Correction: Grey-box modeling and hypothesis testing of functional near-infrared spectroscopy-based cerebrovascular reactivity to anodal high-definition tDCS in healthy humans.

[This corrects the article DOI: 10.1371/journal.pcbi.1009386.].

In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique that contributes to the elucidation of brain biochemistry. 13C MRS enables the detection of specific neurochemicals and their neuroenergetic correlation with neuronal function. The synergistic outcome of 13C MRS and the infusion of 13C-labeled substrates provide an understanding of neurometabolism and the role of glutamate/gamma-aminobutyric acid (GABA) neurotransmission in diseases, such as Alzheimer's disease, schizophrenia, and bipolar disorder. Moreover, 13C MRS provides a window into the altered flux rate of different pathways, including the tricarboxylic acid cycle (TCA) and the glutamate/glutamine/GABA cycle, in health and in various diseases. Notably, the metabolic flux rate of the TCA cycle often decreases in neurodegenerative diseases. Additionally, 13C MRS can be used to investigate several psychiatric and neurological disorders as it directly reflects the real-time production and alterations of key brain metabolites. This review aims to highlight the chronology, the technological advancements, and the applications of 13C MRS in various brain diseases.

Grey-box modeling and hypothesis testing of functional near-infrared spectroscopy-based cerebrovascular reactivity to anodal high-definition tDCS in healthy humans.

Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. Our study presents a grey-box linear model that was developed from a physiologically detailed multi-compartmental neurovascular unit model consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. Then, model linearization was performed on the physiologically detailed nonlinear model to find appropriate complexity (Akaike information criterion) to fit functional near-infrared spectroscopy (fNIRS) based measure of blood volume changes, called cerebrovascular reactivity (CVR), to high-definition (HD) tDCS. The grey-box linear model was applied on the fNIRS-based CVR during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. The grey-box linear models for each of the four nested pathways starting from tDCS scalp current density that perturbed synaptic potassium released from active neurons for Pathway 1, astrocytic transmembrane current for Pathway 2, perivascular potassium concentration for Pathway 3, and voltage-gated ion channel current on the smooth muscle cell for Pathway 4 were fitted to the total hemoglobin concentration (tHb) changes from optodes in the vicinity of 4x1 HD-tDCS electrodes as well as on the contralateral sensorimotor cortex. We found that the tDCS perturbation Pathway 3 presented the least mean square error (MSE, median <2.5%) and the lowest Akaike information criterion (AIC, median -1.726) from the individual grey-box linear model fitting at the targeted-region. Then, minimal realization transfer function with reduced-order approximations of the grey-box model pathways was fitted to the ensemble average tHb time series. Again, Pathway 3 with nine poles and two zeros (all free parameters), provided the best Goodness of Fit of 0.0078 for Chi-Square difference test of nested pathways. Therefore, our study provided a systems biology approach to investigate the initial transient hemodynamic response to tDCS based on fNIRS tHb data. Future studies need to investigate the steady-state responses, including steady-state oscillations found to be driven by calcium dynamics, where transcranial alternating current stimulation may provide frequency-dependent physiological entrainment for system identification. We postulate that such a mechanistic understanding from system identification of the hemodynamics response to transcranial electrical stimulation can facilitate adequate delivery of the current density to the neurovascular tissue under simultaneous portable imaging in various cerebrovascular diseases.

Cortical Excitability through Anodal Transcranial Direct Current Stimulation: a Computational Approach.

The present study analyzes the effect of various anodal transcranial direct current stimulation (tDCS) configurations in terms of electric field and voltage distribution. The work aims to assess the role of tDCS configurations considering subject's specific anatomy in a computational framework. The study considers the effect of conventional and high definition transcranial direct current stimulation (HD-tDCS) by using synthetic magnetic resonance image (MRI) volumes for normal brain and brain with multiple sclerosis (MS) lesions. The configurations presented in this study compare the effect of various m x n HD-tDCS and conventional tDCS on standard Montreal Neurological Institute (MNI152) head model which is a T1 MRI volume obtained by averaging 152 individuals at 1 mm3 resolution. The study evaluates the role of disc, ring, and pad electrodes in various configurations of tDCS application. The approximate surface area for each electrode in HD-tDCS application considered in the study is 113 mm2. The significant difference in voltage distribution has been observed due to 1 × 1 HD-tDCS configuration on synthetic MRI of normal and lesion brain using disc and ring electrodes. For region specific approach, outer ring structured electrode configuration - an extended m x n HD-tDCS configuration is presented in this study. The proposed outer ring HD-tDCS configuration has been compared with m × 1 and m × 2 HD-tDCS configurations with different types of electrodes in terms of focality, induced electric field and voltage generated. On the basis of the insights gained from the analysis of various tDCS configurations on standard, normal and lesion structural data, the design of HD-tDCS as a tool in neuro-rehabilitation has been proposed. This computational model approach is useful in fixing various parameters of current stimulation: intensity, type and arrangement of electrodes and target region by using structural MRI data of an individual prior to the real stimulation in clinical trials.

