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ScienceDirect Comprehensive Psychiatry 60 (2015) 99 – 104 www.elsevier.com/locate/comppsych
The effects of brain wave vibration on oxidative stress response and psychological symptoms Do-Hyeong Lee a , Hye Yoon Park a , Ul Soon Lee d , Kyung-Jun Lee a , Eun Chung Noh c , Joon Hwan Jang a , Do-Hyung Kang a, b,⁎ a
Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea c Interdisciplinary Program of Neuroscience, Seoul National University, Seoul, Republic of Korea d Global Cyber University, Cheonan, Republic of Korea b
Abstract Objective: Brain Wave Vibration (BWV) training is a simple healing practice, a kind of Mind Body Training. This study was designed to investigate the psycho-endocrine differences between BMV practitioners and naïve controls. Methods: The experimental group included 54 individuals who had participated in BWV. The control group included 58 subjects who had not participated in formal BWV. Levels of plasma NO, reactive oxygen species (ROS), and superoxide dismutase (SOD) were measured, and the modified form of the Stress Response Inventory (SRI-MF), the Positive Affect and Negative Affect Scale (PANAS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI) were administered. Results: The BWV group demonstrated significantly higher plasma NO levels (p=0.003), and levels of ROS and SOD did not differ between the two groups. The BWV group showed lower scores in BDI (p=0.009), BAI (p=0.009) and stress level (pb0.001) and higher scores on positive affect (p=0.023) compared with the control group. NO levels were associated with increased positive affect (p = 0.024) only in BWV subjects. Conclusion: BWV may increase NO, a relaxation-related factor, possibly by improving emotional state. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Oxidative stress is associated with stress, aging, and various diseases [1,2]. This is caused primarily by an imbalance between the activities of nitric oxide (NO), reactive oxygen species (ROS) and anti-oxidative enzymes such as superoxide dismutase (SOD) [3]. Oxidative stress leads to inhibition of NO synthase [4]. NO is a key cellular signaling molecule associated with homeostasis and the immune response [4–6]. A previous study showed that serum NO levels were significantly lower in a group with hypertension compared with a sham group [7], and unpredictable chronic mild stress attenuated arterial NO production but increased H2O2 production [8]. It has also
⁎ Corresponding author at: Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, Korea, 110–744. Tel.: +82 2 2072 0690; fax: +82 2 744 7241. E-mail address: [email protected] (D.-H. Kang). http://dx.doi.org/10.1016/j.comppsych.2015.03.003 0010-440X/© 2015 Elsevier Inc. All rights reserved.
been suggested that the relaxation response mediated by NO explains its clinical effects in stress-related disorders [9]. NO binds to soluble guanylate cyclase at a diffusion-controlled rate, leading to a several-100-fold increase in the synthesis of the second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), leading to vasodilation [10]. NO may have a toxic effect when it reacts with superoxide (O2−) to form peroxynitrite (ONOO ¯) [11]. The major defense system against superoxides and peroxynitrite is a group of SODs that catalyze the dismutation of superoxide into oxygen and H2O2 [11,12]. Mammals contain three major isoforms of SOD (SOD1: Cu/ZnSOD, SOD2: MnSOD, SOD3: ecSOD) depending on the metal cofactor and each SOD is present in different cellular location, however they catalyze the same reaction [11–14]. Psychological stress has also been associated with oxidative stress. Rats subjected to the chronic mild stress paradigm showed increased oxidative stress in the submitochondrial particles of the brain [15]. Immobilization stress induced vascular oxidative stress by activating the
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angiotensin-II/AT receptor signaling pathway, thereby provoking endothelial dysfunction, which can contribute to the development of atherosclerosis and hypertension [16]. Studies have shown that meditation training significantly improves the quality of attention, promotes more positive emotional states, and leads to greater reductions in stress compared with control conditions [17,18]. It has been suggested that chronic stress increases the risk of cardiovascular events, whereas yoga and meditation have been shown to contribute to significant reductions in blood pressure and heart rate and appear to improve endothelial-dependent vasodilatation in subjects with coronary artery disease [19]. Moreover, meta-analysis of 209 mindfulness based studies showed significant clinical effects in treating anxiety and depression, and the changes were maintained at follow-up [20]. Mind body training (MBT) is also associated with physiological modifications. Previous study reported that reduced serum lipid peroxide levels is related with stress reduction after the transcendental meditation training [21]. Recently, increased dopamine and melatonin level, and reduced cortisol and norepinephrine level were proven to be associated with meditative states [22]. And a Zen meditation group showed significantly higher levels of serum nitrate + nitrite concentrations and significantly lower