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Cerebral blood flow (CBF) is crucial for brain health. Speckle contrast optical spectroscopy (SCOS) is a technique that has been recently developed to measure CBF, but the use of SCOS to measure human brain function at large source-detector separations with comparable or greater sensitivity to cerebral rather than extracerebral blood flow has not been demonstrated. We describe a fiber-based SCOS system capable of measuring human brain activation induced CBF changes at 33 mm source detector separations using CMOS detectors. The system implements a pulsing strategy to improve the photon flux and uses a data processing pipeline to improve measurement accuracy. We show that SCOS outperforms the current leading optical modality for measuring CBF, i.e. diffuse correlation spectroscopy (DCS), achieving more than 10x SNR improvement at a similar financial cost. Fiber-based SCOS provides an alternative approach to functional neuroimaging for cognitive neuroscience and health science applications. Fiber-based speckle contrast optical spectroscopy measures human brain activation via cerebral blood flow changes, outperforming current methods.

The thermodynamic properties and phase behavior of water in confined regions can vary significantly from that observed in the bulk. This is particularly true for systems in which the confinement is on the molecular-length scale. In this study, we use molecular dynamics simulations and a powerful solvent analysis technique based on inhomogenous solvation theory to investigate the properties of water molecules that solvate the confined regions of protein active sites. Our simulations and analysis indicate that the solvation of protein active sites that are characterized by hydrophobic enclosure and correlated hydrogen bonds induce atypical entropic and enthalpic penalties of hydration. These penalties apparently stabilize the protein-ligand complex with respect to the independently solvated ligand and protein, which leads to enhanced binding affinities. Our analysis elucidates several challenging cases, including the super affinity of the streptavidin-biotin system.

Speckle contrast optical spectroscopy (SCOS) is an emerging camera-based technique that can measure human cerebral blood flow (CBF) with high signal-to-noise ratio (SNR). At low photon flux levels typically encountered in human CBF measurements, camera noise and nonidealities could significantly impact SCOS measurement SNR and accuracy. Thus, a guide for characterizing, selecting, and optimizing a camera for SCOS measurements is crucial for the development of next-generation optical devices for monitoring human CBF and brain function. Here, we provide such a guide and illustrate it by evaluating three commercially available complementary metal–oxide–semiconductor cameras, considering a variety of factors including linearity, read noise, and quantization distortion. We show that some cameras that are well-suited for general intensity imaging could be challenged in accurately quantifying spatial contrast for SCOS. We then determine the optimal operating parameters for the preferred camera among the three and demonstrate measurement of human CBF with this selected low-cost camera. This work establishes a guideline for characterizing and selecting cameras as well as for determining optimal parameters for SCOS systems.

An innovative replica exchange (parallel tempering) method called replica exchange with solute tempering (REST) for the efficient sampling of aqueous protein solutions is presented here. The method bypasses the poor scaling with system size of standard replica exchange and thus reduces the number of replicas (parallel processes) that must be used. This reduction is accomplished by deforming the Hamiltonian function for each replica in such a way that the acceptance probability for the exchange of replica configurations does not depend on the number of explicit water molecules in the system. For proof of concept, REST is compared with standard replica exchange for an alanine dipeptide molecule in water. The comparisons confirm that REST greatly reduces the number of CPUs required by regular replica exchange and increases the sampling efficiency. This method reduces the CPU time required for calculating thermodynamic averages and for the ab initio folding of proteins in explicit water.

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01–4 Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole-cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.

Spatial attention is the cognitive function that coordinates the selection of visual stimuli with appropriate behavioral responses. Recent studies have reported that phase-amplitude coupling (PAC) of low and high frequencies covaries with spatial attention, but differ on the direction of covariation and the frequency ranges involved. We hypothesized that distinct phase-amplitude frequency pairs have differentiable contributions during tasks that manipulate spatial attention. We investigated this hypothesis with electrocorticography (ECoG) recordings from participants who engaged in a cued spatial attention task. To understand the contribution of PAC to spatial attention we classified cortical sites by their relationship to spatial variables or behavioral performance. Local neural activity in spatial sites was sensitive to spatial variables in the task, while local neural activity in behavioral sites correlated with reaction time. We found two PAC frequency clusters that covaried with different aspects of the task. During a period of cued attention, delta-phase/high-gamma (DH) PAC was sensitive to cue direction in spatial sites. In contrast, theta-alpha-phase/beta-low-gamma-amplitude (TABL) PAC robustly correlated with future reaction times in behavioral sites. Finally, we investigated the origins of TABL PAC and found it corresponded to behaviorally relevant, sharp waveforms, which were also coupled to a low frequency rhythm. We conclude that TABL and DH PAC correspond to distinct mechanisms during spatial attention tasks and that sharp waveforms are elements of a coupled dynamical process.

Within diffuse optics, speckle contrast optical spectroscopy (SCOS) has emerged as a promising alternative to the state-of-the-art technique of diffuse correlation spectroscopy (DCS) for continuous, noninvasive bedside monitoring of cerebral blood flow (CBF). Although the two methods theoretically yield equivalent relative indices of CBF (rCBFi), in practice, SCOS-based measurements require experimental calibration to obtain unbiased rCBFi values. To date, there are limited validation studies comparing SCOS and DCS in human subjects, particularly at long source-detector separations (SDS) relevant to adult brain monitoring. We aim to compare rCBFi from SCOS and DCS during concurrent, colocalized measurements on tissue-mimicking phantoms and humans at a large SDS of 3 cm. We conducted concurrent SCOS and DCS measurements on temperature-ramped, two-layer, and flow phantoms, respectively. We also conducted concurrent CBF measurements on 10 healthy volunteers undergoing various physiological challenges (breath-holding, hyperventilation, pressure modulation, and squatting) designed to elicit measurable changes in blood flow. SCOS and DCS operated from a shared pulsed laser source, which enabled pulsation-resolved human CBF measurements at 3 cm SDS (DCS necessitated the use of cardiac-gated averaging). We observed strong agreement ( , slope = 0.98) between SCOS- and DCS-derived rCBFi at 3 cm SDS and an order-of-magnitude improvement in SCOS noise performance relative to DCS during the measurements. Phantom experiments showed a small depth-sensitivity disadvantage for SCOS at the same SDS; however, this was far outweighed by its superior noise performance, yielding an order-of-magnitude improvement in SCOS contrast-to-noise ratio. The results demonstrate the equivalence of properly calibrated SCOS and DCS rCBFi measurements at long SDS in adults, establishing SCOS as a viable alternative to DCS for monitoring CBF. Further validation across larger cohorts and clinical populations is warranted.

We introduce the partition function p m ( n ) , which counts the number of partitions of n having more parts larger than m compared to parts less than or equal to m . We show that the generating function for p m ( n ) is related to the q -Laguerre polynomial. Using relations among q -Laguerre polynomials, we investigate partition identities and inequalities for the partition function p d , α , β ( n ) , which includes p m ( n ) for a special case.