Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Benefits and Harms of Cranial Electrical Stimulation for Chronic Painful Conditions, Depression, Anxiety, and Insomnia: A Systematic Review.

Background: Cranial electrical stimulation (CES) is increasingly popular as a treatment, yet its clinical benefit is unclear. Purpose: To review evidence about the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia. Data Sources: Several databases from inception to 10 October 2017 without language restrictions and references from experts, prior reviews, and manufacturers. Study Selection: Randomized controlled trials of CES versus usual care or sham CES that reported pain, depression, anxiety, or sleep outcomes in any language. Data Extraction: Single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. Data Synthesis: Twenty-eight articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively. Fourteen trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results. Four trials done more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES does not cause serious side effects. Limitation: Most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding. Conclusion: Evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42016023951).

Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder.

OBJECTIVES: External stimulation of the trigeminal nerve (eTNS) is an emerging neuromodulation therapy for epilepsy and depression. Preliminary studies suggest it has an excellent safety profile and is associated with significant improvements in seizures and mood. Neuroanatomical projections of the trigeminal system suggest eTNS may alter activity in structures regulating mood, anxiety, and sleep. In this proof-of-concept trial, the effects of eTNS were evaluated in adults with posttraumatic stress disorder (PTSD) and comorbid unipolar major depressive disorder (MDD) as an adjunct to pharmacotherapy for these commonly co-occurring conditions. MATERIALS AND METHODS: Twelve adults with PTSD and MDD were studied in an eight-week open outpatient trial (age 52.8 [13.7 sd], 8F:4M). Stimulation was applied to the supraorbital and supratrochlear nerves for eight hours each night as an adjunct to pharmacotherapy. Changes in symptoms were monitored using the PTSD Patient Checklist (PCL), Hamilton Depression Rating Scale (HDRS-17), Quick Inventory of Depressive Symptomatology (QIDS-C), and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). RESULTS: Over the eight weeks, eTNS treatment was associated with significant decreases in PCL (p = 0.003; median decrease of 15 points; effect size d 1.5), HDRS-17 (p < 0.001; 42% response rate, 25% remission; d 2.1), and QIDS-C scores (p < 0.001; d 1.8), as well as an improvement in quality of life (Q-LES-Q, p < 0.01). eTNS was well tolerated with few treatment emergent adverse events. CONCLUSIONS: Significant improvements in PTSD and depression severity were achieved in the eight weeks of acute eTNS treatment. This novel approach to wearable brain stimulation may have use as an adjunct to pharmacotherapy in these disorders if efficacy and tolerability are confirmed with additional studies.

An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder.

BACKGROUND: This study examined the potential feasibility and utility of trigeminal nerve stimulation (TNS) for attention-deficit/hyperactivity disorder (ADHD) in youth. METHODS: Twenty-four participants ages 7-14 with ADHD enrolled in an 8-week open trial of TNS administered nightly during sleep, and were assessed weekly with parent- and physician-completed measures of ADHD symptoms and executive functioning as well as measures of treatment compliance, adverse events, and side effects. Computerized tests of cognitive functioning were administered at baseline and weeks 4 and 8. RESULTS: Significant improvements were seen on the ADHD-IV Rating Scale (P < .0001) and parent-completed Conners Global Index (P < .0001), as well as the majority of scales on the parent-completed Behavior Rating Inventory of Executive Functioning (BRIEF). Improvements were also noted on the computerized Attention Network Task (ANT) Incongruent Reaction Time (P = .006), suggesting that TNS has positive effects on response inhibition. CONCLUSIONS: TNS therapy for youth with ADHD appears to be both feasible and without significant risk. Subjective improvements on rating scales and laboratory measures of cognition suggest a potential role for TNS in treating ADHD that merits further investigation. Future research in anticipation of designing definitive controlled efficacy trials should evaluate time to onset of TNS response and durability of treatment effects following TNS discontinuation, as well as validate an effective active sham comparator suitable for blinded studies.

Heart rate variability and treatment outcome in major depression: a pilot study.

Variations in heart rate variability (HRV) have been associated with major depressive disorder (MDD), but the relationship of baseline HRV to treatment outcome in MDD is unclear. We conducted a pilot study to examine associations between resting baseline HRV and MDD treatment outcome. We retrospectively tested several parameters of HRV in an MDD treatment study with escitalopram (ESC, N=26) to generate a model of how baseline HRV related to treatment outcome, and cross-validated the model in a separate trial of MDD treatment with Iyengar yoga (IY, N=16). Lower relative power of very low frequency (rVLF) HRV at baseline predicted improvement in depressive symptoms when adjusted for age and gender (R2>.43 and p<0.05 for both trials). Although vagal parasympathetic measures were correlated with antidepressant treatment outcome, their predictive power was not significant after adjusting for age and gender. In conclusion, baseline resting rVLF was associated with depression treatment outcome in two independent MDD treatment studies. These results should be interpreted with caution due to limited sample size, but a strength of this study is its validation of the rVLF predictor in an independent sample. rVLF merits prospective confirmation as a candidate biomarker.