levels of serum malondialdehyde (MDA) than did a control group [23]. This study was designed to investigate the effect of Brain Wave Vibration (BWV) which is a kind of MBT. BWV training is an eclectic form of yoga and meditation, designed to focus on bodily sensations and facilitate relaxing the mind and releasing negative emotions in the body through natural rhythmic movements [24]. This technique includes ‘warming up’, ‘stretching’, ‘breathing control’, ‘brain wave vibration’ and ‘warm down’ step. The first step of BWV training is to consciously move the body, starting by gently shaking the head to the left and to the right. The second step involves following one’s own natural rhythm and focusing on physical sensations and vibrations, which may spread to all parts of the body. Once the vibration becomes natural and familiar, practitioners reflexively engage in the third step, characterized by an increased awareness of the movement of energy within the body [25,26]. Previously, BWV training showed significant improvement in depression and sleep latency [26]. However, few studies have focused on the relationships between NO, oxidative stress, and antioxidants and psychological constructs such as stress, positive and negative affect, depression, and anxiety in BWV training. Thus, the aim of this study was to identify the chemical and psychological differences between BWV practitioners and naive controls to elucidate the psycho-endocrine effects of BWV. 2. Methods 2.1. Subjects All subjects in the control and BWV groups participated voluntarily in this research. The control group consisted of
70 healthy subjects who had no experience of meditation, yoga, other mind body training. They were recruited from internet advertisement. The BWV group consisted of 73 subjects who were experienced practitioners of “Brain Wave Vibration” mind body training program and practiced BWV on a regular basis for more than 1 year. Twenty-five subjects (control group: 12, BWV group: 13) were excluded due to lack of plasma samples and six subjects in the BWV group were excluded due to lack of psychiatric data. A total of 58 control subjects and 54 BWV subjects completed the Positive Affect and Negative Affect Scale (PANAS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). The Structured Clinical Interview for DSM-IV—Non-patient Version was used to assess the participants’ psychiatric disorders. Participants were excluded if they had any history of psychosis, bipolar disorder, major depressive disorder, anxiety disorder, substance abuse or dependence, significant head injury, seizure disorder, or intellectual impairment which may cause biochemical changes due to medication or psychiatric symptom itself. This study was approved by the Institutional Review Board as following the ethical principles of Seoul National University Hospital, and written informed consent was obtained from all participants. The 54 subjects in the BWV group had been practicing BWV for a mean of 48.8 months (range: 13–144 months, SD: 29.2 months). 2.2. Plasma preparations and biochemical analyses Subjects were requested not to smoke or drink alcohol to prepare for the blood sampling at least 1 week before the study. Venus blood were drawn into an anticoagulant EDTA tube from control and BWV group subjects at random times during the day in a resting state; the subjects were seated at least 30 min before blood sampling. After centrifugation, the separated specimens were frozen at −80 °C until assay. NO production was assessed by Griess reagent (Sigma, G4410) [27]. Plasma was mixed with an equal volume of Griess reagent, and the mixture was loaded into a 96-well plate. After incubation at 45 °C for 40 min, the sample absorbance was measured using a plate reader using a microplate at 540 nm. The NO concentration was determined from a standard curve using NaNO2 [28]. Plasma ROS were detected using 2’,7’-dichlorofluorescein dye (Sigma, D6665). Plasma was incubated in the dark for 1 h. Total fluorescence was measured using a spectrofluorometer (Molecular Devices, Sunnyvale, CA) at an excitation wavelength of 485 nm and an emission wavelength of 538 nm. SOD activity was determined using a commercially available kit (Sigma, 19160). First, 20 μl of each plasma sample was added to each well, followed by 200 μl of WST working solution and 20 μl of enzyme working solution. After mixing, plates were incubated at 37 °C for 20 min. SOD activity was measured with a microplate reader by the absorbance at 450 nm. Enzyme activity is expressed as units per 1 ml.
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Table 1 Demographic characteristics and NO, ROS levels, and SOD activity of participants. Characteristics
Gender, n (male/female) Ages, years (mean±SD) Education level, years Duration of training, months (mean±SD) NO (μM) ROS (μM) SOD activity (unit/ml)
BWV group (n = 54)
Control group (n = 58)
25/29 26.0 ± 2.9 15.0 ± 1.7 48.8 ± 29.2 0.058 ± 0.063) 1378.2 ± 110.0 0.068 ± 0.018
34/24 25.3 ± 3.7 14.8 ± 1.5 – 0.029 ± 0.035 1381.3 ± 132.2 0.063 ± 0.021
Statistics t/x
2
0.26 −1.19 −0.81 – −3.03 0.14 −1.30
p
ES
0.132 0.238 0.422 – 0.003⁎⁎ 0.892 0.195
– – – – −0.569 0.025 −0.256
Abbreviations: ES=Effect Size (Cohen’s d). Nitric Oxide=NO, Reactive oxygen species=ROS, Superoxide dismutase=SOD. ⁎⁎ p b 0.01.
