The subject was a 23-year-old White non-Latino male with no family history of neuropsychiatric disorders and a favorable psychosocial background. His medical history included seasonal allergies, anisocoria, a condition where the pupils of the eyes differ in size, a fractured vertebra, a broken wrist, and six "documented" concussions. The subject was a professional hockey player, and all his injuries were hockey-related. Table 1 summarizes the timeline of the subject's history of concussion. The subject had never been diagnosed with mild TBI (mTBI). His clinical head computed tomography (CT) and magnetic resonance imaging (MRI) exams had been negative (see Figure 1 for representative baseline MRIs). The subject had experienced concussion-related memory gaps and feeling dazed; however, he had never lost consciousness. Thus, he was classified as a "possible TBI" by the Ohio State University TBI screen.
The subject approached Vielight, Inc., in Toronto, Canada about their PBM devices after his last concussion left him with a desire to "improve his mental sharpness." Prior to starting treatment, the subject's symptoms included headaches [six-item Headache Impact Test (HIT-6) score = 76], mild anxiety, difficulty concentrating, and an inability to maintain attention. The subject reported previously trying acupuncture, nutritional supplements, and hyperbaric oxygen treatments for his condition. This report was undertaken as an exercise to observe potential improvements in the subject's cognitive and brain function after PBM treatments.
Vielight provided the subject with two non-thermal, non-laser light-emitting diode (LED) devices as wellness devices for his mental acuity. Vielight requested the subject to undergo neuroimaging and cognitive assessment by the first author so that observations could be made on whether objective neuroimaging data can support changes in cognition. The subject consented to this. The PBM devices used are considered non-regulated under "General Wellness: Policy for Low Risk" published by the Food and Drug Administration in September 2019.
The Vielight Neuro Alpha delivers 810-nm light pulsing at 10 Hz, 50% duty cycle; the Vielight Neuro Gamma delivers 810-nm light pulsing at 40 Hz, 50% duty cycle. Both devices have four transcranial and one intranasal LED modules designed to target nodes of the default mode network (DMN), a group of strongly interconnected brain regions that include the medial prefrontal/anterior cingulate cortex (targeted by the anterior transcranial LED), posterior cingulate cortex/precuneus (targeted by the central posterior transcranial LED), lateral parietal cortex (targeted by two lateral posterior transcranial LEDs), ventromedial prefrontal and entorhinal cortex, and hippocampus (targeted by the intranasal LED).
The posterior transcranial LEDs have a power of 100 milliwatts (mW) each; the anterior transcranial LED, 75 mW; and the intranasal LED, 25 mW. Each posterior transcranial LED has a power density of 100 mW/cm2; the anterior transcranial LED, 75 mW/cm2; and the intranasal LED, 25 mW/cm2. The beam spot size of each LED is about 1 cm2. The energy delivered by posterior transcranial LEDs is 60 joules (J); anterior transcranial LED, 45 J; and intranasal LED, 15 J. The energy density of the posterior transcranial LEDs is 60 J/cm2; anterior transcranial LED, 45 J/cm2; and intranasal LED, 15 J/cm2. Both the PBM devices, programmed to shut off automatically after 20 min, deliver 240 J per 20-min treatment session.
Table 1 summarizes the timeline of the subject's assessments and PBM treatments. After baseline assessments, the subject began home PBM treatments every other day with the Vielight Neuro Gamma device (pulsing 810 nm at 40 Hz). This recommendation was based on a report of cognitive improvements after participants had used the Vielight Neuro Gamma device. However, the subject developed mild headaches after 1 week of using the Neuro Gamma device. Consequently, Vielight advised him to switch to the Neuro Alpha device (pulsing 810 nm at 10 Hz). When the subject's headaches resolved after 10 days, Vielight advised him to alternate between using the Neuro Alpha and Neuro Gamma devices, while keeping the every-other-day schedule of treatments. After 3 weeks, Vielight advised the subject to continue PBM treatments every other day using just the Neuro Alpha device. This decision was based on a report that PBM treatments pulsed at 10 Hz produced the most beneficial effects in an animal model of TBI. Although he remained in training during the PBM treatments, the subject did not play any hockey games and did not suffer any further blows to the head.
