Youth with neurodevelopmental disorders often present with behavioral symptoms thought to be related to disturbances of the autonomic nervous system (ANS), including emotion dysregulation, anxiety, and sensory sensitivity [1, 2]. As a result, there is growing research interest in therapeutic interventions that target ANS function to reduce anxiety and enhance emotional regulation. Cranial electrotherapy stimulation (CES) is a non-invasive form of transcranial current stimulation that is believed to modify brain activity, at least in part, through vagal and other cranial nerve pathways [3, 4]. While CES has been studied in adults for conditions such as anxiety, insomnia, pain, and headaches, there is a paucity of research on its effectiveness in children [5, 6].

Autism, Attention Deficit/Hyperactivity Disorder (ADHD), and other neurodevelopmental conditions often display symptoms of sensory over-responsivity and emotion dysregulation [1, 2]. Treatment has traditionally been approached through methods such as sensory integration-based occupational therapy, behavioral therapies, and clinical drug trials [7, 8, 9, 10, 11]. However, drawbacks such as adverse medication effects and high costs and time burdens for families have led to a need for research into complementary and novel treatment options [12, 13, 14]. Specifically, not all individuals respond in the same way to existing treatments, thus personalized plans must be developed to target specific symptoms and underlying causes for optimal outcomes [15, 16].

Cohesive examinations of the biological etiology of behavioral regulation problems in neurodevelopmental populations point to a common physiological mechanism—the dysregulation of the ANS. The ANS has two branches: the sympathetic nervous system (SNS), also called the “fight, flight, and freeze” system, and the parasympathetic nervous system (PNS), or the “rest and digest” system [17, 18]. The PNS modulates the homeostatic functions of the body and feelings of safety [19]. Low PNS activity is considered one of the main biological mechanisms responsible for ineffective self-regulation, particularly for individuals with neurodevelopmental concerns [20]. The vagus nerve, which contains afferent and efferent pathways, serves as the primary neural substrate of the PNS. Children with disrupted vagal activity have difficulty regulating responses to environmental stimuli, resulting in sensory sensitivities, anxiety, and emotion dysregulation [21].

Recently, there has been growing interest in modulating ANS activity using non-invasive brain neuromodulation techniques to remediate transdiagnostic symptoms associated with neurodevelopmental disorders. One such technique, CES, involves delivering low-level electric stimulation to cutaneous branches of cranial nerves via a pair of electrodes, which may be attached to the earlobes or the scalp, depending on the device being used. CES has been shown to produce physiologic effects on both the central and peripheral nervous systems, leading to changes in mood, cognition, and pain perception [22]. Several researchers have suggested that CES exerts its regulatory effect on the ANS by stimulating the vagus nerve [22, 23], which in turn is thought to modulate neural activity and neurotransmitter systems in the brainstem, limbic system, and prefrontal cortex. Such modulation of brain and vagal activity is thought to underlie the observed stress regulation effect of CES on the brain and body. Indeed, neurophysiological evidence has shown that CES increases cortical alpha wave activity, promoting optimal states of arousal and alertness [24].

Several studies have established the safety of CES with relatively few reported adverse effects [5, 25, 26, 27, 28, 29, 30, 31, 32]. Research investigating the efficacy of CES has primarily focused on adult populations with anxiety and depression. Double-blind placebo-controlled studies have demonstrated promising effects of CES therapy in alleviating both anxiety and depression symptoms in adults [28, 29, 33]. However, therapeutic results have been mixed, with other studies showing limited efficacy relative to sham control conditions [32, 34]. Moreover, very few studies have investigated the effectiveness of CES therapy in pediatric clinical populations. To the best of our knowledge, only one published study has examined its clinical effects in pediatric populations. Specifically, a randomized double-blind study in children and adolescents with Tourette syndrome showed decreased tic burden after CES use; however, there was no significant difference between the sham-CES and active-CES groups [30]. To our knowledge, this is the only CES research conducted on young individuals.

