Although techniques for non-invasive brain stimulation are under intense investigation, an approach that has received limited attention is transcranial photobiomodulation (tPBM), the delivery of near-infrared light to the brain with a laser or light-emitting diode (LED) directed at the scalp. Here we employed functional magnetic resonance imaging (fMRI) to measure the Blood-Oxygenation-Level Dependent (BOLD) signal in n = 20 healthy human participants while concurrently stimulating their right frontal pole with a near-infrared laser. Functional connectivity with the illuminated region increased by up to 15% during stimulation, with a quarter of all connections experiencing a significant increase. The time course of connectivity exhibited a sharp rise approximately 1 minute after illumination onset. Brain-wide connectivity increases were also observed, with connections involving the stimulated hemisphere showing a significantly larger increase than those in the contralateral hemisphere. We subsequently employed MR Thermometry to measure brain temperature during tPBM (separate cohort, n = 20), and found no significant temperature differences between active and sham stimulation. Our findings suggest that near-infrared light synchronizes brain activity with a non-thermal mechanism, underscoring the promise of tPBM as a new technique for stimulating brain function.

Study Objectives Fast frequency sleep spindles are reduced in aging and Alzheimer’s disease (AD), but the mechanisms and functional relevance of these deficits remains unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. Methods Fifty-eight cognitively unimpaired, β-amyloid negative, older adults (mean±SD; 61.4±6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system (CNS) inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13—<16Hz) sleep spindle measures through these AD biomarkers. Results Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea-hypopnea index (AHI), and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. Conclusions These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD.

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Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2°C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.

Background: Owing to its high spatial resolution and penetration depth, transcranial focused ultrasound stimulation (tFUS) is one of the most promising approaches to non-invasive neuromodulation. Identifying the impact of endogenous neural activity on neuromodulation outcome is critical to harnessing the potential of tFUS.Objective: Here we sought to identify the relationship between pre-stimulation neural activity and the neuronal response to tFUS. Methods: We applied 3 min of continuous-wave tFUS to the hippocampal region of the rat while recording local field potentials (LFP) and multi-unit activity (MUA) from the target. We also tested the application of tFUS but with an air gap separating the transducer and the skull, as well as active stimulation of the contralateral olfactory bulb. Results: We observed a modest but significant increase in firing rate during hippocampal tFUS, but not during stimulation of the olfactory bulb or when an air gap was present. Importantly, the observed firing rate increase was significantly modulated by the power of baseline oscillations in the LFP, with low levels of delta (1e3 Hz) and high levels of theta (4e10 Hz) and gamma (30e250 Hz) power producing significantly larger firing rate increases. Firing rate increases were also amplified by a factor of 7Â when stimulation was applied during periods of frequent sharp-wave ripple (SWR) activity. Conclusion: Our findings suggest that baseline brain rhythms may effectively "gate" the response to tFUS.