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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.

Transcranial infrared laser stimulation (TILS) at 1064 nm, 250 mW/cm has been proven safe and effective for increasing neurocognitive functions in young adults in controlled studies using photobiomodulation of the right prefrontal cortex. The objective of this pilot study was to determine whether there is any effect from TILS on neurocognitive function in older adults with subjective memory complaint at risk for cognitive decline (e.g., increased carotid artery intima-media thickness or mild traumatic brain injury). We investigated the cognitive effects of TILS in older adults (ages 49-90, n = 12) using prefrontal cortex measures of attention (psychomotor vigilance task (PVT)) and memory (delayed match to sample (DMS)), carotid artery intima-media thickness (measured by ultrasound), and evaluated the potential neural mechanisms mediating the cognitive effects of TILS using exploratory brain studies of electroencephalography (EEG, n = 6) and functional magnetic resonance imaging (fMRI, n = 6). Cognitive performance, age, and carotid artery intima-media thickness were highly correlated, but all participants improved in all cognitive measures after TILS treatments. Baseline vs. chronic (five weekly sessions, 8 min each) comparisons of mean cognitive scores all showed improvements, significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). The neural studies also showed for the first time that TILS increases resting-state EEG alpha, beta, and gamma power and promotes more efficient prefrontal blood-oxygen-level-dependent (BOLD)-fMRI response. Importantly, no adverse effects were found. These preliminary findings support the use of TILS for larger randomized clinical trials with this non-invasive approach to augment neurocognitive function in older people to combat aging-related and vascular disease-related cognitive decline.

Metabolic mapping with fluorodeoxyglucose (FDG), a radiolabeled glucose analog, was used to assess regional activity changes in the mouse brain that result from extinction of a conditioned emotional response (CER). In the extinction group, Pavlovian tone-foot shock conditioning, followed by repeated tone-alone presentations, resulted in the reduction of the CER (freezing behavior). A second group underwent CER acquisition alone (nonextinction group), and a third group showed no CER after pseudorandom training. Then mice were injected with FDG, and tone-evoked brain activity was mapped. In the auditory system, increased activity resulted from the associative effects of acquisition training. Effects common to extinction and nonextinction groups, presumably reflecting the tone-foot shock association independently of CER expression, were found in the medial geniculate, hippocampus, and subiculum. In the extinction group, a major finding was the elevated activity in prefrontal cortex regions. In addition, brain-behavior correlations between FDG uptake and freezing behavior confirmed that subjects with higher prefrontal activity were more successful at inhibiting the CER. Interregional activity correlations showed extensive functional coupling across large-scale networks in the extinction group. The increased activity of the prefrontal cortex and its negative interactions with other regions within the extinction group suggest a functional network inhibiting the CER composed of prefrontal cortex, medial thalamus, auditory, and hippocampal regions. This is the first time that such a functional network resulting from Pavlovian extinction has been demonstrated, and it supports Pavlov's original hypothesis of extinction as the formation of cortical inhibitory circuits, rather than unlearning or reversal of the acquisition process.

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