Measurements and Modeling of Transient Blood Flow Perturbations Induced by Brief Somatosensory Stimulation

Proper interpretation of BOLD fMRI and other common functional imaging methods requires an understanding of neurovascular coupling. We used laser speckle-contrast optical imaging to measure blood-flow responses in rat somatosensory cortex elicited by brief (2 s) forepaw stimulation. Results show a large increase in local blood flow speed followed by an undershoot and possible late-time oscillations. The blood flow measurements were modeled using the impulse response of a simple linear network, a four-element windkessel. This model yielded excellent fits to the detailed time courses of activated regions. The four-element windkessel model thus provides a simple explanation and interpretation of the transient blood-flow response, both its initial peak and its late-time behavior

Transfer Entropy Estimation and Directional Coupling Change Detection in Biomedical Time Series

Background: The detection of change in magnitude of directional coupling between two non-linear time series is a common subject of interest in the biomedical domain, including studies involving the respiratory chemoreflex system. Although transfer entropy is a useful tool in this avenue, no study to date has investigated how different transfer entropy estimation methods perform in typical biomedical applications featuring small sample size and presence of outliers. Methods: With respect to detection of increased coupling strength, we compared three transfer entropy estimation techniques using both simulated time series and respiratory recordings from lambs. The following estimation methods were analyzed: fixed-binning with ranking, kernel density estimation (KDE), and the Darbellay-Vajda (D-V) adaptive partitioning algorithm extended to three dimensions. In the simulated experiment, sample size was varied from 50 to 200, while coupling strength was increased. In order to introduce outliers, the heavy-tailed Laplace distribution was utilized. In the lamb experiment, the objective was to detect increased respiratoryrelated chemosensitivity to O[subscript 2] and CO[subscript 2] induced by a drug, domperidone. Specifically, the separate influence of end-tidal PO[subscript 2] and PCO[subscript 2] on minute ventilation ([dot over V][subscript E]) before and after administration of domperidone was analyzed. Results: In the simulation, KDE detected increased coupling strength at the lowest SNR among the three methods. In the lamb experiment, D-V partitioning resulted in the statistically strongest increase in transfer entropy post-domperidone for PO2 → [dot over V][subscript E]. In addition, D-V partitioning was the only method that could detect an increase in transfer entropy for PCO[subscript 2] → [dot over V][subscript E], in agreement with experimental findings. Conclusions: Transfer entropy is capable of detecting directional coupling changes in non-linear biomedical time series analysis featuring a small number of observations and presence of outliers. The results of this study suggest that fixed-binning, even with ranking, is too primitive, and although there is no clear winner between KDE and D-V partitioning, the reader should note that KDE requires more computational time and extensive parameter selection than D-V partitioning. We hope this study provides a guideline for selection of an appropriate transfer entropy estimation method.National Institutes of Health (U.S.) (Grant R01-EB001659)National Institutes of Health (U.S.) (Grant R01- HL73146)National Institutes of Health (U.S.) (Grant HL085188-01A2)National Institutes of Health (U.S.) (Grant HL090897-01A2)National Institutes of Health (U.S.) (Grant K24 HL093218-01A1)National Institutes of Health (U.S.) (Cooperative Agreement U01-EB-008577)National Institutes of Health (U.S.) (Training Grant T32-HL07901))American Heart Association (Grant 0840159N

Correlation Between Gait and Near-Infrared Brain Functional Connectivity Under Cognitive Tasks in Elderly Subjects With Mild Cognitive Impairment

Older adults with mild cognitive impairment (MCI) have a high risk of developing Alzheimer’s disease. Gait performance is a potential clinical marker for the progression of MCI into dementia. However, the relationship between gait and brain functional connectivity (FC) in older adults with MCI remains unclear. Forty-five subjects [MCI group, n = 23; healthy control (HC) group, n = 22] were recruited. Each subject performed a walking task (Task 01), counting backward–walking task (Task 02), naming animals–walking task (Task 03), and calculating–walking task (Task 04). The gait parameters and cerebral oxygenation signals from the left prefrontal cortex (LPFC), right prefrontal cortex (RPFC), left motor cortex (LMC), right motor cortex (RMC), left occipital leaf cortex (LOL), and right occipital leaf cortex (ROL) were obtained simultaneously. Wavelet phase coherence was calculated in two frequency intervals: low frequency (interval I, 0.052–0.145 Hz) and very low frequency (interval II, 0.021–0.052 Hz). Results showed that the FC of RPFC–RMC is significantly lower in interval I in Task 03 compared with that in Task 02 in the MCI group (p = 0.001). Also, the right relative symmetry index (IDpsR) is significantly lower in Task 03 compared with that in Task 02 (p = 0.000). The IDpsR is positively correlated with the FC of RPFC–RMC in interval I in the MCI group (R = 0.205, p = 0.041). The gait symmetry such as left relative symmetry index (IDpsL) and IDpsR is significantly lower in the dual-task (DT) situation compared with the single task in the two groups (p < 0.05). The results suggested that the IDpsR might reflect abnormal change in FC of RPFC–RMC in interval I in the MCI population during Task 03. The gait symmetry is affected by DTs in both groups. The findings of this study may have a pivotal role in the early monitoring and intervention of brain dysfunction among older adults with MCI

