4Abstract: The analysis of brain imaging data has recently focused on the examination of the covariances of activity among neural regions during different behaviors. We present some of the theoretical and technical issues surrounding one of these covariance-based methods: structural equation modeling. In structural equation modeling, connections between brain areas are based on known neuroanatomy, and the interregional covariances of activity are used to calculate path coefficients representing the magnitude of the influence of each directional path. The logic behind the use of structural equation modeling stems from the suggestion that brain function is the result of changes in the covariances of activity among neural elements. The technical foundations for neural structural equation models are presented, emphasizing the ability to make inferential comparisons to evaluate the experimental changes in path coefficients. Simulated data sets were used to test the effects of omitted regions and omitted connections. The results suggested that structural modeling algorithms can give hints as to possible external influences and missing paths, but that the final decision as to model modifications requires the guidance of the researcher. The utility of anatomically based models to distinguish between the direct effect of one regon on another, and indirect effects mediated through intervening regions, is demonstrated in an empirical data set that examined the effects of darkness or patterned light on the metabolic activity in the rat visual system. The anatomical framework for the structural equation models revealed that the total impact of ascending thalamocortical influences was modified by corticocortical interactions. Extensions of structural equation modeling to human brain imaging experiments are presented. We conclude by suggesting that neural covariances may be a more accurate way to examine the dynamic functional organization of the central nervous system.
Transcranial infrared laser stimulation (TILS) is a noninvasive form of brain photobiomulation. Cytochrome-c-oxidase (CCO), the terminal enzyme in the mitochondrial electron transport chain, is hypothesized to be the primary intracellular photoacceptor. We hypothesized that TILS up-regulates cerebral CCO and causes hemodynamic changes. We delivered 1064-nm laser stimulation to the forehead of healthy participants ( n = 11), while broadband near-infrared spectroscopy was utilized to acquire light reflectance from the TILS-treated cortical region before, during, and after TILS. Placebo experiments were also performed for accurate comparison. Time course of spectroscopic readings were analyzed and fitted to the modified Beer-Lambert law. With respect to the placebo readings, we observed (1) significant increases in cerebral concentrations of oxidized CCO (Δ[CCO]; >0.08 µM; p < 0.01), oxygenated hemoglobin (Δ[HbO]; >0.8 µM; p < 0.01), and total hemoglobin (Δ[HbT]; >0.5 µM; p < 0.01) during and after TILS, and (2) linear interplays between Δ[CCO] versus Δ[HbO] and between Δ[CCO] versus Δ[HbT]. Ratios of Δ[CCO]/Δ[HbO] and Δ[CCO]/Δ[HbT] were introduced as TILS-induced metabolic-hemodynamic coupling indices to quantify the coupling strength between TILS-enhanced cerebral metabolism and blood oxygen supply. This study provides the first demonstration that TILS causes up-regulation of oxidized CCO in the human brain, and contributes important insight into the physiological mechanisms.
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