2.3. Psychological measures
3. Results
The Positive Affect and Negative Affect Scale (PANAS) [29] was used to measure positive and negative affect. This scale consists of 20 items describing different feelings and emotions in terms of 10 positive and 10 negative affective descriptors. Responses are scored on a five-point scale, with higher scores indicating more intense affect. The reliability of the Korean version PANAS scale, as measured by Cronbach’s alpha was 0.84 [30]. This study used the 22-item modified Stress Response Inventory (SRI-MF) [31] derived from the original SRI questionnaire [32] to assess the stress severity. Each question was scored on a Likert-type scale including “not at all” (0), “somewhat” (1), “moderately” (2), “very much” (3), and “absolutely” (4). The sum of scores was used to assess each subject’s stress level. The 22 questions were categorized into three simplified stress factors: somatization, depression, and anger. Cronbach’s alphas for the SRI were somatization (0.89), depression (0.88), and anger (0.87) [31]. The Beck Depression Inventory (BDI) [33], a 21-item self-report inventory, is one of the most widely used instruments for measuring the severity of depression; items are rated on a scale ranging from 0 (not at all) to 3 (severe). The ratings are then summed across items to yield an overall measure of the intensity of depression (Cronbach’s a 0.85) [34]. The Beck Anxiety Inventory (BAI) [35] is a 21-question self-report inventory that is used for measuring the severity of anxiety. Subjects rate the severity of each symptom on a four-point scale ranging from 0 (not at all) to 3 (severe). The total score, which ranges from 0 to 63, is calculated by summing the ratings for all 21 items (Cronbach’s a 0.94) [36].
No significant differences were observed between the control and BWV groups in terms of age, sex, or educational level (Table 1). Table 1 shows the mean serum levels of NO, ROS, and SOD of both groups. The BWV group exhibited higher NO levels than did the control group (p = 0.003). However, ROS production (p = 0.892) and SOD activity (p = 0.195) did not differ significantly between the control and BWV groups. As seen in Fig. 1, depressive (BDI: 4.6 ± 4.9 vs. 2.5 ± 3.6, t = 2.7, p = 0.009, Cohen’s d = 0.488) and anxiety symptoms (BAI: 5.6 ± 5.8 vs. 3.1 ± 3.9, t = 2.7, p =0.009, Cohen’s d = 0.506) were in significantly less degrees in the BWV than in the control group, and a significantly lower level of stress (SRI: 16.6 ± 12.0 vs. 6.4 ± 6.5, t = 5.4, p b 0.001, Cohen’s d = 1.057) was reported by members of the BWV group. The BWV group also had significantly higher scores for positive affect on the PANAS (29.8 ± 7.4 vs. 32.9 ± 7.1, t = −2.3, p = 0.023, Cohen’s d = −0.427), but the two groups did not differ significantly regarding negative affect (21.1 ± 6.0 vs. 20.2 ± 5.3; t = 0.87, p = 0.385, Cohen’s d = 0.159).
2.4. Statistical analysis Student’s t-test was used to analyze differences between the two groups, and Cohen’s d was calculated as an estimate of effect size. Pearson correlation analysis was used to investigate associations between NO, ROS, or SOD levels and psychological variables. P-values less than 0.05 were considered to indicate statistical significance.
Fig. 1. Differences of Clinical characteristics between BWV (N=54) and control group (N=58). Abbreviations: Positive affect (PA), Negative affect (NA), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI). Stress response inventory (SRI), *p b 0.05, **p b 0.01.
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Fig. 2. Correlations between NO levels and Positive affect in BWV group (N=54). Abbreviations: Nitric Oxide (NO), r = Pearson’s correlation coefficients, *p b 0.05, **p b 0.01.
