Dr. Eugene Ahn of Sylvester Comprehensive Cancer Center discussed mind-body approaches to cancer healing at the 2011 WellBeingWell Conference in Miami.
Polyvagal theory case vingette (health-ptsd-microagressions)Michael Changaris
This slide deck explores a hypothetical clinical case through the lens of poly-vagal theory, micro-aggressions, somatic experiencing and neurodevelopment sequencing.
Dr. Eugene Ahn of Sylvester Comprehensive Cancer Center discussed mind-body approaches to cancer healing at the 2011 WellBeingWell Conference in Miami.
Polyvagal theory case vingette (health-ptsd-microagressions)Michael Changaris
This slide deck explores a hypothetical clinical case through the lens of poly-vagal theory, micro-aggressions, somatic experiencing and neurodevelopment sequencing.
Buddha's Brain: The Practical Neuroscience of Inner Peace - Rick Hanson, PhDRick Hanson
Integrate the latest brain science research with the ancient wisdom of contemplative practice. Discover practical methods for improving mindfulness and concentration, calming the heart, weaving positive experiences into your brain and your self, and then bringing these new strengths into your relationships with both kindness and assertiveness.
More resources are freely offered at http://www.rickhanson.net.
In Feb 2022, Dr. Cassano presented this NYU-MGH study at LifeStance Health. The presentation covers in-vitro and pre-clinical data in support of the use of transcranial PBM for Alzheimer’s disease (AD). The most recent clinical data on PBM for AD were also reviewed. The NYU-MGH study was described: a large randomized, double-blind clinical trial (n=125) sponsored by NIH/NIA and by the Alzheimer’s Association.
Learn more in how the brain functions and how important physical therapy is for recovery.
The basis of neuro rehabilitation.
Brain has an incredible adaptation capacity and here you'll know just how to...explore it
Buddha's Brain: The Practical Neuroscience of Inner Peace - Rick Hanson, PhDRick Hanson
Integrate the latest brain science research with the ancient wisdom of contemplative practice. Discover practical methods for improving mindfulness and concentration, calming the heart, weaving positive experiences into your brain and your self, and then bringing these new strengths into your relationships with both kindness and assertiveness.
More resources are freely offered at http://www.rickhanson.net.
Similar to Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial
In Feb 2022, Dr. Cassano presented this NYU-MGH study at LifeStance Health. The presentation covers in-vitro and pre-clinical data in support of the use of transcranial PBM for Alzheimer’s disease (AD). The most recent clinical data on PBM for AD were also reviewed. The NYU-MGH study was described: a large randomized, double-blind clinical trial (n=125) sponsored by NIH/NIA and by the Alzheimer’s Association.
Learn more in how the brain functions and how important physical therapy is for recovery.
The basis of neuro rehabilitation.
Brain has an incredible adaptation capacity and here you'll know just how to...explore it
EFFECT OF MIRROR THERAPY ON UPPER EXTREMITY MOTOR FUNCTION IN STROKE PATIENTSismailabinji
EFFECT OF MIRROR THERAPY ON UPPER EXTREMITY MOTOR FUNCTION IN STROKE PATIENTS
Stroke is one of the main causes of disability around the globe. plegia (complete paralysis) or paresis (partial weakness ) are common following a stroke. According to the Journal of Physical Therapy Science, about 85 percent of stroke survivors will suffer from hemiplegia, and at least 69 percent will experience a loss of motor function in the upper limb.
Although these changes may not be permanent, some people regain partial or full limb function, the road to recovery can be long. But did you know that it is possible to trick the brain into believing what it sees? Mirror therapy is being used more and more in stroke rehabilitation to dupe the brain and restore limb function.
STROKE: is defined as the rapidly developed clinical signs of global or focal disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than of vascular origin. (WHO, 2017)
MOTOR FUNCTION motor function is the ability to learn or to demonstrate the skillful and efficient assumption, maintenance, modification, and control of voluntary postures and movement patterns.
In mirror therapy, a mirror is placed beside the unaffected limb, blocking the view of the affected limb. This creates the illusion that both limbs are functioning properly.
Mirror theory is based on evidence that action observation activates the same motor areas of the brain as action execution. Observed actions lead to the generation of intended actions, engaging motor planning and execution.
Mirror neurons are type of brain cell that respond equally when we perform an action and when we witness someone else perform the same action. They were first discovered in the early 1990s, when a team of Italian researchers found individual neurons in the brains of macaque monkeys that fired both when the monkeys grabbed an object and also when the monkeys watched another primate grab the same object.
Patient characteristics
Motor abilities
Vision
Trunk control
Non affected limb
Cognitive abilities (Wade DT et al., 2011)
Informing the patient
Possible Negative effect
Environment and required materials
Surrounding
Jewellery and other marks
Mirror
This presentation provides a general introduction to neuroanatomy after cerebral hemispherectomy, a procedure where half the brain is removed to stop intractable epilepsy that originates from one side of the brain. Topics include potential of the remaining hemisphere, cortical plasticity, clinical presentation of hemiparesis due to innervation by only the ipsilateral corticospinal tract, life span impairments. Various case studies discussed.
Presented at the Combined Section Meeting of the American Physical Therapy Association
February 2014
By: Dr. Stella de Bode, Ph.D. Chief Science Officer, The Brain Recovery Project
Nisha Pagan, PT, DPT, NCS, PCS, Owner Wholehearted Pediatric Physical Therapy
The 2016 World Health Organization classification of tumors of the central nervous system broadly employs genetic alterations for diagnostic criteria including isocitrate dehydrogenase-1 (IDH1) mutation or IDH2 mutation, and 1p/19q codeletion,[1] with the goal of creating more homogeneous disease categories with greater prognostic value.[2-5] Molecular diagnostics is becoming an increasingly important aspect of clinical oncologic neuropathology practice.
Similar to Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial (20)
Pallanti Method - Neuroscience applied to Life - Promote Brain Plasticity - Precise Diagnosis beyond behavioral disorders - It is not Medicine or the machine that works by itself: treatment is always holistic, and it is the collaboration between doctor and patient that, together, takes care of the brain - Neuroscienze Applicate alla Vita - Promuovere la Plasticità del Cervello - Farmaci e nuove tecnologie applicate sono strumenti importantissimi ma non curano da soli - Procedere secondo standard terapeutici e linee guida è solo l'inizio ma poi è necessario che la persona sia posta al centro della terapia - Le neuroscienze cliniche sono alla base delle applicazioni personalizzate e, per definizione, integrano in maniera olistica ogni risorsa terapeutica nella collaborazione tra medico e paziente
"Non-Invasive brain stimulation in Psychiatry - Non-invasive brain stimulation (NIBS) techniques represent widely used physical therapies in neurology
and psychiatry. Among the most widely adopted are those based on the use of magnetic fields (TMS,
Transcranial Magnetic Stimulation) or electromagnetic fields (tDCS, transcranial Direct Current
Stimulation) applied to the scalp. In both cases, brain activity is modulated in discrete areas below
the site of delivery through activation or inhibition of the excitability threshold or neuronal discharge.
