INTERVENTION(S): MSI was performed on the right cheek of patients before surgery and 4.9 ± 3.1 days afterward. MAIN OUTCOME MEASURE(S): Average blood volume fraction as measured by MSI and serum cortisol. RESULTS: All but four of the 28 patients (86%) who were assessed as cured by postoperative plasma cortisol measurements of < 3 µg/dL showed a decrease in blood volume fraction (17.7 ± 0.03 vs 15.8 ± 0.03%; P = .0019), whereas an increase was seen in patients with persistent CS (18.5 ± 0.03 vs 21.4 ± 0.04%; P = .0017). Change in blood volume fraction before and after surgery was correlated with postoperative cortisol (rs = 0.58; P = .0003). CONCLUSIONS: Clinical data obtained from 34 patients indicate that a decrease in facial plethora after surgery, as evidenced by a decrease in blood volume fraction, is correlated with CS outcome. This novel technology for the first time identified a physiological mechanism associated with an ancient clinical sign. Furthermore, as a proof of principle, MSI is a promising early marker of cure in patients with CS that complements biochemical and clinical data.

Relative brain signature: a population-based feature extraction procedure to identify functional biomarkers in the brain of alcoholics.

BACKGROUND: A novel feature extraction technique, Relative-Brain-Signature (RBS), which characterizes subjects' relationship to populations with distinctive neuronal activity, is presented. The proposed method transforms a set of Electroencephalography's (EEG) time series in high dimensional space to a space of fewer dimensions by projecting time series onto orthogonal subspaces. METHODS: We apply our technique to an EEG data set of 77 abstinent alcoholics and 43 control subjects. To characterize subjects' relationship to the alcoholic and control populations, one RBS vector with respect to the alcoholic and one with respect to the control population is constructed. We used the extracted RBS vectors to identify functional biomarkers over the brain of alcoholics. To achieve this goal, the classification algorithm was used to categorize subjects into alcoholics and controls, which resulted in 78% accuracy. RESULTS AND CONCLUSIONS: Using the results of the classification, regions with distinctive functionality in alcoholic subjects are detected. These affected regions, with respect to their spatial extent, are frontal, anterior frontal, centro-parietal, parieto-occiptal, and occipital lobes. The distribution of these regions over the scalp indicates that the impact of the alcohol in the cerebral cortex of the alcoholics is spatially diffuse. Our finding suggests that these regions engage more of the right hemisphere relative to the left hemisphere of the alcoholics' brain.

Prefrontal cortex hemodynamics and age: a pilot study using functional near infrared spectroscopy in children.

Cerebral hemodynamics reflect cognitive processes and underlying physiological processes, both of which are captured by functional near infrared spectroscopy (fNIRS). Here, we introduce a novel parameter of Oxygenation Variability directly obtained from fNIRS data -the OV Index-and we demonstrate its use in children. fNIRS data were collected from 17 children (ages 4-8 years), while they performed a standard Go/No-Go task. Data were analyzed using two frequency bands-the first attributed to cerebral autoregulation (CA) (<0.1 Hz) and the second to respiration (0.2-0.3 Hz). Results indicate differences in variability of oscillations of oxygen saturation (SO2) between the two different bands. These pilot data reveal a dynamic relationship between chronological age and OV index in CA associated frequency of <0.1 Hz. Specifically, OV index increased with age between 4 and 6 years. In addition, there was much higher variability in frequencies associated with CA than for respiration across subjects. These findings provide preliminary evidence for the utility of the OV index and are the first to describe the relationship between cerebral autoregulation and age in children using fNIRS methodology.