Given that CES is conjectured to modulate the mediating physiological system implicated in behavioral dysfunction, additional research examining the use of CES in young populations with sensory, anxiety, and emotional concerns is critical. It is also important to understand whether the use of CES is feasible within the context of routine clinical care for children and adolescents with neurobehavioral symptoms.To address this knowledge gap, we examined the feasibility and preliminary efficacy of a 4-week CES intervention on behavioral regulation in a mixed neurodevelopmental sample of children, adolescents, and young adults currently receiving care at clinical centers operated by Cortica Healthcare. Participants in this study received neuromodulation therapy using the Alpha-Stim® AID CES (Electromedical Products International, Inc., Mineral Wells, TX, USA), a mobile phone-sized device that delivers a low-level electrical current through electrodes placed on the earlobes. The clinical protocol involved using the device for approximately 20 minutes a day, 5 days a week, generally at bedtime. Our primary aim was to evaluate adherence, adverse effects, and tolerance to CES device use. Second, we aimed to evaluate change in 3 neurobehavioral symptoms thought to be associated with PNS activity: sensory sensitivities, emotion dysregulation, and anxiety.

In the current study, we investigated the feasibility and preliminary efficacy of a novel neuromodulation therapy in a clinical cohort of children, adolescents, and young adults. We measured symptoms associated with PNS dysregulation commonly experienced by individuals with neurodevelopmental differences: sensory sensitivities, anxiety, and emotion dysregulation [43]. The current work is the first study, to the best of our knowledge, to demonstrate the feasibility and preliminary efficacy of CES therapy on behavioral regulation in a mixed neurodevelopmental cohort within a routine clinical setting.

To assess the feasibility of a scalable CES intervention embedded within an existing clinical practice, we measured adherence to the study and evaluated parent-reported side effects, tolerance, and satisfaction with CES treatment. Approximately 25% of participants were lost to post-test follow-up due to a combination of intolerance of treatment, study dropout, and failure to complete the follow-up survey. Importantly only 9% of participants dropped out of the study during the 4-week trial, compared with 16% of participants who completed the trial but did not complete the post-study questionnaire. This moderate attrition rate, particularly in post-study questionnaire dropout, is likely explained by the fact that the study was conducted within the context of routine clinical care. For example, some patients stopped receiving care at the centers for reasons not related to the intervention (e.g., loss of insurance) and therefore did not follow up. Similarly, families may have been less incentivized to complete follow-up surveys, given that this was an open-label study embedded in a clinical context.

Similarly, while patients were instructed to use the CES device according to a specific protocol (20 minutes a day, 5–7 days a week, at a microcurrent level between 50–150 µA), the self-reported use statistics show some deviation from these instructions. In the first week of the trial, 9% of participants reported using CES for less than 5 days, and there were some reports of microcurrent levels greater than 150 µA. In the last week of the trial, 24% of the participants reported using CES for fewer than 5 days, and participants still reported using the CES device with microcurrent levels outside the specified range. This finding suggests some protocol deviation from the specified instruction and highlights the importance of a remote monitoring system to better regulate home-based CES treatment in future clinical trials.

We also evaluated any reported adverse effects of CES treatment. Adverse events were reported in less than 8% of participants and included rash, headache, sleep problems, vertigo, nausea, diarrhea, anxiety, and urinary accidents. The rate of adverse effects reported in the current study was lower than what is seen in most drug trials [12, 44]. Further, parents reported an average tolerance of 68 (out of 100) for CES, use where 100 was described as “requests and seeks out daily” and 1 designated “unable to use”. A score of 68 can be interpreted as moderately positive tolerability. Similarly, parents reported an average satisfaction score of 59 out of 100. When prompted, “how beneficial do you think CES was for your child?”, a score of 0 reflected “not beneficial at all”, and 100 reflected “extremely beneficial”. Thus, the group-level satisfaction score can be interpreted as average-to-moderate satisfaction. While there are substantial individual differences in participants’ adherence, tolerance, and satisfaction, these findings demonstrate that CES treatment is feasible in this population.

These results offer preliminary evidence for the effectiveness of CES in treating behavioral regulation in children, adolescents, and young adults with neurodevelopmental differences, as an adjunct to other elements of routine clinical care. Specifically, we demonstrated a significant reduction in reported sensory sensitivity, anxiety, and emotion regulation incidents.

In the sensory sensitivity domain, there was a 21% decrease in parent-reported incidences of over-responsivity to sounds, smells, sights, and/or taste problems after CES treatment. Similarly, when analyzed on a continuous scale, the frequency of sensory sensitivities was also significantly reduced. Aside from sensory integration-based occupational therapy, there are few treatment options available for treating individuals struggling with sensory processing disorders [45]. To the best of our knowledge, this is the first study that used neuromodulation techniques to alleviate sensory sensitivities. It has been hypothesized that children with sensory sensitivities have elevated levels of arousal [46]. Therefore, a therapeutic intervention that lowers resting stress physiology may be advantageous in regulating the perceived effects of sensory over-responsivity. These findings suggest the possible utility of CES treatment alongside existing developmental and behavioral therapies.