Both TMS and tDCS have few contraindications, few side effects and validated efficacy across a wide
range of disorders (depression, OCD, chronic pain, Parkinson’s disease, motor stroke, addiction,
etc.): for these disorders the efficacy level is very high (level A) and where this is not reached there
are still measures of approvals from regulatory bodies (FDA, NICE, etc.). For depression and OCD, TMS
therapy is approved for drug-resistant disorders, but this does not mean that TMS is an alternative to
pharmacological treatment; if anything, in many cases it represents an excellent support to improve
the outcomes in combination with pharmacological therapy. Regarding schizophrenia, the most recent
international guidelines identify NIBS with different levels of efficacy on the negative symptoms and
auditory hallucinations present in this disorder: in particular, the level of recommendation is C for TMS
(probable efficacy) and B for tDCS (possible efficacy).
As such, guidelines take a long time to be published, and therefore refer to studies conducted in the
years prior to their publication or revision. However, the most recent publications confirm the efficacy of
these techniques while also supporting the favourable association with concomitant pharmacological
treatments. Both technologies involve a series of therapeutic sessions, the number and frequency of
which depend on the protocols applied, but while TMS treatments are outpatient, for tDCS, remotely
controlled systems allowing home treatment are available.
The new framework programme for research and
innovation for the period 2021-2027, Horizon Europe,
announced new plans to strengthen gender equity in
European organizations. In particular, for all research
organizations and higher education institutions, funding
from the Horizon Europe research programme requires
the adoption of a Gender Equality Plan (GEP). In
parallel, access to funding from the NRP programmes
will also only be allowed to those universities, research
institutions and other public and private entities that
have or commit to adopting in the first year of the
project, a Gender Balance Sheet and a Gender Equality
Plan.
In the broader list of cognitive concerns, neuropsychological testing has shown that attentional impairment may have a specific burden in Fibromyalgia Syndrome (FMS).
Preliminary observations have reported a subset of FMS patient screened for attention disorders fulfilling the actual diagnosis of ADHD, a neurodevelopmental disorder characterized by
developmentally inadequate levels of inattention, hyperactivity and impulsivity that might persist in adulthood. Yet, no study to date has systematically examined the history and the specific
contribution of ADHD to FMS in terms of clinical impact and related specific disabilities.
In this study, 106 individuals with a FMS diagnosis based on the 2010 criteria of the American College of Rheumatology have been assessed for (a) the presence of ADHD; (b) the burden of
disability caused by ADHD versus FMS; (c) the presence of other psychiatric disorders. Results indicated that ADHD was present in 24.5% of FMS individuals, it was associated with higher FMS symptoms severity and a greater functional impairment, particularly in the work/school domain.
Moreover, patients with both FMS and ADHD had higher frequency of substance use disorders than those with FMS only (38.5% versus 3.8%) and mainly opioids. Overall, results suggest that ADHD can increase burden adding specific disability in work and social activities, and it is associated with
a trend for the excessive use of opioid painkillers. Detection of neurodevelopmental and actual symptoms of ADHD is highly recommended especially in patient prone to increase the dose of antipain medication.
Il Prof. Stefano Pallanti ha partecipato con altri esperti in Pandas alla stesura del protocollo di ricerca al meeting tenutosi a Phoenix, Arizona, nell'Aprile del 2019.
Non sono i Farmaci o le Macchine che fanno Guarire - Dopo il Puglilato, anche Giocare a Calcio può far Male al Cervello? - La Foto-Bio-Modulazione Transcranica: dalla Neurologia una Nuova Tecnica per la Cura della Depressione, e non solo - Challenge test per l'ADHD negli Adulti.
La miglior cura possibile – Cura integrata e psichiatria di precisione – Imparare, di nuovo, a stare bene – Video consulenza online è unascelta mirata – L’ADHD negli adulti, il coaching, intervento di cruciale importanza.
Consigli pratici per superare stress: Ansia legata alla nuova coronavirus - fronteggiare l'incertezza, i timori e lo stress.
Ci sono molte cose che puoi fare per gestire la tua ansia.
L’Istituto di Neuroscienze del Prof. Stefano Pallanti è il centro per le Neuroscienze Cliniche e le Terapie di Neuromodulazione – Stimolazione Magnetica Transcranica Ripetitiva (rTMS) – Stimolazione Theta Burst (TBS) – Stimolazione Magnetica Transcranica Profonda (Deep TMS) – Stimolazione Elettrica Transcranica a Corrente Diretta Continua (tDCS) – Foto-Bio-Modulazione, Light Therapy – Pulsating Electrostatic Field Therapy (PESF)
Dr. Stefano Pallanti is a “Physician-Scientist” who applies cutting-edge neuroscience breakthroughs to clinical work by utilizing clinical activities to formulate research hypotheses. Firenze Neuroscienze gives you the latest news on the development of neuroscience as well as activities of Istituto di Neuroscienze del Dr. Stefano Pallanti.
More from Istituto di Neuroscienze del Prof. Stefano Pallanti (17)
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial
1. Original Investigation | Neurology
Effect of Transcranial Low-Level Light Therapy vs Sham Therapy
Among Patients With Moderate Traumatic Brain Injury
A Randomized Clinical Trial
Maria Gabriela Figueiro Longo, MD, MSc; Can Ozan Tan, PhD; Suk-tak Chan, PhD; Jonathan Welt, BS; Arman Avesta, MD; Eva Ratai, PhD; Nathaniel David Mercaldo, PhD;
Anastasia Yendiki, PhD; Jacqueline Namati, PhD; Isabel Chico-Calero, PhD; Blair A. Parry, BA; Lynn Drake, MD; Rox Anderson, MD; Terry Rauch, PhD;
Ramon Diaz-Arrastia, MD, PhD; Michael Lev, MD; Jarone Lee, MD; Michael Hamblin, PhD; Benjamin Vakoc, PhD; Rajiv Gupta, MD, PhD
Abstract
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).
(continued)
Key Points
Question Is near-infrared low-level light
therapy (LLLT) feasible and safe after
moderate traumatic brain injury, and
does LLLT affect the brain and exhibit
neuroreactivity?
Findings In this randomized clinical trial
including 68 patients with moderate
traumatic brain injury who were
randomized to receive LLLT or sham
therapy, 28 patients completed at least 1
LLLT session without any reported
adverse events. In the late subacute
stage, there were statistically significant
differences in the magnetic resonance
imaging–derived diffusion parameters of
the white matter tracts between the
sham- and light-treated groups,
demonstrating neuroreactivity of LLLT.
Meaning The results of this clinical trial
show that transcranial LLLT is feasible,
safe, and affects the brain in a
measurable manner.
+ Invited Commentary
+ Supplemental content
Author affiliations and article information are
listed at the end of this article.