According to the correlation analysis (Fig. 2), BWV group was significantly positively correlated with NO levels and scores for positive affect on the PANAS (r = 0.306, p = 0.024). Furthermore, in correlation analysis after removing two extreme outliers in NO level (A: 0.318 μM, B: 0.297 μM), we found more significant correlation coefficients in BWV group (r = 0.386, p = 0.005). There is no significant relationship between positive affect and ROS (r = 0.850, p = 0.540), SOD (r = −0.40, p = 0.772) levels in BWV group. The control group did not show any significant relationship between positive affect and NO (r = 0.110, p = 0.410), ROS (r= −0.183, p = 0.169), and SOD (r = 0.106, p = 0.430) levels. BDI, BAI, SRI, and negative affect did not show any significant correlation with biochemical variables in both groups. 4. Discussion Although the literature contains research about the effects of MBT on oxidative stress and antioxidants, few studies have been conducted in psycho-endocrine changes and psychological states in BWV training. Thus, our study contributes new information about differences between BWV practitioners and naïve controls in their levels of NO, oxidative stress, and antioxidants as well as psychological factors such as positive affect, BDI/BAI scores, and stress. The main findings of the present study are that 1) the BWV group demonstrated significantly higher levels of NO than did the control group; 2) depression, anxiety, and stress levels were lower and the level of positive affect was higher in BWV group; and 3) NO levels and positive emotions were significantly positively correlated in the BWV group. In this study, the BWV group showed increased levels of NO compared with the control group. This result is consistent with a previous report showing that a meditation group showed significantly higher levels of serum nitrate + nitrite concentration than did controls [23] and another study reported the increased nitric oxide levels in the breath of
meditators [37]. The mechanism of the effect of BWV on NO synthesis is unclear. One possible explanation for this finding is that continuous meditation activates the prefrontal cortex which is associated with releasing endogenous endorphin [38] and it may be coupled with constitutive NO release [39]. Another possible explanation is that NO, which is biosynthesized endogenously from L-arginine and oxygen by various nitric oxide synthase enzymes, may be associated with relaxation [40], since the NO/cGMPdependent protein kinase (cGK) pathway is now recognized as an important mediator of vasodilation [41]. However, these endocrine pathways are still speculative, which is due in part to the complexity and difficulties with analyzing methods. Thus, more longitudinal studies in order to determine the direction and mechanism between meditation and anti-oxidative process are needed. In humans, oxidative stress is involved in many diseases, including atherosclerosis [42], Parkinson's disease [43], heart failure [44], Alzheimer's disease [45], schizophrenia [46], bipolar disorder [47], and others. Common ROS include superoxide radicals, oxygen ions, and peroxides, and these reactive species can cause oxidative damage to cellular proteins, membranes and DNA [3,11]. Under normal conditions, ROS are eliminated by various antioxidant defenses. In terms of enzymatic mechanisms, superoxide dismutase (SOD), which has powerful anti-inflammatory effects [48], catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide [14]. Although we found no difference in SOD and ROS levels between both groups, these results are not unusual, and it has been suggested that SOD plays a role when superoxide concentrations are substantially elevated [13]. According to animal studies, SOD reduces blood pressure in hypertensive rats or mice, but it has no effect on the blood pressure of normal rats or mice [12,49,50]. ROS levels are regulated by the balance between ROS-generating and antioxidant enzymes, which include SOD activity [12]. Therefore, we interpret our results that ROS and SOD activity may vary depending on state, and their levels may remain constant under stable conditions like our subjects’ condition. Further detailed studies of the effect of MBT on ROS, SODs, and other antioxidant defense systems under stressful conditions are needed. We found significant differences between the two groups with regard to BDI and BAI scores, stress levels, and levels of positive affect; these symptoms were within normal limits in both groups. In addition, high NO levels were associated with an increase in positive affect. Meditation has been found in numerous studies to increase positive affect [25,51,52]. And electrophysiology study of brain reported significant increases in left anterior side activation which was previously known to be related with positive affect, in meditators group compared with the controls [52]. In this cross sectional study, we could not know the causal relationship between biochemical variables and psychological factors, however, we could speculate that the increased levels of NO may be mediated by the elevation of
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positive affect through relaxation, and the breathing techniques associated with BWV. Nevertheless, the observed alleviation of oxidative stress may have occurred as a result of another factor, such as stress management [53]. Thus, further study is needed considering duration of training, various biochemical factors, psychological tests and other variables. Meditation has been associated with alleviation of oxidative stress and improvement in antioxidant systems. [53] These results suggest that MBT may exert therapeutic effects on various diseases associated with oxidative stress through increasing NO levels and antioxidant enzymes. In particular, the reduction in stress and the increase in positive affect through BWV would be expected to contribute to the ability of alternative and complementary therapies to reduce oxidative stress in the treatment of many diseases. However, several important limitations exist. First, this study used a crosssectional design and did not confirm the psycho-endocrine changes after training. Thus, a longitudinal study investigating the same people over a longer period of time, including both before and after starting BWV, is required to confirm our findings. And also randomized controlled study is needed to avoid self-selection bias. Second, we had no way of assessing the qualitative/quantitative data to evaluate the efficacy of the BWV. If the training period was identified, we could assess whether duration of training has any impact on the psycho-endocrine status. And use of questionnaire to check BWV frequency or assessment after scheduled training would allow for better assessment of the quality of BWV. Third, even though we tried to restrict smoking and alcohol prior to blood sampling in control group, we could not guarantee that this instruction was obeyed fully. It is important to note that numerous pathophysiologies, including cigarette smoking and drinking, are associated with a biological activity of oxidative process [12]. Thus, controlling these confounders study should be considered in the future study. Finally, mechanisms by which BWV achieves a therapeutic benefit on oxidative stress are not understood. Randomized and multifactorial researches are needed to suggest basic biochemical, psychological evidences of meditation. 