In the anxiety domain, parents reported 18% fewer incidences of separation anxiety (i.e., difficulty being in a room apart from family or going to school), general anxiety (i.e., feelings of worry or nervousness), repetitive physical behaviors (i.e., jumping, spinning, pacing, flapping), and repetitive verbal behaviors (i.e., repeated questioning or commenting). Further, the level of disruptiveness of anxiety-related behaviors was also significantly reduced. The positive effects of CES on anxiety symptoms are aligned with adult literature using CES on anxiety [29, 33, 47]. This finding extends the literature by suggesting the preliminary benefits of CES treatments for anxiety in youth populations.

Finally, parents reported 22% fewer incidences of heightened emotional reactivity (i.e., resistance to novelty or transition, particularly from preferred to non-preferred activities), outbursts (i.e., kicking, hitting, biting, or screaming), meltdowns (i.e., crying, expression of worry or concern, escape/run away), and shutdowns (i.e., laying on the floor, hiding, becoming still and unresponsive). Further, the severity, duration, and frequency of the emotion dysregulation behaviors were significantly reduced. This finding is aligned with research using other forms of neuromodulation therapies that have shown promising effects on children’s inhibitory control [48, 49].

For families of children with neurodevelopmental disabilities, daily life is often impeded by frequent sensory over-responsivity, anxiety-induced behaviors, or other meltdowns or shutdowns related to emotional dysregulation [2, 50]. Behavioral dysregulation symptoms occur when innocuous environmental stimuli are interpreted as threatening, and individuals lack the inhibitory control needed to respond adaptively [1]. The findings presented here suggest that CES may be a useful supplemental treatment method to improve the ability of children and adolescents to adapt to changes in their environment, appropriately perceive and respond to sensory stimuli, and regulate feelings of anxiety and anxiety behaviors.

This study was open-label and did not employ a randomized double-blinded sham-control experimental design, which naturally limits the conclusions that can be drawn about the effects of CES specifically. For example, it is possible that the effects we observed could be attributed to placebo or other subjective biases. Furthermore, it is difficult to draw conclusions about the prevalence of adverse effects from this CES trial without a sham control group. This limitation is partially offset by the fact that we examined real-life applications of CES within the context of clinical care for a large sample of participants, suggesting that it is feasible to use this type of neuromodulation routinely as an adjunct to other treatments and therapies. However, a more rigorous randomized controlled trial would, of course, be necessary to support the evidence-based use of CES as an efficacious treatment modality.

This study would have been strengthened by the inclusion of remote monitoring to reduce participant attrition and increase compliance with the protocol. On the other hand, the results suggest that CES may be beneficial even assuming an “intent-to-treat” type of analysis which may more closely reflect the vicissitudes of clinical care. Another drawback of this study is the lack of self-report or direct observation to evaluate CES treatment efficacy and adverse effects. In other words, our estimates of tolerability and benefit based on caregiver report may not accurately reflect the experiences of children participating in the trial. Finally, this research study would have been strengthened by including a delayed follow-up survey to investigate whether the positive effects endure past the treatment timeframe.

Overall, the current study’s findings provide justification for future research on the use of CES therapy in children, adolescents, and young adults with neurobehavioral symptoms. Ideally, this would take the form of a sham-controlled, double-blinded, randomized clinical trial.

The current study demonstrated acceptable adherence, generally good tolerance, and moderate satisfaction with CES usage. Further, we showed the positive effects of CES usage on behavioral regulation in individuals with neurodevelopmental differences. This study warrants future research using CES in children and adolescents as an adjunct to existing therapeutic options.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

EJM, KAS, and NH designed the research study. MG and EJM performed the research. ABA analyzed the data and contributed to writing the original draft. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was approved by the WIRB-Copernicus Group Institutional Review Board (protocol #20192706). Written informed consent from parents or caregivers, and assent from minor participants was collected prior to enrollment.

We thank the individuals who gave their time to take part in the study and Dr. Mary Steele for her contribution in protocol refinement and recruitment as well as the Cortica Medical Administration team for supporting the project.

This research received no external funding.

ABA, MG, EJM, NH, and KAS are employed by Cortica and EJM, NH, and KAS have an equity stake in Cortica. All authors declare no conflict of interest.