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 1/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
2. Abstract (continued)
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
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337
Introduction
Traumatic brain injury (TBI), a major cause of death and disability, is a significant public health
problem in the US and worldwide.1-3
Traumatic brain injury is defined as an external force-induced
injury that may impair normal brain functions, such as memory, movement, sensation, and emotions.
Such impairments, which are generally underrated and underreported, may have highly variable
clinical presentation.4
Traumatic axonal injury is one of the primary pathophysiologic consequences
of impact and acceleration injuries to the brain.5
White matter tracts are particularly vulnerable to
such injury, which may manifest as chemical and mechanical changes in the affected neurons. While
these changes could trigger cell apoptosis and consequent neural disconnection, they may also
resolve, leading to partial remyelination or even full recovery.6,7
Thus, therapies that can induce
recovery of myelin in axons after head trauma have been a target of research for several years.8
Low-level light therapy (LLLT) uses near-infrared (NIR) light, typically in the 600- to 1100-nm
wavelength range, and is believed to elicit biostimulation mediated by mitochondrial light
absorption. Specifically, cytochrome C oxidase, a large trans-membrane protein complex that is a
part of the respiratory electron transport chain, is thought to absorb the light and upregulate
adenosine triphosphate production.9
The NIR may also upregulate messenger molecules, including
reactive oxygen species and nitric oxide, which in turn activate other transcription factors, such as
nuclear factor-κβ and activator protein-1, that enter the nucleus and cause transcription of a range of
new gene products.
Preclinical studies have explored LLLT in various subsystems, including its vascular and
neuroprotective functions.10,11
Some preclinical studies have further demonstrated improved
functional recovery from TBI in animal models. One such study measured the neurologic injury
severity score of mice exposed to a closed head diffuse axonal injury model of TBI.12
Mice were
treated 4 hours after TBI with LLLT using 4 optical wavelengths: 665, 730, 810, and 980 nm. The
LLLT-treated group exhibited a better functional outcome than the sham group.
Herein, we report the results of what is, to our knowledge, the first prospective, randomized,
interventional clinical trial of LLLT in the setting of acute (within 72 hours) moderate TBI in humans.
The study was designed to assess the safety and feasibility of applying light therapy after moderate
TBI and the neuroreactivity of the injured brain to light therapy based on quantitative magnetic
resonance imaging (MRI) metrics and neurocognitive function assessment. We focused the trial on
moderate TBI to enable easier MRI acquisition compared with patients who experienced severe TBI
and are admitted to the neurointensive care unit. In addition, this TBI category ascertained
significant injury to the brain and ruled out near-normal neurologic status, as might be seen in the
setting of mild TBI.
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 2/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
3. Methods
From November 27, 2015, through July 11, 2019, we conducted a single-center, prospective, double-
blind, placebo-controlled, parallel-group trial in which patients with moderate TBI were randomly
assigned to LLLT or sham treatment. Patients were recruited in the emergency department of the
Massachusetts General Hospital. This Health Insurance Portability and Accountability Act–compliant
trial protocol was approved by the institutional review board at Massachusetts General Hospital and
Human-Subject Research Protection Organization in the Department of Defense. Written informed
consent was obtained. An independent steering committee, an independent data safety and
monitoring board, and the ethics committee reviewed the trial regularly to assess conduct, progress,
and safety. Participants received financial compensation. The trial protocol is available in
Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting
guideline for randomized clinical trials.
A total of 4216 men and women aged 18 to 79 years with acute, blunt TBI were screened to
recruit patients with moderate TBI within 72 hours of injury. Detailed inclusion and exclusion criteria
are provided in the eMethods in Supplement 2. Upon enrollment, patients were randomized using
an interactive, web-based response system with a block design of 9 groups of 10 patients, each with
1:1 assignment to either the LLLT or sham group (Figure 1). The principal investigator (R.G.) and other
study staff (except for the designated study coordinator [M.G.F.L.]), the patients, and the outcomes
assessors were blinded to the randomization.
Study Procedures
Low-level light therapy, which was provided by a custom-built helmet outfitted with 18 clusters of 20
NIR light-emitting diodes (the eMethods in Supplement 2), was started within 72 hours after the TBI.
Treatment was divided into 3 sessions of 20 minutes’ duration with at least 12-hour intervals between
the therapy sessions. The helmet provided an incident fluence of approximately 43 J/cm2
(0.036
W/cm2
× 20 minutes ×60 seconds/min = 43.2 J/cm2
) to the scalp per 20-minute session. Based on
known scalp/skull transmission of NIR light in cadavers, approximately 3% (or 1.3 J/cm2
) of the
incident fluence reached the cortical surface of the brain.
Figure 1. Patient Flow Diagram
4216 Assessed for eligibility
4148 Excluded
3872 Did not meet inclusion criteria
276 Declined to participate or
presented MRI contraindication
68 Randomized
33 Randomized to receive light treatment
28 Received treatment as randomized
5 Did not receive treatment as randomized
(lost to follow-up or withdrew without
receiving treatment)
35 Randomized to receive sham treatment
31 Received treatment as randomized
4 Did not receive treatment as randomized
(lost to follow-up or withdrew without
receiving treatment)
19 Participants completed study
18 Participants with 2 or 3 MRI scans
1 Participant with 1 MRI scan
24 Participants completed study
22 Participants with 2 or 3 MRI scans
2 Participants with 1 MRI scan
9 Excluded
4 Lost to follow-up
5 Withdrew
7 Excluded
3 Lost to follow-up
4 Withdrew
MRI indicates magnetic resonance imaging.
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 3/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
4. The sham treatment was delivered using the same helmet with the controller maintained on the
control position during the application. This position guaranteed that the fans were switched on but
the light-emitting diodes remained in the off position and did not produce any NIR light. Because the
NIR light is nearly invisible to the human eye, clinical staff members in the room and participants were
not able to detect whether light therapy was being given (eFigure 1 in Supplement 2).
Following the helmet application, a baseline brain MRI scan was performed for evaluation of the
acute stage of the trauma. The images were acquired at the earliest opportunity, as soon as the
patient was clinically stable to undergo the MRI scan (the eMethods in Supplement 2). Subsequently,
we acquired 2 follow-up scans, 1 in the early (approximately 2-3 weeks after the trauma) and 1 in the
late (approximately 3 months after the trauma) subacute stages of recovery. When an MRI scan could
not be acquired on time because of any reason, it was performed as soon as feasible.
Detailed methods for assessing structural data are provided in the eMethods in Supplement 2.
