LOS ANGELES—Some stimulating news has come from NeuroSigma, Inc., a Los Angeles-based bioelectronics company that wants to commercialize trigeminal nerve stimulation (TNS) technology for treating neurological and neuropsychiatric disorders. An article investigating TNS, entitled “Trigeminal Nerve Stimulation for Attention-Deficit Hyperactivity Disorder: Cognitive and Electrophysiological Predictors of Treatment Response,” has been published in the Journal of the American Academy of Child & Adolescent Psychiatry.
The paper presents the results of research conducted at the University of California, Los Angeles (UCLA) as part of the pivotal trial of external TNS (eTNS) for pediatric ADHD. Those results support the U.S. Food and Drug Administration’s clearance of the Monarch eTNS System. Research was led by Sandra Loo, Ph.D., professor of Psychiatry at UCLA’s Semel Institute for Neuroscience and Human Behavior.
TNS involves mild electrical stimulation of branches of the trigeminal nerve, including those in the surface of the forehead. Functional neuroimaging data suggests that the mechanism of action of TNS is related to its ability to modulate activity in targeted brain regions. The trigeminal nerve is the largest cranial nerve. It projects either directly or indirectly to specific areas of the brain — like the locus coeruleus, nucleus tractus solitarius, thalamus and the cerebral cortex — involved in ADHD and other disorders.
The research explored the applicability of a precision medicine approach to TNS by testing secondary outcomes of cognitive and electrophysiological (EEG) predictors of treatment response among subjects from the original randomized controlled trial.
“Children aged 8-12 years with ADHD were randomized to four weeks of active or sham TNS treatment; after which, the sham group crossed over into four weeks of open-label treatment,” states the article. “TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of >25%, while non-responders (NR) had <25% reduction post-treatment.”
“The data thus far indicate that the best candidates for TNS treatment are children with ADHD who have executive functioning weakness or deficits,” the article continues. “Across studies, approximately 50% of children with ADHD show executive dysfunction, which reflects difficulties with top down control of attention and response inhibition; this maps on well to the TNS treatment response rate of ~50%.”
“Our work with eTNS suggests that successful treatment response to eTNS appears to address a number of cognitive and neural deficits typically associated with ADHD,” Loo said. “Additional investigations of this new treatment modality are warranted to better understand these effects, to predict which children may benefit prior to initiating treatment, and to provide independent replication in larger samples of children with ADHD.”
The research demonstrated that certain baseline characteristics — like lower working memory performance, deficits on the behavioral ratings of executive functions (BRIEF) scale and lower resting state EEG power in the right frontal brain region — were predictive of positive treatment response to eTNS (p < 0.05). Upon completion of the four week eTNS treatment regimen, responders had significantly higher power in right frontal EEG readings. This was significantly correlated with improvement in executive function and ADHD symptoms.
“Notably, performance on cognitive measures (SWM [Spatial Working Memory] and Flanker task) were not predictive of treatment response and the pattern of scores differed significantly from the behaviorally rated measures of cognitive function. Low correlation between measures has been widely reported, suggesting they represent different aspects of cognitive functioning,” explains the article. “While performance-based measures such as the SWM or Flanker task are thought to measure specific cognitive processes within the context of a controlled environment, behavioral ratings of executive functions encompass a broader set of cognitive skills that are utilized while functioning in everyday environments. Given our hypothesis of the fronto-basal ganglia network involvement, cognitive tasks that involve motor inhibition may show more treatment-related change in future studies.”
The paper also noted that while “the ~50% response rate of TNS is promising, principles based in precision medicine suggest that higher response rates might result from targeting the treatment to particular pathophysiological mechanisms underlying an individual patient’s symptomatic presentation.”
“Dr. Loo and her colleagues have done outstanding work in advancing our understanding of the eTNS mechanism of action. Specifically, the mechanism of action was demonstrated by the treatment-induced changes in frontal brain activity that showed a correlation with clinical outcome,” added Ian Cook, M.D., NeuroSigma’s chief medical officer. “Their findings of baseline predictors of outcome suggest eTNS treatment can be especially valuable to some of the most impaired children with ADHD. We look forward to continuing to advance our eTNS portfolio based on these findings and to expanding our efforts in digital therapeutics.”
In the U.S., the Monarch eTNS System is indicated for treatment of pediatric ADHD as a monotherapy in patients ages 7 through 12 years old who do not currently take prescription ADHD medications. The device is available by prescription, and is intended for use in the home under supervision of a caregiver. The system is also approved in the EU for patients 7 years and older as an adjunctive therapy for drug resistant epilepsy and major depressive disorder, and as a monotherapy for ADHD.
The most common side effects of eTNS use are drowsiness, increase in appetite, sleeping trouble, headache, teeth clenching and fatigue. No serious adverse events have been associated with use of the device. For more information on eTNS, you can visit Monarch’s website.
