A large-scale clinical trial has determined that a specific brain stimulation device, previously cleared by regulators for treating attention-deficit/hyperactivity disorder, does not effectively reduce core symptoms in children and adolescents. The study suggests that positive outcomes reported in earlier, smaller trials were likely driven by the placebo effect rather than the electrical stimulation itself. These findings were published in Nature Medicine.
The rationale for this study stems from the significant demand for non-pharmacological treatments for neurodevelopmental conditions. Attention-deficit/hyperactivity disorder impacts a substantial percentage of school-age youth and often persists into adulthood. While stimulant medications are generally effective, they can produce unwanted side effects and some families prefer to avoid drug-based interventions.
In 2019, the U.S. Food and Drug Administration cleared the Monarch external Trigeminal Nerve Stimulation system for use in children. This decision was based largely on a pilot study involving 62 participants. That initial study used a control condition that did not involve any active electrical stimulation, which may have allowed participants to guess their treatment assignment.
To address the limitations of previous research, a collaborative team designed a more rigorous confirmation trial. The study was led by first authors Aldo Alberto Conti, Natali Bozhilova, and Irem Ece Eraydin, who are affiliated with King’s College London and the University of Southampton. Senior authors Samuele Cortese and Katya Rubia oversaw the project, aiming to provide definitive evidence regarding the device’s efficacy.
The scientific premise behind this treatment involves the anatomy of the trigeminal nerve. This nerve has branches across the forehead and connects directly to the brainstem. Stimulation of this nerve is thought to activate the locus coeruleus, a brain region involved in regulating arousal and attention.
The researchers hypothesized that activating this pathway would increase the release of neurotransmitters like noradrenaline. Deficiencies in these chemical messengers are often associated with the symptoms of inattention and impulsivity. The team sought to verify if this biological mechanism translates to observable behavioral improvements in a large, diverse group.
The trial included 150 children and adolescents aged 8 to 18 years who had a confirmed diagnosis of the disorder. The participants were recruited from multiple sites in the United Kingdom, ensuring a representative sample. Approximately 40 percent of the participants continued taking their prescribed stimulant medication during the trial, while the rest were unmedicated.
The study employed a randomized, double-blind design, meaning neither the families nor the researchers knew who received the active treatment. Participants were assigned effectively by chance to either the active group or the sham group. The intervention period lasted for four weeks and required nightly use of the device.
The active treatment involved wearing a patch on the forehead that delivered electrical pulses at a frequency of 120 Hertz. Parents or caregivers applied the device at bedtime, and it remained operational for roughly eight hours during sleep. The electrical current was adjusted to a level that was perceptible but comfortable for the child.
To ensure the control group remained unaware of their status, the researchers designed a sophisticated sham protocol. The sham device looked identical to the active one and delivered electrical pulses for 30 seconds at the start of every hour. This intermittent pulsing mimicked the physical sensation of the treatment without delivering the continuous therapeutic frequency.
This specific design feature was intended to maintain “blinding” throughout the study. Surveys conducted during the trial confirmed that this strategy worked. The majority of parents and children in both groups could not accurately guess which treatment they were receiving.
The primary measure of success was the ADHD Rating Scale, a standardized tool used to assess symptom severity. Parents completed this assessment weekly to track changes in inattention and hyperactivity. The researchers also collected data on secondary outcomes, including sleep quality, emotional regulation, and anxiety levels.
The team also utilized objective measures to complement the subjective parent ratings. Participants wore wrist-based activity trackers to measure physical restlessness and hyperactivity. Additionally, the researchers used eye-tracking technology to measure pupil size, which can serve as a physiological marker for arousal and attention levels.
The results indicated that symptoms decreased in both the active and the sham groups over the course of the four weeks. However, the statistical analysis revealed no significant difference between the two groups on the primary outcome. The magnitude of improvement was nearly identical for those receiving real stimulation and those receiving the sham.
This finding implies that the perceived benefits were likely the result of the placebo response. In trials involving medical technology, the expectation of benefit can be particularly strong, a phenomenon sometimes called “neuro-enchantment.” The families’ belief that the device would help likely contributed to the reported symptom reduction in both groups.
Regarding secondary outcomes, the study found no significant differences for most measures. Sleep patterns, anxiety levels, and objective hyperactivity scores were similar between the active and control groups. The physiological pupil measurements also failed to show the expected changes in brain arousal systems.
There was one specific area where the active treatment showed a statistical advantage. Participants in the active group reported a greater reduction in “mind-wandering” compared to the control group. This was measured using a specific scale designed to assess unrelated internal thoughts.
The safety profile of the device was found to be excellent. Adverse events were generally mild and included issues such as headaches, fatigue, or skin irritation at the patch site. These side effects occurred at similar rates in both the active and sham groups, confirming the device is well-tolerated.
Adherence to the treatment protocol was notably high. Over 93 percent of the participants used the device for the required amount of time each night. This high level of compliance suggests that the treatment is acceptable to families and easy to integrate into a nightly routine.
A potential misinterpretation of these results would be to dismiss the technology entirely. The reduction in mind-wandering suggests that the stimulation may be having some effect on specific brain networks. However, this isolated finding is not sufficient to support the device as a standalone treatment for the broad clinical syndrome.
The study does have certain limitations that warrant mention. The analysis relied heavily on parent ratings, which can be influenced by caregiver stress or expectations. The researchers attempted to gather teacher ratings to provide an external perspective, but the response rate from schools was too low to be included.
Another limitation involves the self-reported nature of the adherence data. While families reported high usage, the device logs were not reliable enough to verify the exact duration of stimulation for every participant. Future studies would benefit from more robust automatic data logging to ensure treatment fidelity.
The inclusion of medicated participants might be seen as a confounding factor. However, the researchers conducted a separate analysis of only the unmedicated participants. This sub-analysis produced the same result, confirming that medication status did not mask the device’s lack of efficacy.
These findings present a challenge to the current regulatory status of the device. The study provides evidence that the specific stimulation parameters used do not offer a clinical benefit over a placebo. The authors suggest that clinical guidelines and regulatory clearances may need to be revisited in light of this new, higher-quality data.
Future research could investigate if different stimulation frequencies or longer treatment durations might yield different results. It is also possible that specific subgroups of patients might respond better than others. For now, the evidence indicates that external trigeminal nerve stimulation should not be recommended as a primary treatment for this condition.
The study, “External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial,” was authored by Aldo Alberto Conti, Natali Bozhilova, Irem Ece Eraydin, Dominic Stringer, Lena Johansson, Robert Marhenke, Andrea Bilbow, Sahid El Masri, Joshua Hyde, Giovanni Giaroli, Holan Liang, Federico Fiori, Mitul Ashok Mehta, Paramala Santosh, Ben Carter, Samuele Cortese and Katya Rubia.