Briefly, we used brain imaging software (FreeSurfer; FreeSurfer Inc) to perform automated
segmentation and cortical parcellation of the T1-weighted volumetric images.13
The presence of
chronic white matter disease was evaluated using Fazekas scale, which is used to quantify chronic
small-vessel ischemia disease based on T2 hyperintensity.14
The scale is split into periventricular and
deep white matter, and the score ranges from 0 (no disease) to 3 (the most severe disease). A
neuroradiologist (R.G.) evaluated the 3D T2-SPACE-FLAIR images to detect the presence of T2
hyperintensities and their degree (0, absent; 1, mild; 2, moderate; and 3, severe). The longitudinal
stream from the software Tracts Constrained by Underlying Anatomy (TRACULA)15
was used to
automatically delineate 18 major white matter tracts in each participant.
For each white matter tract, 2 main diffusion parameters, namely, radial diffusivity (RD) and
axial diffusivity (AD), were calculated. Radial diffusivity, in part, reflects the overall integrity of
myelination in a tract (water diffuses more through demyelinated axonal membranes), while AD is a
measure of overall axonal integrity (water diffuses less along sheared axons).16,17
From the RD and AD
values, which represent 2 independent parameters for each tract, 2 derived parameters—fractional
anisotropy (FA) and mean diffusivity (MD)—were also calculated to obtain a measure of the overall
health of a white matter tract.
Clinical assessments were performed using the Rivermead Post-Concussion Symptoms
Questionnaire (RPQ)—a validated questionnaire to access postconcussion syndrome18,19
—at
baseline, 14 days, 3 months, and 6 months after the trauma. The RPQ is a 16-item self-assessment
questionnaire completed via an in-person or phone interview. Each item in the questionnaire is
assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). The questions in the
RPQ can be grouped in 2 nonoverlapping sets: the RPQ-3 includes early, objective, physical
symptoms, and the RPQ-13 group includes later, more cognitive and behavioral symptoms. The
RPQ-3 encompasses headache, dizziness, nausea, and vomiting. The RPQ-13 includes questions
evaluating noise sensitivity, sleep disturbance, fatigue, irritability, depressed mood, forgetfulness,
poor concentration, longer thinking time, blurred vision, light sensitivity, double vision, and
restlessness. The RPQ-3 score ranges from 0 to 12 (best to worst) and the RPQ-13 ranges from 0 to 52
(best to worst). The baseline RPQ score was assessed in the emergency department at the first
opportunity when the patient became capable of answering the questions after their enrollment into
the study.20
Clinical data were collected through an electronic data-capture system with built-in
checks to assess data integrity and flag missing values.
Outcome Measures and Hypotheses
The outcome measures were safety profile of LLLT compared with the sham treatment and the effect
of LLLT on diffusion parameters of the 18 major white matter tracts and the RPQ scores compared
with the sham treatment. The null hypothesis was that there was no difference between the LLLT
and sham treatment groups in terms of adverse events (safety), RPQ scores (clinical symptoms of
TBI), and diffusion parameters (neuroreactivity).
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 4/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
5. Instead of using a more sophisticated neuropsychological test instrument, our study relied on
the RPQ score. All patients in this study were enrolled in the emergency department, and the patient
enrollment spanned more than 2.5 years. the specifics of the study design necessitated that the
baseline neuropsychological test be administered in the emergency department. The RPQ is feasible
for this setting: it is a rapid questionnaire, making it appropriate for use in the emergency department
environment. The RPQ can be administered by any trained researcher at any time of the day, avoiding
the necessity of a higher-level specialist to be available in the emergency department at all times.
The RPQ also has good test-retest reliability.20
The study was powered to show neuroreactivity using
quantitative MRI metrics. Specifically, the study was not powered to show statistically significant
differences on clinical outcome measures or any neuropsychological parameters. The variability of
clinical and/or behavioral measures would have necessitated a much larger patient enrollment.
Statistical Analysis
All statistical analyses were performed using R, version 3.6.0 (The R Foundation for Statistical
Computing). Differences and associations were considered statistically significant at a 2-tailed
P < .05. All results are presented as mean (SD) unless noted otherwise. Baseline differences across
groups were compared using 1-way analysis of variance for continuous variables (eg, age and RPQ
scores) and via χ2
test for categorical variables.
To test neuroreactivity of LLLT via its effect on the diffusion tensor parameters, we used a linear
mixed-effect (LME) model with treatment (LLLT vs sham) and time point (acute, early subacute, and
late subacute) as fixed effects and tract and time point nested within each patient as random effects.
All patients with at least 1 MRI were included in this analysis. Conformity of the data to statistical
assumptions was checked by investigating QQ plots of the data. Linear mixed-effect models, which
are akin to multiple regression models that can account for correlations due to repeated measures,
have several advantages in this context. Linear mixed-effect modeling allowed us to pool all of the
data across treatment groups and 3 time points, as well as across all 18 tracts, to examine associations
robustly. Moreover, because the LME model allows partially repeated measures, it can accommodate
data from patients with missing time points (eg, missing MRI sequences). In addition, the LME model
treats each time point as a separate variable. Therefore, any baseline difference in diffusion tensor
imaging parameters across the LLLT and sham groups did not confound the overall analysis, enabling
one to robustly identify differences in diffusion tensor imaging parameters across the treatment
groups while explicitly accounting for repeated measurements, within-tract and within-patient
correlations, and missing time points.
A similar LME model (treatment group and time point as fixed effects, and patient as a random
effect) was used to test for the effect of LLLT on clinical symptoms). The P values for the fixed effects
in the LME model were calculated using a type III analysis of variance table with the Satterthwaite
degrees of freedom method.21
Results
Of the 4216 patients screened, 344 patients met the inclusion/exclusion criteria and 68 were
enrolled in the study between 2015 and 2018. Nine patients discontinued the study before any study-
specific procedures were performed because they either withdrew consent (n = 5) or were lost to
follow-up (n = 4) before their first LLLT session. The remaining 59 patients were assigned to LLLT or
sham treatment groups. An additional 16 patients were lost to follow-up or withdrew consent before
the first MRI scan. Forty-three patients (21 [48.8%] women, 22 [51.2%] men; mean [SD] age, 50.5
[17.4] years) had at least 1 MRI scan, and 40 patients completed MRI scans at least at 2 points: 18 in
the LLLT group and 22 in the sham group (Figure 1).
All of the 68 included patients were selected based on abnormal findings from head computed
tomographic imaging. Their Glasgow Coma Scale score at hospital admission ranged between 13 and
15, except for 1 patient (1.5%) who was intubated before arriving at the hospital, and the Glasgow
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 5/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
6. Coma Scale score was assessed after extubation. Twelve patients (17.6%) were under the influence
of alcohol or drugs at the time of evaluation, which could be a confounder for the Glasgow Coma
Scale evaluation. During the course of hospitalization, 6 patients (8.8%) needed intensive care unit
support and 32 patients (47.1%) needed physical or occupational therapy (Table 1). All patients
received whatever supportive treatment was needed for their TBI and other associated injuries
following the hospital guidelines and the judgment of their care team. Thirty-eight patients (55.9%)
received antiepileptic drug treatment during the first 7 days for seizure prophylaxis (Table 1; eTable 1
in Supplement 2). For the 43 patients included in our analysis, there were no substantial differences
between the groups at baseline in terms of demographics (age and sex), nature of injury, or clinical
findings (Table 1; eTable 1 in Supplement 2).
