Therapeutic Effect of Neuromodulation on Anxiety Disorders by High-Definition Transcranial Electrical Stimulation

Overview

High-definition transcranial electrical stimulation (HD-tES) is a non-invasive brain neuromodulation technique that applies a small electrical current to the scalp to alter neural excitability and stimulate localized brain activation. Previous clinical trials have explored the use of HD-tES for treating mental health conditions such as depression, anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder. This trial aims to investigate the efficacy and safety of HD-tES in ameliorating anxiety symptoms among patients with generalized anxiety disorder (GAD), thereby validating its potential as a treatment for anxiety disorders. Participants will be randomly assigned to one of four HD-tES treatment groups: (1) HD-tES inhibitory waveform (cDC+cTBS) applied to the right dorsolateral prefrontal cortex (DLPFC) for 10 minutes, followed by sham excitatory waveform (aDC+iTBS) stimulation applied to the left DLPFC for 10 minutes. (2) Sham inhibitory waveform (cDC+cTBS) stimulation applied to the right DLPFC for 10 minutes, followed by HD-tES excitatory waveform (aDC+iTBS) applied to the left DLPFC for 10 minutes. (3) HD-tES inhibitory waveform (cDC+cTBS) applied to the right DLPFC for 10 minutes, followed by HD-tES excitatory waveform (aDC+iTBS) applied to the left DLPFC for 10 minutes. (4) Sham inhibitory waveform (cDC+cTBS) stimulation applied to the right DLPFC for 10 minutes, followed by sham excitatory waveform (aDC+iTBS) stimulation applied to the left DLPFC for 10 minutes. Regardless of the group assignment, participants will undergo treatment sessions over a 2-week period, with five sessions per week and no more than one session per day. Each session lasts approximately 20 minutes. Assessments will be conducted before the treatment, weekly during the treatment period (at the end of the first and second weeks), and a follow-up evaluation will be performed one week after the conclusion of the treatment.

Interventions

• Device HD-R_cDC+cTBS & sham-L_aDC+iTBS
  HD-tES inhibitory waveform (cDC+cTBS) applied to the right dorsolateral prefrontal cortex (DLPFC) for 10 minutes, followed by sham excitatory waveform (aDC+iTBS) stimulation applied to the left DLPFC for 10 minutes.
• Device sham-R_cDC+cTBS & HD-L_aDC+iTBS
  Sham inhibitory waveform (cDC+cTBS) stimulation applied to the right DLPFC for 10 minutes, followed by HD-tES excitatory waveform (aDC+iTBS) applied to the left DLPFC for 10 minutes.
• Device HD-R_cDC+cTBS & HD-L_aDC+iTBS
  HD-tES inhibitory waveform (cDC+cTBS) applied to the right DLPFC for 10 minutes, followed by HD-tES excitatory waveform (aDC+iTBS) applied to the left DLPFC for 10 minutes.
• Device sham-R_cDC+cTBS & sham-L_aDC+iTBS
  Sham inhibitory waveform (cDC+cTBS) stimulation applied to the right DLPFC for 10 minutes, followed by sham excitatory waveform (aDC+iTBS) stimulation applied to the left DLPFC for 10 minutes.

Primary outcome measures

• Change in severity of anxious symptoms as assessed by Hamilton Anxiety Rating Scale (HAM-A) and after intervention [Time frame: Assessments will be conducted before the treatment, weekly during the treatment period (at the end of the first and second weeks), and a follow-up evaluation will be performed one week after the conclusion of the treatment.]
• Change in state and trait anxiety as assessed by State-Trait Anxiety Inventory (STAI) after intervention [Time frame: Assessments will be conducted before the treatment, weekly during the treatment period (at the end of the first and second weeks), and a follow-up evaluation will be performed one week after the conclusion of the treatment.]

Secondary outcome measures (5)

• Change in severity of depressive symptoms as assessed by Hamilton Depression Scale (HAM-D) after intervention [Time frame: Assessments will be conducted before the treatment, weekly during the treatment period (at the end of the first and second weeks), and a follow-up evaluation will be performed one week after the conclusion of the treatment.]
• Change in sleep quality as assessed by Pittsburgh Sleep Quality Index (PSQI) after intervention [Time frame: Assessments will be conducted before the treatment, weekly during the treatment period (at the end of the first and second weeks), and a follow-up evaluation will be performed one week after the conclusion of the treatment.]
• Self-rated anxiety level as assessed by Visual Analog Scale (VAS) [Time frame: Within 3 minute after each intervention session (a total of 10 sessions, 5 sessions/week, lasting 2 weeks)]
• Heart Rate Variability (HRV) as assessed by NeXus-10MK Ⅱ [Time frame: Within 10 minutes after each intervention session (a total of 10 sessions, 5 sessions/week, lasting 2 weeks)]
• Side effects as assessed by Side Effects Questionnaire [Time frame: Within 10 minutes after each intervention session (a total of 10 sessions, 5 sessions/week, lasting 2 weeks)]

