Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study

Abstract

Background Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on the functional connectivity of the brain when at rest has not been well studied. Purpose To use functional MRI to assess the effect of LLLT on whole-brain resting-state functional connectivity (RSFC) in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. Materials and Methods This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients presenting to the emergency department with moderate TBI from November 2015 to July 2019. Participants were randomized for LLLT and sham treatment. The primary outcome of the study was to assess structural connectivity, and RSFC was collected as the secondary outcome. MRI was used to measure RSFC in 82 brain regions in participants during the three recovery phases. Healthy individuals who did not receive treatment were imaged at a single time point to provide control values. The Pearson correlation coefficient was estimated to assess the connectivity strength for each brain region pair, and estimates of the differences in Fisher z-transformed correlation coefficients (hereafter, z differences) were compared between recovery phases and treatment groups using a linear mixed-effects regression model. These analyses were repeated for all brain region pairs. False discovery rate (FDR)-adjusted P values were computed to account for multiple comparisons. Quantile mixed-effects models were constructed to quantify the association between the Rivermead Postconcussion Symptoms Questionnaire (RPQ) score, recovery phase, and treatment group. Results RSFC was evaluated in 17 LLLT-treated participants (median age, 50 years [IQR, 25-67 years]; nine female), 21 sham-treated participants (median age, 50 years [IQR, 43-59 years]; 11 female), and 23 healthy control participants (median age, 42 years [IQR, 32-54 years]; 13 male). Seven brain region pairs exhibited a greater change in connectivity in LLLT-treated participants than in sham-treated participants between the acute and subacute phases (range of z differences, 0.37 [95% CI: 0.20, 0.53] to 0.45 [95% CI: 0.24, 0.67]; FDR-adjusted P value range, .010-.047). Thirteen different brain region pairs showed an increase in connectivity in sham-treated participants between the subacute and late-subacute phases (range of z differences, 0.17 [95% CI: 0.09, 0.25] to 0.26 [95% CI: 0.14, 0.39]; FDR-adjusted P value range, .020-.047). There was no evidence of a difference in clinical outcomes between LLLT-treated and sham-treated participants (range of differences in medians, -3.54 [95% CI: -12.65, 5.57] to -0.59 [95% CI: -7.31, 8.49]; P value range, .44-.99), as measured according to RPQ scores. Conclusion Despite the small sample size, the change in RSFC from the acute to subacute phases of recovery was greater in LLLT-treated than sham-treated participants, suggesting that acute-phase LLLT may have an impact on resting-state neuronal circuits in the early recovery phase of moderate TBI. ClinicalTrials.gov Identifier: NCT02233413 © RSNA, 2024 Supplemental material is available for this article.

Graphical abstract

Figure 1:

Flow diagram of participant enrollment for the low-level light therapy trial. TBI = traumatic brain injury.

Figure 2:

Functional MRI brain maps of resting-state functional connectivity in representative age- and sex-matched participants. (A, B) Axial (top) and coronal (bottom) views show whole-brain connectivity, with the seed at the left (L) superior frontal region, in a 36-year-old female participant in the low-level light therapy (LLLT) treatment group (A) and a 38-year-old female participant in the sham treatment group (B) during the acute, subacute, and late-subacute phases (columns, from left to right, in both A and B) of traumatic brain injury recovery. (C) Axial (top left), coronal (bottom left), and sagittal (right) views in a 38-year-old female control participant are shown for comparison; the solid green circle in the sagittal view indicates the location of the left superior frontal seed region. The color bar indicates that brain regions with warm colors (red, orange, yellow) show resting-state fluctuations that have significant positive correlation (r of 0 to 1) with those of the left superior frontal region, and brain regions with cold colors (blue) show resting-state fluctuations that have significant negative correlation (r of −1 to 0) with those of the left superior frontal region. Brain regions that have functional connectivity with the left superior frontal seed in the LLLT-treated participant (arrowheads in A) but not in the sham-treated participant (arrowheads in B) are shown. The arrow in A additionally shows brain regions with positive correlation with the seed in the LLLT-treated participant, but negative correlation with the seed in the sham-treated participant (arrow in B). All connections shown here achieved a false discovery rate–adjusted P < .005.

Figure 3:

Connectograms show changes in connectivity strength as estimated by the differences in Fisher z-transformed correlation values between the (A) low-level light therapy (LLLT) and sham treatment groups and in the (B) LLLT treatment group and (C) sham treatment group, individually, from the acute to subacute phases of traumatic brain injury recovery. The parcellated brain regions are assigned unique colors based on the RGB color model, per the FreeSurfer neuroimaging software, and abbreviations are listed on the right. The number of brain region pairs with positive differences in connectivity strength is shown at the top of the connectogram in red, with those connections mapped with red-shaded lines in the connectogram. The number of brain region pairs with negative differences in connectivity strength is shown at the top of the connectogram in dark blue, with those connections mapped with blue-shaded lines in the connectogram. The darker the shade of red or blue lines, the larger the difference in connectivity strength, as indicated by the color bar. All connections shown achieved a false discovery rate–adjusted P < .05. bankssts = banks of the superior temporal sulcus.

Figure 4:

Connectograms show changes in connectivity strength as estimated by the differences in Fisher z-transformed correlation values between the (A) low-level light therapy (LLLT) treatment group and (B) sham treatment group from the subacute to late-subacute phases of traumatic brain injury recovery. The parcellated brain regions are assigned unique colors based on the RGB color model, per the FreeSurfer neuroimaging software, and abbreviations are listed at the bottom. The number of brain region pairs showing positive differences in connectivity is shown at the top of the connectogram in red, with those connections mapped with red-shaded lines. The number of brain region pairs showing negative differences in connectivity strength is shown at the top of the connectogram in dark blue, with those connections mapped with blue-shaded lines. The darker the shade of red or blue lines, the larger the difference is in connectivity strength, as indicated by the color bar. All connections shown achieved a false discovery rate–adjusted P < .05. bankssts = banks of the superior temporal sulcus.