5. Conclusions In conclusion, BWV which is a kind of MBT may increase NO levels, which elicit relaxation through increases in positive affect. These findings suggest that the positive affect elicited by BWV can protect the body from various diseases related to oxidative stress, thereby reflecting the close interactions between mind and body. Acknowledgment This research was supported by Grant Nos. 04-2010-0480 and 04-2012-0790 from the Seoul National University Hospital Research Funds. The Seoul National University Hospital had no further role in study design; in the collection,
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analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Liu J, Mori A. Stress, aging, and brain oxidative damage. Neurochem Res 1999;24(11):1479-97. [2] Konishi T. Brain oxidative stress as basic target of antioxidant traditional oriental medicines. Neurochem Res 2009;34(4):711-6. [3] Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch Eur J Physiol 2010;459(6):923-39. [4] Sun J, Druhan LJ, Zweier JL. Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production. Arch Biochem Biophys 2010;494(2):130-7. [5] Wolin MS. Reactive Oxygen Species and Nitric Oxide in Vascular Function. Studies on Pediatric Disorders. Springer; 2014 p.15-33. [6] Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 2013;60:1-4. [7] Khazaei M, Zarei M, Sharifi MR, Pourshanazari AA. Effect of hypertension and its reverse on serum nitric oxide concentration and vascular permeability in two-kidney one-clip hypertensive rats. Gen Physiol Biophys 2011;30(2):115. [8] d'Audiffret AC, Frisbee SJ, Stapleton PA, Goodwill AG, Isingrini E, Frisbee JC. Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease? J Appl Physiol 2010;108(5):1041-51. [9] Dusek JA, Benson H. Mind-body medicine: a model of the comparative clinical impact of the acute stress and relaxation responses. Minn Med 2009;92(5):47. [10] Derbyshire ER, Marletta MA. Biochemistry of soluble guanylate cyclase. cGMP: Generators, Effectors and Therapeutic Implications. Springer; 200917-31. [11] Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol Cell Physiol 1996;40(5):C1424. [12] Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011;15(6):1583-606. [13] Imlay JA. What biological purpose is served by superoxide reductase? J Biol Inorg Chem 2002;7(6):659-63. [14] Van Raamsdonk JM, Hekimi S. Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci 2012;109(15):5785-90. [15] Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, et al. Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res 2009;43(9):864-9. [16] Chung I-M, Kim Y-M, Yoo M-H, Shin M-K, Kim C-K, Suh SH. Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. Atherosclerosis 2010;213(1):109-14. [17] Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in meditation. Trends Cogn Sci 2008;12(4):163-9. [18] Peterson LG, Pbert L. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 1992;149:936-43. [19] Sivasankaran S, Pollard‐Quintner S, Sachdeva R, Pugeda J, Hoq SM, Zarich SW. The effect of a six‐week program of yoga and meditation on brachial artery reactivity: Do psychosocial interventions affect vascular tone? Clin Cardiol 2006;29(9):393-8. [20] Khoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, et al. Mindfulness-based therapy: A comprehensive meta-analysis. Clin Psychol Rev 2013;33(6):763-71.
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ScienceDirect Comprehensive Psychiatry 60 (2015) 99 – 104 www.elsevier.com/locate/comppsych
The effects of brain wave vibration on oxidative stress response and psychological symptoms Do-Hyeong Lee a , Hye Yoon Park a , Ul Soon Lee d , Kyung-Jun Lee a , Eun Chung Noh c , Joon Hwan Jang a , Do-Hyung Kang a, b,⁎ a
Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea c Interdisciplinary Program of Neuroscience, Seoul National University, Seoul, Republic of Korea d Global Cyber University, Cheonan, Republic of Korea b
Abstract Objective: Brain Wave Vibration (BWV) training is a simple healing practice, a kind of Mind Body Training. This study was designed to investigate the psycho-endocrine differences between BMV practitioners and naïve controls. Methods: The experimental group included 54 individuals who had participated in BWV. The control group included 58 subjects who had not participated in formal BWV. Levels of plasma NO, reactive oxygen species (ROS), and superoxide dismutase (SOD) were measured, and the modified form of the Stress Response Inventory (SRI-MF), the Positive Affect and Negative Affect Scale (PANAS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI) were administered. Results: The BWV group demonstrated significantly higher plasma NO levels (p=0.003), and levels of ROS and SOD did not differ between the two groups. The BWV group showed lower scores in BDI (p=0.009), BAI (p=0.009) and stress level (pb0.001) and higher scores on positive affect (p=0.023) compared with the control group. NO levels were associated with increased positive affect (p = 0.024) only in BWV subjects. Conclusion: BWV may increase NO, a relaxation-related factor, possibly by improving emotional state. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Oxidative stress is associated with stress, aging, and various diseases [1,2]. This is caused primarily by an imbalance between the activities of nitric oxide (NO), reactive oxygen species (ROS) and anti-oxidative enzymes such as superoxide dismutase (SOD) [3]. Oxidative stress leads to inhibition of NO synthase [4]. NO is a key cellular signaling molecule associated with homeostasis and the immune response [4–6]. A previous study showed that serum NO levels were significantly lower in a group with hypertension compared with a sham group [7], and unpredictable chronic mild stress attenuated arterial NO production but increased H2O2 production [8]. It has also
⁎ Corresponding author at: Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, Korea, 110–744. Tel.: +82 2 2072 0690; fax: +82 2 744 7241. E-mail address: [email protected] (D.-H. Kang). http://dx.doi.org/10.1016/j.comppsych.2015.03.003 0010-440X/© 2015 Elsevier Inc. All rights reserved.