Feasibility and Safety
In this study, 28 patients received LLLT. We were able to obtain conclusive, self-reported safety data
via interviews from 19 of these patients and no adverse events referable to LLLT were identified. For
the remaining 9 patients, direct phone calls or other methods to contact them failed. We reviewed
their medical records and primary care physician notes for any reported adverse events or hospital
admissions. No such adverse events were identified by this review of records. We, therefore,
assumed them to be free of any adverse events referable to LLLT.
All 18 patients who successfully completed LLLT were able to do so without any complications.
The helmet application was feasible even in patients with subgaleal hemorrhage, soft tissue swelling,
and small dressings applied to portions of the head. Some patients found the helmet to be tight and
noted that they would have preferred a slightly bigger helmet. There were no adverse events
associated with the helmet application in either group. The symptoms described by the patients
during their RPQ interview were all common symptoms of TBI.
There was a progressive decrease in RPQ-3 symptom severity score—reflective of 3 objective
symptoms (ie, headache, dizziness, and nausea/vomiting)—throughout the study up to the 6-month
follow-up (mean [SD] sham: 4.5 [3.1] in the acute phase vs 2.5 [3.3] at 6 months, LLLT: 3.9 [3.2] vs
0.8 [1.7], and LME time effect, P<.01) (treatment: P = .40 and time × treatment: P = .97). Across both
groups, there was no statistically significant decrease in time effect with RPQ-13 (P = .91) (treatment:
P = .67, and time × treatment: P = .89) and RPQ-total (P = .39) (treatment: P = .61, and
time × treatment: P = .91). Even though there was an apparent reduction in all 3 symptom scores in
the LLLT group, this difference did not reach statistical significance (treatment effects P > .40, and
time × treatment interaction P > .89 for all 3 RPQ measures (Figure 2). That TBI symptom severity
was comparable across the LLLT and sham groups over time suggests the safety of LLLT in the acute
stage of trauma.
Neuroreactivity
One MRI scan was deemed low quality and excluded from analysis; for the remaining 42 patients (18
in the LLLT group and 24 in the sham group), there was at least 1 MRI scan available for quantitative
analysis. A summary of all diffusion parameters is presented in eTable 2 in Supplement 2.
Table 2 presents the point estimates for the fixed effects (time, treatment group, and their
interaction) from the LME model for diffusion parameters at different stages of recovery and for
different treatment groups (LLLT and sham). The variance components of the random effects are
given in eTable 3 in Supplement 2. Temporal trajectories of each tract are shown in eFigure 2 in
Supplement 2. Passage of time had a statistically significant effect on all diffusion parameters except
RD, irrespective of light or sham treatment status. The probability that the manifested temporal
evolution (Figure 3) could arise purely from chance was computed by LME model to be 0.11, 0.02,
0.04, and 0.02 for RD, AD, MD, and FA, respectively. In addition, all diffusion parameters except AD
were modulated by treatment status. The probability that the exhibited interaction between time
and treatment status (Figure 3) could arise purely from chance was RD (P < .001), AD (P = .47), MD
(P < .001), and FA (P < .001). Our results show that the temporal evolution of all diffusion parameters
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 6/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
7. Table 1. Demographic and Clinical Characteristics of 43 Participants Who Completed the Study
Parameter
No. (%)
P valueTotal (N = 43) Sham (n = 24) LLLT (n = 19)
Sex
Women 21 (48.8) 12 (50.0) 9 (47.4) .864
Men 22 (51.2) 12 (50.0) 10 (52.6)
Age, mean (SD), y 50.49 (17.44) 54.00 (14.68) 46.05 (19.93) .14
Injury mechanism
Bike/motorcycle accident
.10
With helmet 4 (9.3) 4 (16.7) 0
Without helmet 1 (2.3) 0 1 (5.3)
Fall 25 (58.1) 14 (58.3) 11 (57.9)
Other 1 (2.3) 1 (4.2) 0
Pedestrian accident with car/motorcycle/bike 4 (9.3) 3 (12.5) 1 (5.3)
Car crash
Restrained 3 (7.0) 0 3 (15.8)
Unrestrained 1 (2.3) 1 (4.2) 0
Violence/assault 4 (9.3) 1 (4.2) 3 (15.8)
History
Hypertension 15 (34.9) 9 (37.5) 6 (31.6) .69
Diabetes (type 1 or 2) 7 (16.3) 4 (16.7) 3 (15.8) .94
Imaging findings
Hemorrhage
Extracranial 18 (41.9) 10 (41.7) 8 (42.1) .98
Epidural 2 (4.7) 0 2 (10.5) .10
Acute subdural 13 (30.2) 9 (37.5) 4 (21.1) .24
Subarachnoid 19 (44.2) 13 (54.2) 6 (31.6) .14
Edema 1 (2.3) 1 (4.2) 0 (0.0) .37
Contusion 4 (9.3) 2 (8.3) 2 (10.5) .81
Hemorrhage
Intraparenchymal 7 (16.3) 3 (12.5) 4 (21.1) .45
Intraventricular 1 (2.3) 0 (0.0) 1 (5.3) .26
Skull fracture 10 (23.3) 6 (25.0) 4 (21.1) .76
Intracranial air 2 (4.7) 1 (4.2) 1 (5.3) .87
Facial fracture 12 (27.9) 8 (33.3) 4 (21.1) .38
Orbital injury 5 (11.6) 3 (12.5) 2 (10.5) .84
Fazekas scalea
Periventricular white matter hyperdensities
Absent (0) / caps or pencil-thin lining (1) 37 (86.0) 19 (79.2) 18 (94.7)
.44
Smooth halo (2) 4 (9.3) 3 (12.5) 1 (5.3)
Irregular periventricular signal extending into
the deep white matter (3)
1 (2.3) 1 (4.2) 0
Deep white matter hyperdensities
Absent (0) / punctate foci (1) 35 (81.4) 19 (79.2) 16 (84.2)
.64Beginning confluence (2) 6 (14.0) 3 (12.5) 3 (15.8)
Large confluent areas (3) 1 (2.3) 1 (4.2) 0
Antiepileptic drug prophylaxis 24 (55.8) 14 (58.3) 10 (52.6) .71
Therapy
Physical 19 (44.2) 13 (54.2) 6 (31.6) .14
Occupational 13 (30.2) 8 (33.3) 5 (26.3) .62
Speech 5 (11.6) 4 (16.7) 1 (5.3) .25
Rehabilitation 3 (7.0) 3 (12.5) 0 .11
ICU stay 3 (7.0) 3 (12.5) 0 .11
RPQ scores, mean (SD)b
RPQ-3 4.28 (3.13) 4.55 (3.13) 3.94 (3.19) .56
RPQ-13 11.92 (8.71) 12.64 (7.83) 10.94 (9.98) .56
RPQ-Total 16.21 (10.83) 17.18 (10.01) 14.88 (12.08) .53
Abbreviations: LLLT, low-level light therapy; RPQ,
Rivermead Post-Concussion Questionnaire.
a
The Fazekas scale is split into periventricular and
deep white matter, and the score ranges from 0 (no
disease) to 3 (the most severe disease).
b
The RPQ is a 16-item self-assessment questionnaire.