Frequency-specific network topologies in the resting human brain

A community is a set of nodes with dense inter-connections, while there are sparse connections between different communities. A hub is a highly connected node with high centrality. It has been shown that both communities and hubs exist simultaneously in the brain’s functional connectivity network, as estimated by correlations among low-frequency spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signal changes (0.01–0.10 Hz). This indicates that the brain has a spatial organization that promotes both segregation and integration of information. Here, we demonstrate that frequency-specific network topologies that characterize segregation and integration also exist within this frequency range. In investigating the coherence spectrum among 87 brain regions, we found that two frequency bands, 0.01–0.03 Hz (very low frequency [VLF] band) and 0.07–0.09 Hz (low frequency [LF] band), mainly contributed to functional connectivity. Comparing graph theoretical indices for the VLF and LF bands revealed that the network in the former had a higher capacity for information segregation between identified communities than the latter. Hubs in the VLF band were mainly located within the anterior cingulate cortices, whereas those in the LF band were located in the posterior cingulate cortices and thalamus. Thus, depending on the timescale of brain activity, at least two distinct network topologies contributed to information segregation and integration. This suggests that the brain intrinsically has timescale-dependent functional organizations

Improved assessment of hypoperfusion, blood-brain barrier disruption, and ischemic cellular damage in stroke patients using magnetic resonance imaging

Introduction Emerging magnetic resonance imaging (MRI) techniques can potentially improve clinical decision-making in acute stroke. First, however, these techniques need to be investigated in a routine clinical setting and their use thoroughly validated by comparing them to established methods and relevant clinical outcomes. In this dissertation, we studied three MRI methods for assessment of cerebral perfusion without exogenous contrast agents, quantification of blood-brain barrier disruption, and improved detection of infratentorial ischemic damage. Methods In Study I, we compared a contrast agent-free method for measuring perfusion, known as BOLD delay (from the blood-oxygenation-level-dependent signal), to the clinical reference standard, dynamic susceptibility contrast MRI (DSC-MRI) in 30 stroke patients within 24 hours of symptom onset. In Study II, we used dynamic contrast-enhanced MRI (DCE-MRI) to quantify blood-brain barrier (BBB) leakage in 54 stroke patients within 48 hours of symptom onset. In Study III, we compared the diagnostic performance of a stimulated echo acquisition mode (STEAM) diffusion weighted imaging (DWI) sequence to that of the clinical reference standard, an echo planar imaging (EPI) DWI sequence, in 57 patients with suspected infratentorial stroke. Results BOLD delay was closely related to DSC-MRI parameters that reflect both macrovascular delay and microvascular perfusion and was capable of distinguishing severe hypoperfusion from milder blood flow changes (Study I). We quantified BBB permeability and observed an increase in leakage over time in ischemic lesions. Leakage was also present in contralateral tissue, where it decreased over time (Study II). STEAM-DWI showed good agreement with EPI-DWI and a high sensitivity to ischemia, with far fewer intraparenchymal artifacts than EPI-DWI (Study III). Conclusions This dissertation shows that BOLD delay, DCE-MRI, and STEAM-DWI can be incorporated into routine MRI protocols for the assessment of stroke patients. They provide useful information regarding perfusion, BBB permeability, and infratentorial ischemic damage and have the potential to influence acute stroke diagnosis and management. The dissertation also highlights several weaknesses of these methods, opening up paths for further research and improvement.Einführung Innovative Magnetresonanztomographie-Techniken (MRT) bergen das Potential klinische Therapieentscheidungen beim akuten Schlaganfall positiv beeinflussen zu können. Diese Techniken müssen jedoch zuerst in der klinischen Routine evaluiert und genau validiert werden, indem man sie mit etablierten Methoden und deren Ergebnissen vergleicht. In dieser Dissertation wurden drei MRT-Techniken zum verbesserten Nachweis infratentorieller Schlaganfälle, Beurteilung der Bluthirnschranken-Störung und Kontrastmittel-freien Perfusion untersucht. Methoden In Studie I wurde eine Kontrastmittel-freie Methode der Perfusionsmessung, bekannt als "BOLD („blood-oxygenation-level-dependent“) delay" mit dem klinischen Referenzstandard, der DSC-MRT („dynamic susceptibility contrast“) bei 30 Schlaganfallpatienten innerhalb von 24 Stunden nach Symptombeginn verglichen. In Studie II wurde die DCE-MRT („dynamic contrast-enhanced“) eingesetzt, um eine Störung der Bluthirnschranke bei 54 Schlaganfallpatienten innerhalb von 48 Stunden nach Symptombeginn quantitativ erfassen zu können. In Studie III wurde die diagnostische Aussagekraft der STEAM („stimulated echo acquisition mode“) diffusions-gewichtete (DWI) Sequenz mit der klinischen Referenzmethode, der echoplanaren (EPI=echo planar imaging) DWI bei 57 Patienten mit fraglichen infratentoriellen Schlaganfall evaluiert. Ergebnisse Die BOLD Technik zeigte einen engen Zusammenhang mit DSC-MRT Parametern hinsichtlich Folgen von Stenosen/Verschlüssen der zerebralen Arterien. Eine schwere Minderdurchblutung konnte von leichten Veränderungen der Blutflusses unterschieden werden (Studie I). Störungen der Bluthirnschranke konnten quantitativ erfaßt und eine weitere Zunahme im ischämischen Areal im zeitlichen Verlauf beobachtet werden. Eine Störung der Bluthirnschranke fand sich auch im „gesunden“ kontraläsionalen Hirngewebe, die sich im zeitlichen Verlauf besserte (Studie II). Die STEAM-DWI zeigte eine gute Übereinstimmung mit der EPI-DWI und eine hohe Sensitivität mit deutlich weniger intraparenchymalen Artefakten als die EPI-DWI (Studie III). Schlußfolgerungen Diese Dissertation konnte zeigen, daß der BOLD delay, die DCE-Technik und die STEAM-DWI für die MRT Schlaganfalldiagnostik in Routine-Protokolle inkorporiert werden könnte. Damit stünden aussagekräftige Zusatzinformationen zu Perfusion, Bluthirnschrankenpermeabilität und Detektion von infratentoriellen Schlaganfällen zur Verfügung mit der Möglichkeit besserer Therapieoptionen. Diese Dissertation zeigt auch die Schwächen dieser Methoden auf und eröffnet damit einen Weg für weitere Forschungsmöglichkeiten und Verbesserungen