Neuromodulation for depression: invasive and noninvasive (deep brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation).

Major depressive disorder is among the most disabling illnesses and, despite best practices with medication and psychotherapy, many patients remain ill even after several treatment trials. For many of these patients with treatment-resistant or pharmacoresistant depression, treatment with neuromodulation offers an alternative. Options range from systems that are implanted to others that are entirely noninvasive. This review surveys recent literature to update readers on 3 particular interventions: deep brain stimulation, transcranial magnetic stimulation, and trigeminal nerve stimulation. Additional comparative research is needed to delineate the relative advantages of these treatments, and how best to match individual patients to neuromodulation intervention.

Trigeminal nerve stimulation in major depressive disorder: acute outcomes in an open pilot study.

Most patients with major depressive disorder (MDD) do not recover with initial pharmacotherapy, and many pursue combination treatments. Combining a medication with neuromodulation offers an alternative to purely pharmacologic strategies. In prior open and double-blind controlled trials for drug-resistant epilepsy, adjunctive external trigeminal nerve stimulation (eTNS) was found to be safe and well tolerated, to significantly reduce seizures, and to be associated with an improvement in depressive symptoms. Here, we present a comprehensive description of the first open pilot investigation in MDD. In this 8-week trial, eleven adults with unipolar MDD received nightly stimulation (V(1) branch). All entered with moderate to severe symptom levels despite at least two antidepressant medication trials in this episode. All the eleven adults completed the acute trial, without serious adverse events. Symptoms of depression improved significantly, whether assessed with clinician- or self-rated scales (all p < 0.01; effect sizes d 1.0-1.8), as did quality of life (p < 0.02). Four of the 11 achieved remission. These improvements from nightly adjunctive eTNS in treatment-resistant depression merit replication under double-blind conditions.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy.

OBJECTIVE: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Trigeminal nerve stimulation: seminal animal and human studies for epilepsy and depression.

The unique ability to stimulate bilaterally, extracranially, and non-invasively may represent a significant advantage to invasive neuromodulation therapies. In humans thus far the technique has been applied noninvasively, and is termed external trigeminal nerve stimulation (eTNSTM).

Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial.

Modulation of brain activity via trigeminal nerve stimulation is an emerging therapy in drug-resistant epilepsy. This cranial nerve also projects to structures implicated in depression (such as the nucleus tractus solitarius and locus coeruleus). We examined the effects of external trigeminal nerve stimulation in major depressive disorder as an adjunct to pharmacotherapy. Five adults (mean age 49.6, SD 10.9, three females and two males) participated in an 8-week open-label outpatient trial; all had persistent symptoms despite adequate pharmacotherapy, with a mean score on the 28-item Hamilton Depression Rating Scale of 25.4 (SD=3.9) at entry. Nightly stimulation over the V(1) branch was well tolerated. Both the clinician-rated 28-item Hamilton Depression Rating Scale (P=0.006) and the self-rated Beck Depression Inventory (P=0.0004) detected significant symptomatic improvement. This novel neuromodulation approach may have use as an adjunct to pharmacotherapy in major depressive disorder. Additional larger trials are needed to delineate efficacy and tolerability with greater reliability.

Yoga as a complementary treatment of depression: effects of traits and moods on treatment outcome.

Preliminary findings support the potential of yoga as a complementary treatment of depressed patients who are taking anti-depressant medications but who are only in partial remission. The purpose of this article is to present further data on the intervention, focusing on individual differences in psychological, emotional and biological processes affecting treatment outcome. Twenty-seven women and 10 men were enrolled in the study, of whom 17 completed the intervention and pre- and post-intervention assessment data. The intervention consisted of 20 classes led by senior Iyengar yoga teachers, in three courses of 20 yoga classes each. All participants were diagnosed with unipolar major depression in partial remission. Psychological and biological characteristics were assessed pre- and post-intervention, and participants rated their mood states before and after each class. Significant reductions were shown for depression, anger, anxiety, neurotic symptoms and low frequency heart rate variability in the 17 completers. Eleven out of these completers achieved remission levels post-intervention. Participants who remitted differed from the non-remitters at intake on several traits and on physiological measures indicative of a greater capacity for emotional regulation. Moods improved from before to after the yoga classes. Yoga appears to be a promising intervention for depression; it is cost-effective and easy to implement. It produces many beneficial emotional, psychological and biological effects, as supported by observations in this study. The physiological methods are especially useful as they provide objective markers of the processes and effectiveness of treatment. These observations may help guide further clinical application of yoga in depression and other mental health disorders, and future research on the processes and mechanisms.