Each item in the questionnaire is assessed on a
5-point scale ranging from 0 (no problem) to 4
(severe problem). RPQ-3 assessment includes early,
objective, and physical symptoms of TBI; RPQ-13
assessment includes later, more cognitive and
behavioral symptoms.
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 7/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
8. (except RD) was modulated by time course, and further impacted by light treatment for all
parameters except AD.
In both groups, a time-dependent evolution of all diffusion parameters (AD, RD, MD, and FA)
was evident even at the subacute stage for FA (−0.006, 95% CI, −0.011 to −0.001; P = .02), but not
for RD (P = .06), AD (P = .44), or MD (P = .49) (Table 2; Figure 3). Time-dependent change in all 4
parameters across both groups reached statistical significance in the late subacute stage for AD
(P = .04), RD (P < .001), MD (P < .001), and FA (P = .04).
When considered across all time points (ie, without taking into account any time-dependent
evolution of parameters), LLLT did not have a significant effect on diffusion parameters (treatment
effect P > .80 for all 4 parameters). However, there was a time and treatment interaction effect at the
late subacute stage for RD (0.013; 95% CI, 0.006-0.019; P < .001), MD (0.008; 95% CI,
0.001-0.015; P = .03), and FA (−0.018; 95% CI, −0.026 to −0.010; P < .001), but not for AD (−0.001;
95% CI, −0.014 to 0.012, P = .84).
Accounting for sex, age, or for variable lengths of white matter tracts by normalizing diffusion
tensor imaging parameters by the length of each tract did not change these results. Our results
demonstrate that LLLT modulates the temporal evolution of RD, MD, and FA.
Figure 2. Evolution of Clinical Symptoms of Traumatic Brain Injury (TBI) in the Low-Level Light Therapy and Sham Groups
20
15
10
5
0
RPQscore
RPQ-13 assessmentB
Acute 2 wk 3 mo 6 mo
5
6
4
3
2
1
0
RPQscore
RPQ-3 assessmentA
Acute 2 wk 3 mo 6 mo
20
15
10
5
0
RPQscore
Total RPQC
Acute 2 wk 3 mo 6 mo
Sham
Light treatment
Scores on the Rivermead Post-Concussion Symptoms Questionnaire, a 16-item self-assessment questionnaire. Each item in the questionnaire is assessed on a 5-point scale ranging
from 0 (no problem) to 4 (severe problem). Bars show the standard error of the mean. A, Scores from RPQ-3 assessment, including early, objective, and physical symptoms of TBI.
Time: P < .001, treatment: P = .40, and time × treatment: P = .97. B, Scores from RPQ-13 assessment, including later, more cognitive and behavioral symptoms. Time: P = .91,
treatment: P = .67, and time × treatment: P = .89. C, Total RPQ scores. Time: P = .39, treatment: P = .61, and time × treatment: P = .91.
Table 2. Point Estimates of the Diffusion Parameters at Different Stages of Recovery and Effect of LLLT
Predictor
Axial diffusivity, 10−3
mm2
s−1
Radial diffusivity, 10−3
mm2
s−1
Mean diffusivity, 10−3
mm2
s−1
Fractional anisotropy
Estimate (95% CI) P Value Estimate (95% CI) P Value Estimate (95% CI) P Value Estimate (95% CI) P Value
Intercepta
0.831 (0.771-0.892) <.001 0.374 (0.345-0.402) <.001 0.526 (0.487-0.565) <.001 0.479 (0.467-0.491) <.001
Early subacute
stage
−0.003 (−0.011 to 0.005) .44 0.004 (−0.000 to 0.008) .055 0.002 (−0.003 to 0.006) .49 −0.006 (−0.011 to −0.001) .02
Late subacute
stage
−0.009 (−0.017 to −0.001) .04 −0.009 (−0.013 to −0.005) <.001 −0.009 (−0.013 to −0.004) <.001 0.005 (0.000-0.010) .04
LLLT 0.009 (−0.083 to 0.102) .85 0.004 (−0.040 to 0.048) .84 0.006 (−0.053 to 0.065) .84 0.001 (−0.017 to 0.019) .95
Early subacute
stage ×
treatment
−0.007 (−0.020 to 0.006) .27 −0.006 (−0.012 to 0.000) .06 −0.007 (−0.014 to 0.001) .08 0.001 (−0.007 to 0.009) .77
Late subacute
stage ×
treatment
−0.001 (−0.014 to 0.012) .84 0.013 (0.006-0.019) <.001 0.008 (0.001-0.015) .03 −0.018 (−0.026 to −0.010) <.001
Abbreviation: LLLT, low-level light therapy.
a
The estimated mean value at the acute stage across both groups. Estimates for early and late subacute stage show the predicted difference from the acute stage (intercept) across
both groups, and the estimate for LLLT shows the predicted difference between the treatment groups across all time points. The last 2 predictors show the interaction between
recovery stages (early vs late subacute) and treatment (light vs sham) groups.
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 8/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
9. Discussion
Consistent with our primary hypothesis, this study indicated the feasibility and safety of LLLT for
patients with moderate TBI. Low-level light exposure is purported to confer beneficial vascular and
neuroprotective effects. This beneficial effect is supported by multiple preclinical studies in animal
models.10-12,22-24
The first clinical study of LLLT, which targeted ischemic stroke (NEST-1),25
delivered
light through a handheld device placed against the shaved scalp at 20 predetermined locations for
2 minutes at each location. In NEST-1, the treated group showed improvements on the National
Institutes of Health Stroke Severity scale over the study timeframe (ie, baseline and 5, 30, 60, and 90
days after stroke). A follow-up study of 660 patients (NEST-2)26
demonstrated the benefit of the
LLLT, which was statistically significant after controlling for several confounding variables (advanced
age, multiple strokes, and more severe strokes).27
NEST-3 was terminated after an interim analysis
showed no difference in the primary end point between the transcranial laser therapy and
sham groups.28
Despite these studies, a fundamental question about the neuroreactivity of LLLT remains. Our
results provide what is, to our knowledge, the first direct evidence that trans-cranial LLLT targets and
engages neural substrates that play an integral role in the pathophysiologic effects of moderate TBI.
Our observation that LLLT modulates temporal evolution of radial diffusivity supports the
notion that light therapy affects myelin repair pathways. The process of demyelination/remyelination
is distinct from axonal damage to a neuron. Therefore, changes in RD and AD can be decoupled as
they are governed by distinct pathophysiologic mechanisms. Because the temporal evolution of RD,
but not AD, is statistically significantly affected by light therapy, our results suggest that these 2
processes are differentially affected by NIR light for moderate TBI. Since the degree of damage to the
axons and surrounding myelin is a function of the severity of the neurotrauma, our observations
should not be generalized to mild or severe TBI.