NONINVASIVE NEAR-INFRARED DIFFUSE OPTICAL MONITORING OF CEREBRAL HEMODYNAMICS AND AUTOREGULATION

Many cerebral diseases are associated with abnormal cerebral hemodynamics and impaired cerebral autoregulation (CA). CA is a mechanism to maintain cerebral blood flow (CBF) stable when mean arterial pressure (MAP) fluctuates. Evaluating these abnormalities requires direct measurements of cerebral hemodynamics and MAP. Several near-infrared diffuse optical instruments have been developed in our laboratory for hemodynamic measurements including near-infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS), hybrid NIRS/DCS, and dual-wavelength DCS flow-oximeter. We utilized these noninvasive technologies to quantify CBF and cerebral oxygenation in different populations under different physiological conditions/manipulations. A commercial finger plethysmograph was used to continuously monitor MAP. For investigating the impact of obstructive sleep apnea (OSA) on cerebral hemodynamics and CA, a portable DCS device was used to monitor relative changes of CBF (rCBF) during bilateral thigh cuff occlusion. Compared to healthy controls, smaller reductions in rCBF and MAP following cuff deflation were observed in patients with OSA, which might result from the impaired vasodilation. However, dynamic CAs quantified in time-domain (defined by rCBF drop/MAP drop) were not significantly different between the two groups. We also evaluated dynamic CA in frequency-domain, i.e., to quantify the phase shifts of low frequency oscillations (LFOs) at 0.1 Hz between cerebral hemodynamics and MAP under 3 different physiological conditions (i.e., supine resting, head-up tilt (HUT), paced breathing). To capture dynamic LFOs, a hybrid NIRS/DCS device was upgraded to achieve faster sampling rate and better signal-to-noise. We determined the best hemodynamic parameters (i.e., CBF, oxygenated and total hemoglobin concentrations) among the measured variables and optimal physiological condition (HUT) for detecting LFOs in healthy subjects. Finally, a novel dual-wavelength DCS flow-oximeter was developed to monitor cerebral hemodynamics during HUT-induced vasovagal presyncope (VVS) in healthy subjects. rCBF was found to have the best sensitivity for the assessment of VVS among the measured variables and was likely the final trigger of VVS. A threshold of ~50% rCBF decline was observed which can completely separate subjects with or without presyncope, suggesting its potential role for predicting VVS. With further development and applications, NIRS/DCS techniques are expected to have significant impacts on the evaluation of cerebral hemodynamics and autoregulation

Functional networks and network perturbations in rodents

Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed

生体信号の移動エントロピー解析に基づく自律神経機能の評価に関する研究

Tohoku University吉澤