Modal Analysis of Cerebrovascular Effects for Digital Health Integration of Neurostimulation Therapies-A Review of Technology Concepts.

Transcranial electrical stimulation (tES) is increasingly recognized for its potential to modulate cerebral blood flow (CBF) and evoke cerebrovascular reactivity (CVR), which are crucial in conditions like mild cognitive impairment (MCI) and dementia. This study explores the impact of tES on the neurovascular unit (NVU), employing a physiological modeling approach to simulate the vascular response to electric fields generated by tES. Utilizing the FitzHugh-Nagumo model for neuroelectrical activity, we demonstrate how tES can initiate vascular responses such as vasoconstriction followed by delayed vasodilation in cerebral arterioles, potentially modulated by a combination of local metabolic demands and autonomic regulation (pivotal locus coeruleus). Here, four distinct pathways within the NVU were modeled to reflect the complex interplay between synaptic activity, astrocytic influences, perivascular potassium dynamics, and smooth muscle cell responses. Modal analysis revealed characteristic dynamics of these pathways, suggesting that oscillatory tES may finely tune the vascular tone by modulating the stiffness and elasticity of blood vessel walls, possibly by also impacting endothelial glycocalyx function. The findings underscore the therapeutic potential vis-à-vis blood-brain barrier safety of tES in modulating neurovascular coupling and cognitive function needing the precise modulation of NVU dynamics. This technology review supports the human-in-the-loop integration of tES leveraging digital health technologies for the personalized management of cerebral blood flow, offering new avenues for treating vascular cognitive disorders. Future studies should aim to optimize tES parameters using computational modeling and validate these models in clinical settings, enhancing the understanding of tES in neurovascular health.

Brain Imaging Databases.

The availability of neuroimaging-based databases is helping immensely to understand the brain function in healthy and diseased conditions. This viewpoint highlights the objectives, commonalities, and differences within these existing databases and pointers for researchers to choose a particular database. We introduce a multimodal multidisease database, SWADESH, and its comparison with the existing databases. A futuristic database blueprint is proposed for housing multidisease, multimodal, and longitudinal brain imaging data systematically organized in a matrix form along with neuropsychological assessment scores for the identification of causal disease processes. The information-rich databases will ultimately assist with the systematic identification of prime features linked to causal disease processes, leading to the design of appropriate clinical trials for successful therapeutic interventions.

Blood Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The characteristic pathological manifestation of AD includes the deposition of extracellular insoluble ß amyloid plaques and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein. Cost effective and minimally invasive peripheral blood-based biomarkers are critical for early AD diagnosis. Currently, the plasma based two fraction of ß amyloid peptide ratio (Aß42/40) and phosphorylated tau (p-tau) are considered as blood-based biomarkers for AD diagnosis. Recent research indicates that oxidative stress (OS) occurs prior to amyloid plaque (Aß) formation and abnormal tau phosphorylation in AD. The imbalance of the master antioxidant, glutathione (GSH), and prooxidants (iron, zinc, and copper)─plays a crucial role in AD neurodegeneration. We present peripheral blood-based OS related biomarkers that are mechanistically involved in the disease process and may serve as a novel screening tool for early detection of AD onset. This OS based approach may also provide a quick and cost efficient method to monitor the effects of disease-modifying therapies in AD clinical trials.

SWADESH: a multimodal multi-disease brain imaging and neuropsychological database and data analytics platform.

Multimodal neuroimaging data of various brain disorders provides valuable information to understand brain function in health and disease. Various neuroimaging-based databases have been developed that mainly consist of volumetric magnetic resonance imaging (MRI) data. We present the comprehensive web-based neuroimaging platform "SWADESH" for hosting multi-disease, multimodal neuroimaging, and neuropsychological data along with analytical pipelines. This novel initiative includes neurochemical and magnetic susceptibility data for healthy and diseased conditions, acquired using MR spectroscopy (MRS) and quantitative susceptibility mapping (QSM) respectively. The SWADESH architecture also provides a neuroimaging database which includes MRI, MRS, functional MRI (fMRI), diffusion weighted imaging (DWI), QSM, neuropsychological data and associated data analysis pipelines. Our final objective is to provide a master database of major brain disease states (neurodegenerative, neuropsychiatric, neurodevelopmental, and others) and to identify characteristic features and biomarkers associated with such disorders.

Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

Perspective: Disentangling the effects of tES on neurovascular unit.

