An open label trial to assess the safety and efficacy of transcranial photobiomodulation (tPBM) in improving autistic traits in ADHD youth.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable presentation of difficulties with socialization, reciprocal communication, and restrictive/repetitive behaviors. An increasingly higher prevalence of ASD is documented in each successive epidemiological survey and the disorder is now estimated to affect up to 2% of youth in the general population. This rise in prevalence is in part attributed to improved recognition of autism in intellectually capable populations.

There exists no established pharmacological treatment for the core features of ASD.

Current practice consists of well-established evidence-based pharmacotherapies that are available for the management of comorbid psychiatric disorders, in order to improve quality of life and reduce symptom severity in ASD. Clinical trials of available treatment options reveal that compared to general population, individuals with ASD may be more susceptible to adverse effects of medications which could be dose-related, and may have lower adherence to treatment. New treatments for core deficits in ASD are needed; an intervention requiring no medication may offer better compliance and tolerability.

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common psychiatric disorder recognized in youth and adults with ASD, and greatly adds to their morbidity and dysfunction, particularly in those with intact intellectual capacity. The prevalence of ADHD in the general population of school-age children is approximately 3% to 5%, although some reports show even higher incidence. Nearly two-thirds of referred populations of youth (ranging from 59-83%) and adults (ranging from 37-68%) with ASD suffer from ADHD.

Both ADHD and ASD have strong shared heritable components according to the evidence from twin and family studies. Up to 15% of youth with ADHD suffer from ASD and experience greater morbidity and dysfunction. This confounding effect of ASD seems to be symptom dependent and not contingent upon reaching full diagnostic threshold. In fact, up to a third of ADHD youth without ASD diagnosis still struggle with persistent symptoms of ASD (henceforth termed autistic traits [ATs]) and associated compromised outcomes. Presence of ATs is associated with a more complicated course of ADHD, characterized as increased comorbid psychopathology, more impaired interpersonal, school, family, and cognitive functioning. Anti-ADHD medications effectively mitigate core symptoms of ADHD, but offer no improvement in the ATs. Youth with ADHD continue to suffer from the impairments associated with ATs that prognosticate a compromised course in multiple domains of functioning despite effective treatment of ADHD. Treating comorbid ATs in patients with ADHD could prevent functional deterioration, and improve long term outcomes. As yet, there exists no known treatment for the core features of ASD or ATs.

A novel treatment approach for social and cognitive deficits is based on transcranial application of Light Emitting Diode (LED), an invisible, non-ionizing electromagnetic wave. Referred to as Transcranial Photobiomodulation, tPBM consists of exposing bilaterally the frontal brain to a non-ionizing electromagnetic wave. The transcranial photobiomodulation (tPBM) is invisible, penetrates the skin and skull into brain tissue, is non-invasive, and minimally dissipated as thermal energy. The benefits of tPBM are wavelength specific. A mitochondrial enzyme, the cytochrome c oxidase, is the primary chromophore for the tPBM at wavelengths of 830-850 nanometers. What follows is, increased adenosine triphosphate (ATP) production, through the respiratory chain. Ultimately, the increased ATP leads to increased energy metabolism for the cell, and it is hypothesized that a signaling cascade is also activated promoting cellular plasticity and cytoprotection.

Unique properties of the tPBM have led to novel therapeutic applications in neurology, for treatment following acute ischemic stroke subjects, and in dermatology for treatment of alopecia. In psychiatric care, tPBM has been shown to be safe, effective and well tolerated compared the sham treatment in patients with Major Depressive Disorder (MDD).

These properties of the tPBM have led to novel therapeutic applications in neurology. In acute ischemic stroke subjects, acute treatment with the tPBM led to significantly better outcome as compared to sham. These results were confirmed in a different cohort of stroke patients with mild to moderate severity of illness. Both studies on stroke subjects showed no significant difference in rate of adverse events, as well as serious adverse events, between the tPBM and sham treated subjects. The tPBM has also been used as a treatment of alopecia and in animal models for methanol-induced retinal toxicity. The tPBM is already widely used for non-invasive assessment of brain function (replacing functional magnetic resonance imaging in studies of infants and young adults, under the name of Near Infrared Spectroscopy) underscoring the relatively low risk of tPBM.

Proposed treatment with tPBM has been previously studied in patients with Major Depressive Disorder (MDD). MDD has been associated with deficits in brain bioenergetic metabolism. In an experimental model of depression, the mitochondrial respiratory chain (the cellular site for energy production) was found to be inhibited by chronic stress. Depressed subjects have also significantly lower production of ATP (an energy vector) in their muscle tissue and greater incidence of deletions in their mitochondrial DNA. Data from magnetic resonance spectroscopy in subjects with MDD showed that response to the augmentation of a selective serotonin reuptake inhibitor (SSRI) with triiodothyronine (a thyroid hormone) is associated with restoration of the levels of ATP in the brain. A preliminary open study in 10 depressed subjects has shown that the tPBM was safe, effective and well tolerated.