been suggested that the relaxation response mediated by NO explains its clinical effects in stress-related disorders [9]. NO binds to soluble guanylate cyclase at a diffusion-controlled rate, leading to a several-100-fold increase in the synthesis of the second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), leading to vasodilation [10]. NO may have a toxic effect when it reacts with superoxide (O2−) to form peroxynitrite (ONOO ¯) [11]. The major defense system against superoxides and peroxynitrite is a group of SODs that catalyze the dismutation of superoxide into oxygen and H2O2 [11,12]. Mammals contain three major isoforms of SOD (SOD1: Cu/ZnSOD, SOD2: MnSOD, SOD3: ecSOD) depending on the metal cofactor and each SOD is present in different cellular location, however they catalyze the same reaction [11–14]. Psychological stress has also been associated with oxidative stress. Rats subjected to the chronic mild stress paradigm showed increased oxidative stress in the submitochondrial particles of the brain [15]. Immobilization stress induced vascular oxidative stress by activating the
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angiotensin-II/AT receptor signaling pathway, thereby provoking endothelial dysfunction, which can contribute to the development of atherosclerosis and hypertension [16]. Studies have shown that meditation training significantly improves the quality of attention, promotes more positive emotional states, and leads to greater reductions in stress compared with control conditions [17,18]. It has been suggested that chronic stress increases the risk of cardiovascular events, whereas yoga and meditation have been shown to contribute to significant reductions in blood pressure and heart rate and appear to improve endothelial-dependent vasodilatation in subjects with coronary artery disease [19]. Moreover, meta-analysis of 209 mindfulness based studies showed significant clinical effects in treating anxiety and depression, and the changes were maintained at follow-up [20]. Mind body training (MBT) is also associated with physiological modifications. Previous study reported that reduced serum lipid peroxide levels is related with stress reduction after the transcendental meditation training [21]. Recently, increased dopamine and melatonin level, and reduced cortisol and norepinephrine level were proven to be associated with meditative states [22]. And a Zen meditation group showed significantly higher levels of serum nitrate + nitrite concentrations and significantly lower levels of serum malondialdehyde (MDA) than did a control group [23]. This study was designed to investigate the effect of Brain Wave Vibration (BWV) which is a kind of MBT. BWV training is an eclectic form of yoga and meditation, designed to focus on bodily sensations and facilitate relaxing the mind and releasing negative emotions in the body through natural rhythmic movements [24]. This technique includes ‘warming up’, ‘stretching’, ‘breathing control’, ‘brain wave vibration’ and ‘warm down’ step. The first step of BWV training is to consciously move the body, starting by gently shaking the head to the left and to the right. The second step involves following one’s own natural rhythm and focusing on physical sensations and vibrations, which may spread to all parts of the body. Once the vibration becomes natural and familiar, practitioners reflexively engage in the third step, characterized by an increased awareness of the movement of energy within the body [25,26]. Previously, BWV training showed significant improvement in depression and sleep latency [26]. However, few studies have focused on the relationships between NO, oxidative stress, and antioxidants and psychological constructs such as stress, positive and negative affect, depression, and anxiety in BWV training. Thus, the aim of this study was to identify the chemical and psychological differences between BWV practitioners and naive controls to elucidate the psycho-endocrine effects of BWV. 2. Methods 2.1. Subjects All subjects in the control and BWV groups participated voluntarily in this research. The control group consisted of