Eligibility criteria

Inclusion criteria

• Age between 18 and 65 years.
• Diagnosed with Generalized Anxiety Disorder (GAD) by a psychiatrist according to DSM-5 criteria.
• Hamilton Anxiety Rating Scale (HAM-A) score ≥ 14.
• Hamilton Depression Rating Scale (HAM-D; 17-item version) score ≤ 17.
• Has been consistently receiving psychological counseling and/or medication with stable types and dosages for at least 6 weeks prior to enrollment; or is deemed unsuitable for medication and/or psychological counseling; or refuses medication and/or psychological counseling.

Exclusion criteria

• Received rTMS or any other form of non-invasive brain stimulation techniques within 2 weeks prior to the study and during the study period.
• Presence of severe neurological disorders (e.g., stroke, brain tumor, epilepsy, organic brain diseases) or psychiatric disorders (e.g., schizophrenia and other psychotic disorders, bipolar disorder, obsessive-compulsive disorder, other types of anxiety disorders, substance abuse).
• Severe or unstable physiological conditions that may affect the autonomic or central nervous system (e.g., acute gastrointestinal diseases, cardiovascular diseases, thyroid disorders).
• History of cardiac arrhythmia.
• Presence of implanted medical electronic devices (e.g., pacemakers).
• Presence of metallic implants in the head or neck region.
• Open wounds on the scalp at the site of electrode contact.
• History of head surgery or significant head trauma that, based on physician evaluation, makes the individual unsuitable for inclusion.
• Individuals with significant suicide risk (HAM-D Item 3 score on suicidal risk ≥ 3).
• Presence of immune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases).
• Individuals with abnormal or heightened sensitivity to electrical stimulation, making them unable to tolerate it.
• Pregnancy (for female participants: must be postmenopausal or surgically sterilized. Females of childbearing potential must have a negative pregnancy test. Female participants capable of becoming pregnant and their male partners with female partners capable of becoming pregnant must agree to use effective contraception during the trial and for 4 months after the last study intervention, such as oral contraceptives, dual barrier methods, or intrauterine devices, or agree to abstain from sexual activity during this period. Non-childbearing females are defined as those who have undergone bilateral oophorectomy or are postmenopausal).
• Taking medications that lower the seizure threshold.
• Alcohol or substance abuse.
• Convexity skull defects or elevated intracranial pressure.
• Breastfeeding women.
• Other conditions deemed unsuitable for transcranial electrical stimulation based on physician evaluation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Nitsche MA, Doemkes S, Karakose T, Antal A, Liebetanz D, Lang N, Tergau F, Paulus W. Shaping the effects of transcranial direct current stimulation of the human motor cortex. J Neurophysiol. 2007 Apr;97(4):3109-17. doi: 10.1152/jn.01312.2006. Epub 2007 Jan 24. PMID 17251360
• Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000 Sep 15;527 Pt 3(Pt 3):633-9. doi: 10.1111/j.1469-7793.2000.t01-1-00633.x. PMID 10990547
• Williams JA, Imamura M, Fregni F. Updates on the use of non-invasive brain stimulation in physical and rehabilitation medicine. J Rehabil Med. 2009 Apr;41(5):305-11. doi: 10.2340/16501977-0356. PMID 19363560
• Reed T, Cohen Kadosh R. Transcranial electrical stimulation (tES) mechanisms and its effects on cortical excitability and connectivity. J Inherit Metab Dis. 2018 Jul 13;41(6):1123-30. doi: 10.1007/s10545-018-0181-4. Online ahead of print. PMID 30006770
• Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull. 2007 May 30;72(4-6):208-14. doi: 10.1016/j.brainresbull.2007.01.004. Epub 2007 Jan 24. PMID 17452283
• Polania R, Nitsche MA, Ruff CC. Studying and modifying brain function with non-invasive brain stimulation. Nat Neurosci. 2018 Feb;21(2):174-187. doi: 10.1038/s41593-017-0054-4. Epub 2018 Jan 8. PMID 29311747
• Hummel FC, Voller B, Celnik P, Floel A, Giraux P, Gerloff C, Cohen LG. Effects of brain polarization on reaction times and pinch force in chronic stroke. BMC Neurosci. 2006 Nov 3;7:73. doi: 10.1186/1471-2202-7-73. PMID 17083730
• Guleyupoglu B, Febles N, Minhas P, Hahn C, Bikson M. Reduced discomfort during high-definition transcutaneous stimulation using 6% benzocaine. Front Neuroeng. 2014 Jul 11;7:28. doi: 10.3389/fneng.2014.00028. eCollection 2014. PMID 25071548

Identifiers

NCT: NCT06775145 · 202312116DINB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