Cranial electrotherapy stimulation affects mood state but not levels of peripheral neurotrophic factors or hypothalamic-pituitary-adrenal axis regulation


Roh, HT. & So, W-Y. Cranial electrotherapy stimulation affects mood state but not levels of peripheral neurotrophic factors or hypothalamic-pituitary-adrenal axis regulation. Technology and health care: Official Journal of the European Society for Engineering and Medicine. 2017; 25(3):403–412.

Funding Source, Location of Study, or Author’s Affiliation
Sports and Health Care Major, College of Humanities and Arts, Korea National University of Transportation, Chungbuk, Korea.

Alpha-Stim® 100

Key Variables
Changes in neurotrophic factors and mood.

The present study aimed to evaluate changes in the hypothalamic-pituitary-adrenal (HPA) axis response and levels of neurotrophic factors, blood cortisol, adrenocorticotropic hormone (ACTH), neurogenesis, and neuroplasticity; as well as changes in mood state, in patients undergoing Cranial Electrotherapy Stimulation (CES) therapy.

A randomized controlled trial (RCT) designed to assess changes in the HPA axis response and levels of neurotrophic factors, and changes in mood states following a period of eight weeks of treatment in a Sham comparator and Active CES group. Blood samples were collected before and following treatment and changes in mood state in both groups.

Primary Outcome Measure
Baseline and eight-week post-treatment levels of

  • Cortisol
  • Adrenocorticotropic Hormone (ACTH)
  • Brain-Derived Neurotrophic Factor (BDNF)
  • Nerve Growth Factor (NGF)

Secondary Outcome Measure
Changes in mood state were also examined at the time of blood collection using the Korean version of Profile of Mood States (KPOMS).

Key Inclusion Criteria

  • Body mass index (BMI) under 30kg/m2

Key Exclusion Criteria

  • Significant history of medical problems, drug use, or mental illness
  • Chronic diseases such as hypertension or diabetes
  • History of smoking
  • Participation in a regular exercise program in the last six months

Protocol Summary
Participants were randomly assigned to either a Sham CES group (n=25) or an Active CES group (n=25). Randomization of each group was conducted using a simple online randomization algorithm ( Anthropometric measure, blood, hormone, and neurotrophic factors were measured at baseline and eight weeks post-treatment.

  • Anthropometric measurements: Height, weight, and body composition were measured. Height was measured using a stadiometer, while weight and body composition were measured using an Inbody720 device that utilizes an eight-polar bio-impedance analysis method.
  • Blood sampling & analyses: 8 ml blood samples were collected from cardinal veins in the forehand of each participant using a 22-gauge needle, serum separator tube, and ethylenediamine tetra-acetic acid tube. Collected blood was centrifuged at 3000 rpm for 15 minutes to analyze blood levels of cortisol, ACTH, BDNF, and nerve growth factor NGF. Samples were refrigerated at −80◦C until further analysis.
  • Levels of HPA axis regulation-related hormones: Plasma cortisol and ACTH levels were analyzed via radioimmunoassay (RIA) and immunoradiometric assay (IRMA) using a Cortisol Coat-A-Count® Kit and an ACTH IRMA (CT) Kit respectively.
  • Peripheral neurotrophic factor levels: Serum BDNF and NGF levels were analyzed via sandwich enzyme-linked immunosorbent assay. A Human BDNF ELISA Kit was used to analyze levels of BDNF, while an NGF sandwich ELISA Kit was used to analyze NGF levels. Levels were quantified at 450 nm absorbance using a microplate reader.
  • Mood state: Changes in mood state were assessed using the Korean version of the Profile of Mood States (KPOMS), adapted from the original version developed by McNair et al. (1992). The questionnaire consists of 65 items scored along a five-point Likert scale and is divided into six sub-domains: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment.

Device Application Protocol
CES treatment using Alpha-Stim® 100 was conducted in 20-minute sessions, three times per week for eight weeks. Clip electrodes were attached to both earlobes of patients in the Active CES group, who received treatment with a current of 100 μA at a frequency of 0.5 Hz, according to manufacturer instructions and following the methods utilized in advanced studies by Kirsch and Nichols (2013), and Anderson et al. (2014). The same procedure was followed for the Sham CES group, though the power of device remained off.

Statistical Analysis Plan
Data are expressed as means and standard deviations (SD), and were analyzed using SPSS version 21.0. Two-way repeated-measures analyses of variance (ANOVA) were conducted to assess time and group differences in each variable. Both independent and dependent t-tests were conducted to examine significant interactions. The level of significance was set at a value of 0.05.


Fifty (50) healthy postmenopausal women were randomly assigned to either a Sham CES group (n=25) or an Active CES group (n=25).

Data Analysis
Changes in hormones associated with HPA axis regulation and neurotrophic factors following CES treatment revealed no significant differences to levels of plasma cortisol, plasma ACTH, serum BDNF, and serum NGF, or interaction between time and group following CES treatment (p>0.05).

CES (Cranial Electrotherapy Stimulation); CV (Coefficient of Variation); ACTH (Adrenocorticotropic Hormone); BDNF (Brain-Derived Neurotrophic Factor); NGF (Nerve Growth Factor).