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

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.

Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial.

Importance: Preclinical studies have shown that transcranial near-infrared low-level light therapy (LLLT) administered after traumatic brain injury (TBI) confers a neuroprotective response. Objectives: To assess the feasibility and safety of LLLT administered acutely after a moderate TBI and the neuroreactivity to LLLT through quantitative magnetic resonance imaging metrics and neurocognitive assessment. Design, Setting, and Participants: A randomized, single-center, prospective, double-blind, placebo-controlled parallel-group trial was conducted from November 27, 2015, through July 11, 2019. Participants included 68 men and women with acute, nonpenetrating, moderate TBI who were randomized to LLLT or sham treatment. Analysis of the response-evaluable population was conducted. Interventions: Transcranial LLLT was administered using a custom-built helmet starting within 72 hours after the trauma. Magnetic resonance imaging was performed in the acute (within 72 hours), early subacute (2-3 weeks), and late subacute (approximately 3 months) stages of recovery. Clinical assessments were performed concomitantly and at 6 months via the Rivermead Post-Concussion Questionnaire (RPQ), a 16-item questionnaire with each item assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). Main Outcomes and Measures: The number of participants to successfully and safely complete LLLT without any adverse events within the first 7 days after the therapy was the primary outcome measure. Secondary outcomes were the differential effect of LLLT on MR brain diffusion parameters and RPQ scores compared with the sham group. Results: Of the 68 patients who were randomized (33 to LLLT and 35 to sham therapy), 28 completed at least 1 LLLT session. No adverse events referable to LLLT were reported. Forty-three patients (22 men [51.2%]; mean [SD] age, 50.49 [17.44] years]) completed the study with at least 1 magnetic resonance imaging scan: 19 individuals in the LLLT group and 24 in the sham treatment group. Radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) showed significant time and treatment interaction at 3-month time point (RD: 0.013; 95% CI, 0.006 to 0.019; P < .001; MD: 0.008; 95% CI, 0.001 to 0.015; P = .03; FA: -0.018; 95% CI, -0.026 to -0.010; P < .001).The LLLT group had lower RPQ scores, but this effect did not reach statistical significance (time effect P = .39, treatment effect P = .61, and time × treatment effect P = .91). Conclusions and Relevance: In this randomized clinical trial, LLLT was feasible in all patients and did not exhibit any adverse events. Light therapy altered multiple diffusion tensor parameters in a statistically significant manner in the late subacute stage. This study provides the first human evidence to date that light therapy engages neural substrates that play a role in the pathophysiologic factors of moderate TBI and also suggests diffusion imaging as the biomarker of therapeutic response. Trial Registration: ClinicalTrials.gov Identifier: NCT02233413.

Wide-Field Functional Microscopy of Peripheral Nerve Injury and Regeneration.

Severe peripheral nerve injuries often result in partial repair and lifelong disabilities in patients. New surgical techniques and better graft tissues are being studied to accelerate regeneration and improve functional recovery. Currently, limited tools are available to provide in vivo monitoring of changes in nerve physiology such as myelination and vascularization, and this has impeded the development of new therapeutic options. We have developed a wide-field and label-free functional microscopy platform based on angiographic and vectorial birefringence methods in optical coherence tomography (OCT). By incorporating the directionality of the birefringence, which was neglected in the previously reported polarization-sensitive OCT techniques for nerve imaging, vectorial birefringence contrast reveals internal nerve microanatomy and allows for quantification of local myelination with superior sensitivity. Advanced OCT angiography is applied in parallel to image the three-dimensional vascular networks within the nerve over wide-fields. Furthermore, by combining vectorial birefringence and angiography, intraneural vessels can be discriminated from those of the surrounding tissues. The technique is used to provide longitudinal imaging of myelination and revascularization in the rodent sciatic nerve model, i.e. imaged at certain sequential time-points during regeneration. The animals were exposed to either crush or transection injuries, and in the case of transection, were repaired using an autologous nerve graft or acellular nerve allograft. Such label-free functional imaging by the platform can provide new insights into the mechanisms that limit regeneration and functional recovery, and may ultimately provide intraoperative assessment in human subjects.