The following neuropsychological tests were administered pre- and post-treatment: California Verbal Learning Test II (CVLT-II), D-KEFS Color Word Interference test, Trail Making Test (TMT), Digit Span subtest of the Wechsler Adult Intelligence Scale-III (WAIS-III), and verbal and category (semantic) fluency. The following scans were acquired on a Siemens 3-Tesla Trio scanner with a 32-channel receiver head coil pre- and post-treatment: structural T1-weighted 3D Magnetization Prepared Rapid Gradient Echo image [repetition time (TR)/echo/time (TE)/inversion time (TI) = 2,500/2.98/1,100 ms, 1 x 1 x 1 mm3 resolution], arterial spin-labeled (ASL) magnetic resonance images (MRI) acquired with echo-planar imaging (EPI) sequence (700 ms inversion of arterial spins, 1,900 ms total transit time of spins, 100 ms tag thickness; 13 ms echo time; field of view: 256 mm, 64 x 64 matrix, 24 4-mm tick axial slices; 52 tag + control image pairs with 22.5 ms time lag between slices), and resting-state functional MRI (RS-fMRI) (8-min 12-s EPI sequence with 140 time points, 3,000 ms TR, 30 ms TE, 80  flip angle, 48 3.3-mm-thick slices, 3.3 x 3.3 x 3.3 mm3 resolution; 64 x 64 matrix).
FreeSurfer 6.0 and FreeSurfer's longitudinal stream were used to process the structural MR images and to extract volumes from anatomical regions of interest (ROIs). Total cortical gray matter (GM) volume was derived by summing the Desikan-Killiany atlas cortical ROIs bilaterally. Total subcortical GM, thalamic, and hippocampal volumes were derived from FreeSurfer's automatic subcortical segmentation. Hippocampal subfield volumes were derived from the FreeSurfer's hippocampal subfield segmentation. The volumes from right and left hemisphere ROIs were combined.
Statistical Parametric Mapping (SPM, version 8) was used to process the ASL-MRI data, which included motion correction, aligning each ASL frame to the first frame using a rigid body transformation, and least squares fitting. Perfusion-weighted images were computed as the difference between the mean of tagged and untagged ASL data sets. To account for signal decay during acquisition and to allow for intensities in meaningful physiological units, the perfusion-weighted images were intensity scaled. After geometric distortion correction, the ASL images were aligned to structural T1-weighted images. To estimate GM perfusion and to minimize the effects of the lower perfusion in white matter on the perfusion estimates, a partial volume correction was performed using the assumption that GM perfusion is 2.5 times greater than white matter perfusion. The FreeSurfer generated anatomical ROIs were used to analyze the ASL MRI perfusion data. Mean ASL perfusion values from the cerebellum were used as a control for the meta-ROIs. Total cortical GM perfusion was derived by averaging ASL perfusion values across all the Desikan-Killiany atlas cortical ROIs bilaterally. Frontal, parietal, temporal, and occipital lobe perfusion were derived by averaging CBF values across the Desikan-Killiany ROIs that corresponded to each lobe bilaterally. Hippocampal perfusion was derived by averaging ASL perfusion values from the right and left FreeSurfer hippocampal ROIs.
CONN-fMRI Functional Connectivity toolbox version 17 was used to analyze the functional connectivity data. Blood oxygen level-dependent (BOLD) signal noise from the white matter and cerebral spinal fluid was characterized with the principal component-based noise-correction "CompCor" method utilized in the CONN toolbox. Band-pass filtering was performed with a frequency window of 0.008-0.09 Hz and each scan was Hanning weighted. The ACC was chosen as a seed region to examine ROI-to-ROI functional connectivity with other brain regions. Bivariate-regression analyses were used to determine the linear association of the BOLD time series between each pair of sources in first-level analyses.