The decrease in FA at the late subacute phase could be interpreted as an indication that NIR
aggravates or amplifies the injury. However, the clinical evolution (Figure 2) does not support this
since the RPQ scores at 6 months were lower in the LLLT group. Moreover, the total NIR light dose
deployed in this study is less than the established threshold dose when light may cause cell
retardation and potential neural damage.29
A prior animal model of myelin remodeling has shown a
Figure 3. Effect of Light Treatment on Diffusion Parameters
0.550
0.540
0.530
0.520
0.510
0.500
Diffusion,10-3mm2s–1
Mean diffusivityB
0.875
0.850
0.825
0.800
Diffusion,10-3mm2s–1
Axial diffusivityA
Sham
Light treatment
Acute 2 wk 6 mo Acute 2 wk 6 mo
0.50
0.49
0.48
0.47
0.46
0.45
Diffusion
Fractional anisotropyD
0.390
0.400
0.380
0.370
0.360
0.350
Diffusion,10-3mm2s–1
Radial diffusivityC
Acute 2 wk 6 mo Acute 2 wk 6 mo
The effect of light treatment on diffusion parameters
as predicted by linear mixed effect model. Error bars
represent standard error of the mean. A, Axial
diffusivity. Time, P = .02; treatment, P = .89; time x
treatment, P = .47. B. Mean diffusivity. Time, P = .04;
treatment, P = .08; time x treatment, P < .001. C,
Radial diffusivity. Time, P = .11; treatment, P = .77, time
x treatment, P < .001. D, Fractional anisotropy. Time,
P = .02; treatment, P = .58; time x treatment, P < .001.
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 9/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
11. Biomedical Imaging, Boston, Massachusetts (Chan, Yendiki); School of Medicine, University of Michigan, Ann
Arbor (Welt); Department of Radiology, Yale School of Medicine, New Haven, Connecticut (Avesta); Office of
Secretary of Defense, Department of Defense, Washington, DC (Rauch); Department of Neurology, University of
Pennsylvania, Philadelphia (Diaz-Arrastia).
Author Contributions: Drs Longo and Tan (co-first authors) contributed equally to this work. Dr Gupta had full
access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Welt, Avesta, Chico-Calero, Parry, Drake, Anderson, Rauch, Diaz-Arrastia, Lev, Hamblin,
Vakoc, Gupta.
Acquisition, analysis, or interpretation of data: Figueiro Longo, Tan, Chan, Welt, Avesta, Ratai, Mercaldo, Yendiki,
Namati, Parry, Rauch, Lev, Lee, Vakoc.
Drafting of the manuscript: Figueiro Longo, Tan, Chan, Mercaldo, Vakoc, Gupta.
Critical revision of the manuscript for important intellectual content: Figueiro Longo, Welt, Avesta, Ratai, Yendiki,
Namati, Chico-Calero, Parry, Drake, Anderson, Rauch, Diaz-Arrastia, Lev, Lee, Hamblin, Vakoc.
Statistical analysis: Tan, Mercaldo, Rauch, Gupta.
Obtained funding: Avesta, Drake, Anderson, Vakoc, Gupta.
Administrative, technical, or material support: Figueiro Longo, Welt, Avesta, Namati, Chico-Calero, Parry, Drake,
Rauch, Lev, Lee, Vakoc, Gupta.
Supervision: Welt, Avesta, Chico-Calero, Anderson, Lev, Lee, Hamblin, Vakoc, Gupta.
Conflict of Interest Disclosures: Dr Namati reported receiving grants from Department of Defense during the
conduct of the study. Dr Parry reported receiving grants from the Department of Defense during the conduct of
the study. Dr Drake reported receiving grants from the Department of Defense during the conduct of the study. Dr
Anderson reported receiving grants from the Department of Defense during the conduct of the study. Dr Diaz-
Arrastia reported receiving stock options from Neural Analytics Inc, Brain Box Solutions Inc, and Nia Therapeutics
Inc, and consulting fees from Pinteon Therapeutics and MesoScale Discoveries outside the submitted work. Dr Lev
reported receiving personal fees from GE Healthcare and Takeda Pharm outside the submitted work. Dr Lee
reported receiving grants from the Department of Defense during the conduct of the study, serving as a consultant
to Butterfly Network Inc, and receiving research grants from Nihon-Kohden and Beckman Coulter outside the
study. Dr Hamblin reported receiving personal fees from Vielight Inc, JOOVV Inc, ARC LED Inc, Transdermal cap
Inc, Hologenix Inc, and MB Lasertherapy outside the submitted work. No other disclosures were reported.
Funding/Support: This research fund was partially supported by grants from Air Force contract
FA8650-17-C-9113; Army USAMRAA Joint Warfighter Medical Research Program, contract W81XWH-15-C-0052;
and Congressionally Directed Medical Research Program W81XWH-13-2-0067.
Role of the Funder/Sponsor: The grant support was used for design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
REFERENCES
1. Ewing-Cobbs L, Johnson CP, Juranek J, et al. Longitudinal diffusion tensor imaging after pediatric traumatic
brain injury: Impact of age at injury and time since injury on pathway integrity. Hum Brain Mapp. 2016;37(11):
3929-3945. doi:10.1002/hbm.23286
2. Centers for Disease Control and Prevention. Surveillance Report of Traumatic Brain Injury–Related Emergency
Department Visits, Hospitalizations, and Deaths. 2014. Updated 2019. Accessed April 4, 2020. https://www.cdc.
gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-508.pdf
3. Defense and Veterans Brain Injury Center. DoD TBI Worldwide Numbers for TBI. Updated 2019. Accessed April
4, 2020. https://dvbic.dcoe.mil/dod-worldwide-numbers-tbi
4. Marr AL, Coronado VG. Central Nervous System Injury Surveillance Data Submission Standards—2002. Centers
for Disease Control and Prevention, National Center for Injury Prevention and Control; 2004.
5. Reeves TM, Phillips LL, Povlishock JT. Myelinated and unmyelinated axons of the corpus callosum differ in
vulnerability and functional recovery following traumatic brain injury. Exp Neurol. 2005;196(1):126-137. doi:10.