Behind the scenes: A medical natural language processing project.

Advancement of Artificial Intelligence (AI) capabilities in medicine can help address many pressing problems in healthcare. However, AI research endeavors in healthcare may not be clinically relevant, may have unrealistic expectations, or may not be explicit enough about their limitations. A diverse and well-functioning multidisciplinary team (MDT) can help identify appropriate and achievable AI research agendas in healthcare, and advance medical AI technologies by developing AI algorithms as well as addressing the shortage of appropriately labeled datasets for machine learning. In this paper, our team of engineers, clinicians and machine learning experts share their experience and lessons learned from their two-year-long collaboration on a natural language processing (NLP) research project. We highlight specific challenges encountered in cross-disciplinary teamwork, dataset creation for NLP research, and expectation setting for current medical AI technologies.

Comparing deep learning and concept extraction based methods for patient phenotyping from clinical narratives.

In secondary analysis of electronic health records, a crucial task consists in correctly identifying the patient cohort under investigation. In many cases, the most valuable and relevant information for an accurate classification of medical conditions exist only in clinical narratives. Therefore, it is necessary to use natural language processing (NLP) techniques to extract and evaluate these narratives. The most commonly used approach to this problem relies on extracting a number of clinician-defined medical concepts from text and using machine learning techniques to identify whether a particular patient has a certain condition. However, recent advances in deep learning and NLP enable models to learn a rich representation of (medical) language. Convolutional neural networks (CNN) for text classification can augment the existing techniques by leveraging the representation of language to learn which phrases in a text are relevant for a given medical condition. In this work, we compare concept extraction based methods with CNNs and other commonly used models in NLP in ten phenotyping tasks using 1,610 discharge summaries from the MIMIC-III database. We show that CNNs outperform concept extraction based methods in almost all of the tasks, with an improvement in F1-score of up to 26 and up to 7 percentage points in area under the ROC curve (AUC). We additionally assess the interpretability of both approaches by presenting and evaluating methods that calculate and extract the most salient phrases for a prediction. The results indicate that CNNs are a valid alternative to existing approaches in patient phenotyping and cohort identification, and should be further investigated. Moreover, the deep learning approach presented in this paper can be used to assist clinicians during chart review or support the extraction of billing codes from text by identifying and highlighting relevant phrases for various medical conditions.

Specificity and biologic activities of novel anti-membrane IgM antibodies.

The concept that the B-cell Receptor (BCR) initiates a driver pathway in lymphoma-leukemia has been clinically validated. Previously described unique BCR Ig-class-specific sequences (proximal domains (PDs)), are not expressed in serum Ig (sIg). As a consequence of sequence and structural differences in the membrane IgM (mIgM) µ-Constant Domain 4, additional epitopes distinguish mIgM from sIgM. mAbs generated to linear and conformational epitopes, restricted to mIgM and not reacting with sIgM, were generated despite the relative hydrophobicity of the PDm sequence. Anti-PD mAbs (mAb1, mAb2, and mAb3) internalize mIgM. Anti-mIgM mAb4, which recognizes a distinct non-ligand binding site epitope, mediates mIgM internalization, and in low-density cultures, growth inhibition, anti-clonogenic activity, and apoptosis. We show that mAb-mediated mIgM internalization generally does not interrupt BCR-directed cell growth, however, mAb4 binding to a non-ligand binding site in the mIgM PDm-µC4 domain induces both mIgM internalization and anti-tumor effects. BCR micro-clustering in many B-cell leukemia and lymphoma lines is demonstrated by SEM micrographs using these new mAb reagents. mAb4 is a clinical candidate as a mediator of inhibition of the BCR signaling pathway. As these agents do not bind to non-mIgM B-cells, nor cross-react to non-lymphatic tissues, they may spare B-cell/normal tissue destruction as mAb-drug conjugates.