70 healthy subjects who had no experience of meditation, yoga, other mind body training. They were recruited from internet advertisement. The BWV group consisted of 73 subjects who were experienced practitioners of “Brain Wave Vibration” mind body training program and practiced BWV on a regular basis for more than 1 year. Twenty-five subjects (control group: 12, BWV group: 13) were excluded due to lack of plasma samples and six subjects in the BWV group were excluded due to lack of psychiatric data. A total of 58 control subjects and 54 BWV subjects completed the Positive Affect and Negative Affect Scale (PANAS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). The Structured Clinical Interview for DSM-IV—Non-patient Version was used to assess the participants’ psychiatric disorders. Participants were excluded if they had any history of psychosis, bipolar disorder, major depressive disorder, anxiety disorder, substance abuse or dependence, significant head injury, seizure disorder, or intellectual impairment which may cause biochemical changes due to medication or psychiatric symptom itself. This study was approved by the Institutional Review Board as following the ethical principles of Seoul National University Hospital, and written informed consent was obtained from all participants. The 54 subjects in the BWV group had been practicing BWV for a mean of 48.8 months (range: 13–144 months, SD: 29.2 months). 2.2. Plasma preparations and biochemical analyses Subjects were requested not to smoke or drink alcohol to prepare for the blood sampling at least 1 week before the study. Venus blood were drawn into an anticoagulant EDTA tube from control and BWV group subjects at random times during the day in a resting state; the subjects were seated at least 30 min before blood sampling. After centrifugation, the separated specimens were frozen at −80 °C until assay. NO production was assessed by Griess reagent (Sigma, G4410) [27]. Plasma was mixed with an equal volume of Griess reagent, and the mixture was loaded into a 96-well plate. After incubation at 45 °C for 40 min, the sample absorbance was measured using a plate reader using a microplate at 540 nm. The NO concentration was determined from a standard curve using NaNO2 [28]. Plasma ROS were detected using 2’,7’-dichlorofluorescein dye (Sigma, D6665). Plasma was incubated in the dark for 1 h. Total fluorescence was measured using a spectrofluorometer (Molecular Devices, Sunnyvale, CA) at an excitation wavelength of 485 nm and an emission wavelength of 538 nm. SOD activity was determined using a commercially available kit (Sigma, 19160). First, 20 μl of each plasma sample was added to each well, followed by 200 μl of WST working solution and 20 μl of enzyme working solution. After mixing, plates were incubated at 37 °C for 20 min. SOD activity was measured with a microplate reader by the absorbance at 450 nm. Enzyme activity is expressed as units per 1 ml.
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Table 1 Demographic characteristics and NO, ROS levels, and SOD activity of participants. Characteristics
Gender, n (male/female) Ages, years (mean±SD) Education level, years Duration of training, months (mean±SD) NO (μM) ROS (μM) SOD activity (unit/ml)
BWV group (n = 54)
Control group (n = 58)
25/29 26.0 ± 2.9 15.0 ± 1.7 48.8 ± 29.2 0.058 ± 0.063) 1378.2 ± 110.0 0.068 ± 0.018
34/24 25.3 ± 3.7 14.8 ± 1.5 – 0.029 ± 0.035 1381.3 ± 132.2 0.063 ± 0.021
Statistics t/x
2
0.26 −1.19 −0.81 – −3.03 0.14 −1.30
p
ES
0.132 0.238 0.422 – 0.003⁎⁎ 0.892 0.195
– – – – −0.569 0.025 −0.256
Abbreviations: ES=Effect Size (Cohen’s d). Nitric Oxide=NO, Reactive oxygen species=ROS, Superoxide dismutase=SOD. ⁎⁎ p b 0.01.
2.3. Psychological measures
3. Results
The Positive Affect and Negative Affect Scale (PANAS) [29] was used to measure positive and negative affect. This scale consists of 20 items describing different feelings and emotions in terms of 10 positive and 10 negative affective descriptors. Responses are scored on a five-point scale, with higher scores indicating more intense affect. The reliability of the Korean version PANAS scale, as measured by Cronbach’s alpha was 0.84 [30]. This study used the 22-item modified Stress Response Inventory (SRI-MF) [31] derived from the original SRI questionnaire [32] to assess the stress severity. Each question was scored on a Likert-type scale including “not at all” (0), “somewhat” (1), “moderately” (2), “very much” (3), and “absolutely” (4). The sum of scores was used to assess each subject’s stress level. The 22 questions were categorized into three simplified stress factors: somatization, depression, and anger. Cronbach’s alphas for the SRI were somatization (0.89), depression (0.88), and anger (0.87) [31]. The Beck Depression Inventory (BDI) [33], a 21-item self-report inventory, is one of the most widely used instruments for measuring the severity of depression; items are rated on a scale ranging from 0 (not at all) to 3 (severe). The ratings are then summed across items to yield an overall measure of the intensity of depression (Cronbach’s a 0.85) [34]. The Beck Anxiety Inventory (BAI) [35] is a 21-question self-report inventory that is used for measuring the severity of anxiety. Subjects rate the severity of each symptom on a four-point scale ranging from 0 (not at all) to 3 (severe). The total score, which ranges from 0 to 63, is calculated by summing the ratings for all 21 items (Cronbach’s a 0.94) [36].