Transcranial electrical stimulation (tES) can modulate the neurovascular unit, including the perivascular space morphology, but the mechanisms are unclear. In this perspective article, we used an open-source "rsHRF toolbox" and an open-source functional magnetic resonance imaging (fMRI) transcranial direct current stimulation (tDCS) data set to show the effects of tDCS on the temporal profile of the haemodynamic response function (HRF). We investigated the effects of tDCS in the gray matter and at three regions of interest in the gray matter, namely, the anodal electrode (FC5), cathodal electrode (FP2), and an independent site remote from the electrodes (PZ). A "canonical HRF" with time and dispersion derivatives and a finite impulse response (FIR) model with three parameters captured the effects of anodal tDCS on the temporal profile of the HRF. The FIR model showed tDCS onset effects on the temporal profile of HRF for verum and sham tDCS conditions that were different from the no tDCS condition, which questions the validity of the sham tDCS (placebo). Here, we postulated that the effects of tDCS onset on the temporal profile of HRF are subserved by the effects on neurovascular coupling. We provide our perspective based on previous work on tES effects on the neurovascular unit, including mechanistic grey-box modeling of the effects of tES on the vasculature that can facilitate model predictive control (MPC). Future studies need to investigate grey-box modeling of online effects of tES on the neurovascular unit, including perivascular space, neurometabolic coupling, and neurovascular coupling, that can facilitate MPC of the tES dose-response to address the momentary ("state") and phenotypic ("trait") factors.

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective.

Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) are increasingly demonstrated by the large variability in the effects of tES. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not "realistic" in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization at the point of care is proposed in this perspective article based on systems analysis of the neurovascular effects of tES. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). During tES, the transient sensations can have arousal effects on the hemodynamics, so we present a healthy case series for black-box modeling of fNIRS−pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a one-step Granger cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p < 0.05). Moreover, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed the HbT response to be significantly different (paired-samples t-test, p < 0.05) between the ipsilesional and contralesional hemispheres for primary motor cortex tDCS and cerebellar tDCS, which was subserved by the smooth muscle cells. Here, our opinion is that various physiological pathways subserving the effects of tES can lead to state−trait variability, which can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced-dimensions model and a stochastic, derivative-free covariance matrix adaptation evolution strategy. We conclude from our computational analysis that human-in-the-loop optimization of the effects of tES at the point of care merits investigation in future studies for reducing inter-subject and intra-subject variability in neuromodulation.

Comprehensive Account of Sodium Imaging and Spectroscopy for Brain Research.

Sodium (23Na) is a vital component of neuronal cells and plays a key role in various signal transmission processes. Hence, information on sodium distribution in the brain using magnetic resonance imaging (MRI) provides useful information on neuronal health. 23Na MRI and MR spectroscopy (MRS) improve the diagnosis, prognosis, and clinical monitoring of neurological diseases but confront some inherent limitations that lead to low signal-to-noise ratio, longer scan time, and diminished partial volume effects. Recent advancements in multinuclear MR technology have helped in further exploration in this domain. We aim to provide a comprehensive description of 23Na MRI and MRS for brain research including the following aspects: (a) theoretical background for understanding 23Na MRI and MRS fundamentals; (b) technological advancements of 23Na MRI with respect to pulse sequences, RF coils, and sodium compartmentalization; (c) applications of 23Na MRI in the early diagnosis and prognosis of various neurological disorders; (d) structural-chronological evolution of sodium spectroscopy in terms of its numerous applications in human studies; (e) the data-processing tools utilized in the quantitation of sodium in the respective anatomical regions.

Interplay Between Hippocampal Glutathione Depletion and pH Increment in Alzheimer's Disease.

Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain.

A Novel Near Infrared Spectroscopy Based Device for Albumin Estimation.

In this paper we have proposed a fluorescence based spectroscopy device which can be used to quantitatively estimate the amount of albumin that gets excreted out of our body. Albumin is a significant protein in bio-fluids and performs a wide range of metabolic functions. The dye that has been used as a fluorescent indicator for the presence of albumin in this study has been earlier tested with bovine serum albumin (BSA) and human serum albumin (HSA) with satisfactory results. The method is based on principle of fluorescence in near infrared range (NIR) of 700 to 850 nm by using a novel dye with the test mixture. The chosen near infrared range has a benefit of absence of the auto fluorescence of the bio-molecules present in urine other than the albumin molecules. The system consists of: light source, spectroscopic chamber, sensing and computational unit. The study shows the stability and reproducibility of device so as to avoid fluctuations of voltage and other undesirables. The optimization with bovine serum albumin and human serum albumin has been done and the device can sense as low as 100 nM concentration precisely and accurately.Clinical Relevance-The system being presented is intended for developing a low cost point of care testing device for determining albumin concentration in urine.