1016/j.expneurol.2005.07.014
6. Armstrong RC, Mierzwa AJ, Marion CM, Sullivan GM. White matter involvement after TBI: clues to axon and
myelin repair capacity. Exp Neurol. 2016;275(Pt 3):328-333. doi:10.1016/j.expneurol.2015.02.011
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 11/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
12. 7. Mierzwa AJ, Marion CM, Sullivan GM, McDaniel DP, Armstrong RC. Components of myelin damage and repair in
the progression of white matter pathology after mild traumatic brain injury. J Neuropathol Exp Neurol. 2015;74
(3):218-232. doi:10.1097/NEN.0000000000000165
8. Thunshelle C, Hamblin MR. Transcranial low-level laser (light) therapy for brain injury. Photomed Laser Surg.
2016;34(12):587-598. doi:10.1089/pho.2015.4051
9. Capaldi RA. Structure and function of cytochrome C oxidase. Annu Rev Biochem. 1990;59(1):569-596. doi:10.
1146/annurev.bi.59.070190.003033
10. Bossini PS, Fangel R, Habenschus RM, et al. Low-level laser therapy (670 nm) on viability of random skin flap
in rats. Lasers Med Sci. 2009;24(2):209-213. doi:10.1007/s10103-008-0551-5
11. Corazza AV, Jorge J, Kurachi C, Bagnato VS. Photobiomodulation on the angiogenesis of skin wounds in rats
using different light sources. Photomed Laser Surg. 2007;25(2):102-106. doi:10.1089/pho.2006.2011
12. Wu Q, Xuan W, Ando T, et al. Low-level laser therapy for closed-head traumatic brain injury in mice: effect of
different wavelengths. Lasers Surg Med. 2012;44(3):218-226. doi:10.1002/lsm.22003
13. Reuter M, Schmansky NJ, Rosas HD, Fischl B. Within-subject template estimation for unbiased longitudinal
image analysis. Neuroimage. 2012;61(4):1402-1418. doi:10.1016/j.neuroimage.2012.02.084
14. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s
dementia and normal aging. AJR Am J Roentgenol. 1987;149(2):351-356. doi:10.2214/ajr.149.2.351
15. Yendiki A, Reuter M, Wilkens P, Rosas HD, Fischl B. Joint reconstruction of white-matter pathways from
longitudinal diffusion MRI data with anatomical priors. Neuroimage. 2016;127(127):277-286. doi:10.1016/j.
neuroimage.2015.12.003
16. Song S-K, Sun S-W, Ramsbottom MJ, Chang C, Russell J, Cross AH. Dysmyelination revealed through MRI as
increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002;17(3):1429-1436. doi:10.1006/nimg.
2002.1267
17. Aung WY, Mar S, Benzinger TL. Diffusion tensor MRI as a biomarker in axonal and myelin damage. Imaging
Med. 2013;5(5):427-440. doi:10.2217/iim.13.49
18. King NS, Crawford S, Wenden FJ, Moss NEG, Wade DT. The Rivermead Post Concussion Symptoms
Questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol. 1995;
242(9):587-592. doi:10.1007/BF00868811
19. Ingebrigtsen T, Waterloo K, Marup-Jensen S, Attner E, Romner B. Quantification of post-concussion symptoms
3 months after minor head injury in 100 consecutive patients. J Neurol. 1998;245(9):609-612. doi:10.1007/
s004150050254
20. Eyres S, Carey A, Gilworth G, Neumann V, Tennant A. Construct validity and reliability of the Rivermead Post-
Concussion Symptoms Questionnaire. Clin Rehabil. 2005;19(8):878-887. doi:10.1191/0269215505cr905oa
21. Satterthwaite FE. An approximate distribution of estimates of variance components. Biometrics. 1946;2(6):
110-114. doi:10.2307/3002019
22. Zhang R, Mio Y, Pratt PF, et al. Near infrared light protects cardiomyocytes from hypoxia and reoxygenation
injury by a nitric oxide dependent mechanism. J Mol Cell Cardiol. 2009;46(1):4-14. doi:10.1016/j.yjmcc.2008.
09.707
23. Hemvani N, Chitnis DS, Bhagwanani NS. Helium-neon and nitrogen laser irradiation accelerates the phagocytic
activity of human monocytes. Photomed Laser Surg. 2005;23(6):571-574. doi:10.1089/pho.2005.23.571
24. Liang HL, Whelan HT, Eells JT, et al. Photobiomodulation partially rescues visual cortical neurons from
cyanide-induced apoptosis. Neuroscience. 2006;139(2):639-649. doi:10.1016/j.neuroscience.2005.12.047
25. Lampl Y, Zivin JA, Fisher M, et al. Infrared laser therapy for ischemic stroke: a new treatment strategy: results
of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke. 2007;38(6):1843-1849. doi:10.1161/
STROKEAHA.106.478230
26. Zivin JA, Albers GW, Bornstein N, et al; NeuroThera Effectiveness and Safety Trial-2 Investigators.
Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke. 2009;40(4):1359-1364.
doi:10.1161/STROKEAHA.109.547547
27. Huisa BN, Stemer AB, Walker MG, Rapp K, Meyer BC, Zivin JA; NEST-1 and -2 investigators. Transcranial laser
therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2. Int J Stroke. 2013;8(5):315-320. doi:10.
1111/j.1747-4949.2011.00754.x
28. Hacke W, Schellinger PD, Albers GW, et al; NEST 3 Committees and Investigators. Transcranial laser therapy in
acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device
trial. Stroke. 2014;45(11):3187-3193. doi:10.1161/STROKEAHA.114.005795
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 12/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020
13. 29. Sommer AP, Pinheiro ALB, Mester AR, Franke R-P, Whelan HT. Biostimulatory windows in low-intensity laser
activation: lasers, scanners, and NASA’s light-emitting diode array system. J Clin Laser Med Surg. 2001;19(1):29-33.
doi:10.1089/104454701750066910
30. Yano R, Hata J, Abe Y, et al. Quantitative temporal changes in DTI values coupled with histological properties
in cuprizone-induced demyelination and remyelination. Neurochem Int. 2018;119:151-158. doi:10.1016/j.neuint.
2017.10.004
31. Edlow BL, Copen WA, Izzy S, et al. Diffusion tensor imaging in acute-to-subacute traumatic brain injury:
a longitudinal analysis. BMC Neurol. 2016;16:2. doi:10.1186/s12883-015-0525-8
SUPPLEMENT 1.
Trial Protocol
SUPPLEMENT 2.
eMethods. Detailed Methods
eReferences
eTable 1. Demographic and Clinical Characteristics of Participants at Enrollment Into the Study
eTable 2. Summary of the Brain Diffusion Parameters Based on the Time-Point and Treatment Group
eTable 3. Random Effects and Other Statistical Parameters Derived From the Linear Mixed Effect Model
eFigure 1. LLLT Helmet
eFigure 2. Temporal Evolution of Each of the 18 Individual White Matter Tracts
SUPPLEMENT 3.
Data Sharing Statement
JAMA Network Open | Neurology Effect of Transcranial Low-Level Light vs Sham Therapy Among Patients With Traumatic Brain Injury
JAMA Network Open. 2020;3(9):e2017337. doi:10.1001/jamanetworkopen.2020.17337 (Reprinted) September 14, 2020 13/13
Downloaded From: https://jamanetwork.com/ on 10/28/2020