More recently, a proof of concept study was conducted with tPBM, in an open label, prospective design with 10 patients with a diagnosis of ASD between ages 18 and 55. Five patients met the rigorous responder criteria, and a statistically significant improvement was observed in all clinician and patient rated measures at midpoint and endpoint. Efficacy measures revealed that tPBM substantially improved ATs in 7 patients (70%), and was well tolerated with no treatment-limiting side-effects or serious adverse events. Adherence rate among participants was 98%.

These findings suggest that tPBM may be a promising treatment for core social deficits associated with ASD and is a safe, feasible treatment approach. The major risk of tPBM when using a laser as the light source is associated with accidental retinal exposure, when beams are projected through the lens, with increased risk of macular degeneration. LED light does not share the same risk level as laser light sources. Based on these promising results, this novel treatment approach is safe, well-tolerated and associated with statistically and clinically significant improvements in symptoms of ASD.

The researchers hypothesize that tPBM will be safe and effective in the treatment of ATs in youth with ADHD, and will improve social functioning, which stimulants do not address.

Aforementioned proof-of-concept study was blessed with a fast pace of recruitment, with 10 participants over a period of 18 months, despite its demanding nature for our patients. Even faster and more efficient recruitment along with a less demanding schedule for our patients is possible. Telemedicine substitutes for face-to-face office visits through a remote, two-way video-conference through secure Internet access. Telemedicine use in the clinical setting has successfully provided specialist advice with favorable patient outcomes, satisfaction, and costs. Clinical trials are the gold standard for evaluating new therapeutic opportunities in medicine, efforts aimed at improving their efficiency are needed to facilitate patient participation in a manner that reduces dropout, and Telemedicine may offer such opportunity.

The researchers propose an open label trial to assess the safety and efficacy of tPBM in improving ATs in ADHD youth with comorbid ATs. Eligible participants will be youth with adequately treated ADHD who present with comorbid ATs of at least moderate severity. Participants will receive tPBM daily for 8 weeks. Participants who meet eligibility criteria will be mailed the tPBM device. They will be able to administer the treatment in the comfort of home, at scheduled intervals. Accurate application of tPBM, its safety, and efficacy will be assessed during regular scheduled meetings with study clinician. These meetings will all be conducted via telemedicine with HIPAA compliant communication technology. Safety of and treatment response to tPBM will be monitored by parent- and clinician-rated measures during regularly scheduled visits. The study will address the question whether tPBM is effective for the treatment of ATs in youth with ADHD, and whether it is acceptable among our patients.

Certain aspects of tPBM render it a feasible intervention. It can be delivered at home. It does not require ingestion of any substances. It is possible that the exposure to tPBM might be more acceptable than use of medications among some minority groups. This intervention does not require providers with specific cultural expertise or second language proficiency.

The tPBM treatment can be completed in the comfort of participants' homes, while monitoring their safety and response during scheduled medicine visits. The advantage of the tPBM treatment approach compared to pharmacotherapy is that adherence can be easily monitored. This study will answer whether tPBM has an effect on ASD symptoms in ADHD and whether it is acceptable among our patients, for whom frequent visits otherwise would be prohibitive or render it inaccessible. As such, the researchers propose the inclusion of a telemedicine visits in this study protocol.

Inclusion Criteria:

• Male or female participants between 9 and 17 years of age (inclusive)
• Participant fulfills Diagnostic and Statistical Manual of Mental Disorders-5 diagnostic criteria for Attention Deficit Hyperactivity Disorder as established by the clinical diagnostic interview.
• Participants with at least moderate severity of Autism Spectrum Disorder symptoms as demonstrated by Social Responsiveness Scale raw score ≥ 75 or Clinician Global Impression-Autistic Traits severity score ≥ 4
• Participants must understand the nature of the study. Participants must sign an Institutional Review Board-approved informed consent form before initiation of any study procedures.
• Participants are willing and able to cooperate with all tests, examinations and demonstrate ability to appropriately administer the study treatment required by the protocol.
• Participants must have access to a computer with camera and broadband internet connection

Exclusion Criteria:

• Impaired intellectual capacity (clinically determined)
• Serious chronic medical or psychiatric condition that, in the investigator's opinion, puts the subject at risk
• The subject has a significant skin condition at the procedure sites (i.e., hemangioma, scleroderma, psoriasis, rash, open wound or tattoo)
• The subject has an implant of any kind in the head (e.g. stent, clipped aneurysm, embolised AVM, implantable shunt - Hakim valve)
• Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment including: Visudine (verteporfin) - for age related macular degeneration; Aminolevulinic Acid- for actinic keratoses; Photofrin (porfimer sodium) - for esophageal cancer, non-small cell lung cancer; Levulan Kerastick (aminolevulinic acid HCl) - for actinic keratosis; 5-aminolevulinic acid; and (ALA)- for non-melanoma skin cancer
• Current treatment with a psychotropic medication on a dose that has not been stable for at least 4 weeks prior to initiating study treatment.
• Pregnant or nursing females
• Investigator and his/her immediate family

Seven participants were excluded from the analysis.

Adverse events in all participants who started treatment (baseline through week 10 follow-up visit)