Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental conditions, with a worldwide prevalence of 5-7%.
The limitations of the standard treatment
The most effective treatment is with psychostimulant medication, which has a high effect size, with 70% of patients responding to it, and mild side effects relative to other psychotropic medications. Nordic registry data have associated long-term stimulant medication with better outcomes later in life such as less comorbidities, lower levels of substance abuse, less traffic accidents, lower suicide rates, etc.
However, while stimulants are very effective in randomised controlled trials typically conducted over one to two months, there is limited evidence for longer-term efficacy. Furthermore, there is evidence that the brain adapts to the medication which may explain limited longer-term efficacy. This may also be the reason for poor adherence with over 50% of teenagers no longer taking it.
Children and adults with ADHD and their families furthermore prefer non-drug treatments. However, most non-drug treatments that have been tried in ADHD, do not work, including behavioural and psychological treatments, neurofeedback, cognitive training, nutrition, exercise, etc.
Why trigeminal nerve stimulation (TNS) could be an alternative, user-preferred non-drug treatment:
We investigated whether non-invasive brain stimulation with trigeminal nerve stimulation (TNS) could be an alternative non-drug treatment for ADHD.
TNS stimulates the V1 branch of the trigeminal nerve via a battery powered patch placed on the person’s forehead which stimulates the locus coeruleus and the brain stem. These regions are important for arousal which is typically diminished in people with ADHD. TNS is thought to stimulate other brain regions such as frontal and thalamic areas via the brainstem in a bottom-up manner.
TNS has been shown to improve ADHD symptoms in a pilot randomised controlled trial (RCT) in the USA, where it was given to 62 children with ADHD to use every night for 8 hours for 1 month. The improvement in ADHD symptoms was associated with increased activation over right frontal regions, which are typically under-activated in ADHD relative to typical children. The findings led to clearance of TNS as the first device based non-drug treatment for children with ADHD by the Food and Drug Administration (FDA), USA. However, the placebo condition was no stimulation at all, and blinding was not tested after 4 weeks. The findings could hence be related to a placebo effect, which we know is substantially larger when participants are given high-tech neuromodulation devices as opposed to placebo conditions in drug studies.
We therefore decided to replicate the study in a larger sample of children and adolescents with ADHD, and devising a better controlled sham condition that would avoid the placebo effect. Furthermore, we tested effects on a wide range of clinical and cognitive measures, on objective hyperactivity and autonomous nervous system measures, on a large battery of ADHD-relevant tasks and tested whether the effects would persist 6 months later. We also tested underlying mechanistic effects including arousal in pupillometry.
The study design of our large multicentre, double-blind RCT of TNS in 150 children and adolescents with ADHD
- The study was a phase 2b, double-blind, sham-controlled confirmatory RCT testing the effects of TNS in 150 children and adolescents with a research or clinical diagnosis of ADHD across London and Southampton
- We included a wider age range of children and adolescents with ADHD than the previous study (8-18 years)
- We also included stimulant medicated children, as long as they did not change the medication regime over the 4 weeks of the treatment.
- We tested the effects of nightly administration (~8-9 hours) during sleep of real versus sham TNS over 4 weeks in children and adolescents
- Real TNS provided 30s stimulation ON and 30s OFF during the night (~4 hours of stimulation. Participants set the device to be perceptible but not painful
- Sham TNS provided 30s ON then OFF every hour (i.e. total of ~4 min of simulation)
- We tested the effects of 4 weeks of real versus sham TNS on:
- On clinical symptoms of ADHD (primary outcome)
- On several secondary outcomes including:
- Objective hyperactivity, measured in a wrist-held device
- Persistence of effects 6 months after the stimulation
- Effects on other clinical measures such as self-rated ADHD severity by children (SDQ), measures of anxiety, depression (R-CADS-25), sleep (SDSCC), mind-wandering (MEWS), and emotion regulation (ARI)
- Safety (adverse event reporting; side effects questionnaires for TNS)
- Physiological measures (heart rate, heart rate variability)
- Cognitive performance
- Arousal measures (i.e., pupil diameter).
What we found
A total of 150 young people with ADHD took part in the study, 75 received real TNS and 75 sham TNS.
- High retention, adherence, and compliance and high safety and tolerability:
The RCT was very successful in that it retained 98% of participants in the trial, 93% of participants adhered to it and 93% were compliant, i.e. they used the device on average 26 out of the 28 nights of treatment. TNS was also very safe with no serious adverse events and no differences in side effects between the real and sham condition. Most participants considered it a mild or no burden to do, i.e. TNS is very tolerable.
- Blinding was successful:
Blinding was successful in that guesses to treatment arm were balanced across groups and participants did not know which treatment arm they were in.
- TNS had no clinical efficacy (primary outcome)
However, real versus sham TNS did not improve ADHD symptoms.
TNS had no effects on any secondary measures
It also did not improve any of the other secondary outcome except for mind-wandering, which was however one out of 16 measures and the finding hence needs to be considered with caution.
TNS did not elicit cognitive improvement
There was also no improvement in the performance of an attention task
TNS showed no effects on any other measures
TNS had no effects on objective measures of hyperactivity or arousal.
Conclusion
- TNS is overall very safe and tolerable for children with ADHD.
- However, it is not effective in improving ADHD symptoms, objective measures of hyperactivity, other associated clinical behaviours nor cognitive functions and should therefore not be given as a treatment for ADHD.
- The positive findings in the previous USA trial are likely due to “neuro-enchantment”, i.e. a neurotechnology enhanced placebo effect, given that the placebo condition was no stimulation at all, and participants were likely to know what study arm they were in. It is known that the placebo effect is larger with high-tech neurostimulation than with placebo drugs. This is particularly the case for those with psychiatric disorders where there is evidence for differences in their brains (which in itself might trigger a nocebo effect) and who believe that those differences can be addressed with brain stimulation. Indeed, the placebo effect size in our sham group was 0.9 which is more than twice as high as the placebo effect size in meta-analyses of drug studies in ADHD which is around 0.4.
- The study illustrates the importance of controlling for the placebo effect in neuromodulation trials.