No significant differences were observed between the control and BWV groups in terms of age, sex, or educational level (Table 1). Table 1 shows the mean serum levels of NO, ROS, and SOD of both groups. The BWV group exhibited higher NO levels than did the control group (p = 0.003). However, ROS production (p = 0.892) and SOD activity (p = 0.195) did not differ significantly between the control and BWV groups. As seen in Fig. 1, depressive (BDI: 4.6 ± 4.9 vs. 2.5 ± 3.6, t = 2.7, p = 0.009, Cohen’s d = 0.488) and anxiety symptoms (BAI: 5.6 ± 5.8 vs. 3.1 ± 3.9, t = 2.7, p =0.009, Cohen’s d = 0.506) were in significantly less degrees in the BWV than in the control group, and a significantly lower level of stress (SRI: 16.6 ± 12.0 vs. 6.4 ± 6.5, t = 5.4, p b 0.001, Cohen’s d = 1.057) was reported by members of the BWV group. The BWV group also had significantly higher scores for positive affect on the PANAS (29.8 ± 7.4 vs. 32.9 ± 7.1, t = −2.3, p = 0.023, Cohen’s d = −0.427), but the two groups did not differ significantly regarding negative affect (21.1 ± 6.0 vs. 20.2 ± 5.3; t = 0.87, p = 0.385, Cohen’s d = 0.159).
2.4. Statistical analysis Student’s t-test was used to analyze differences between the two groups, and Cohen’s d was calculated as an estimate of effect size. Pearson correlation analysis was used to investigate associations between NO, ROS, or SOD levels and psychological variables. P-values less than 0.05 were considered to indicate statistical significance.
Fig. 1. Differences of Clinical characteristics between BWV (N=54) and control group (N=58). Abbreviations: Positive affect (PA), Negative affect (NA), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI). Stress response inventory (SRI), *p b 0.05, **p b 0.01.
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Fig. 2. Correlations between NO levels and Positive affect in BWV group (N=54). Abbreviations: Nitric Oxide (NO), r = Pearson’s correlation coefficients, *p b 0.05, **p b 0.01.
According to the correlation analysis (Fig. 2), BWV group was significantly positively correlated with NO levels and scores for positive affect on the PANAS (r = 0.306, p = 0.024). Furthermore, in correlation analysis after removing two extreme outliers in NO level (A: 0.318 μM, B: 0.297 μM), we found more significant correlation coefficients in BWV group (r = 0.386, p = 0.005). There is no significant relationship between positive affect and ROS (r = 0.850, p = 0.540), SOD (r = −0.40, p = 0.772) levels in BWV group. The control group did not show any significant relationship between positive affect and NO (r = 0.110, p = 0.410), ROS (r= −0.183, p = 0.169), and SOD (r = 0.106, p = 0.430) levels. BDI, BAI, SRI, and negative affect did not show any significant correlation with biochemical variables in both groups. 4. Discussion Although the literature contains research about the effects of MBT on oxidative stress and antioxidants, few studies have been conducted in psycho-endocrine changes and psychological states in BWV training. Thus, our study contributes new information about differences between BWV practitioners and naïve controls in their levels of NO, oxidative stress, and antioxidants as well as psychological factors such as positive affect, BDI/BAI scores, and stress. The main findings of the present study are that 1) the BWV group demonstrated significantly higher levels of NO than did the control group; 2) depression, anxiety, and stress levels were lower and the level of positive affect was higher in BWV group; and 3) NO levels and positive emotions were significantly positively correlated in the BWV group. In this study, the BWV group showed increased levels of NO compared with the control group. This result is consistent with a previous report showing that a meditation group showed significantly higher levels of serum nitrate + nitrite concentration than did controls [23] and another study reported the increased nitric oxide levels in the breath of
meditators [37]. The mechanism of the effect of BWV on NO synthesis is unclear. One possible explanation for this finding is that continuous meditation activates the prefrontal cortex which is associated with releasing endogenous endorphin [38] and it may be coupled with constitutive NO release [39]. Another possible explanation is that NO, which is biosynthesized endogenously from L-arginine and oxygen by various nitric oxide synthase enzymes, may be associated with relaxation [40], since the NO/cGMPdependent protein kinase (cGK) pathway is now recognized as an important mediator of vasodilation [41]. However, these endocrine pathways are still speculative, which is due in part to the complexity and difficulties with analyzing methods. Thus, more longitudinal studies in order to determine the direction and mechanism between meditation and anti-oxidative process are needed. In humans, oxidative stress is involved in many diseases, including atherosclerosis [42], Parkinson's disease [43], heart failure [44], Alzheimer's disease [45], schizophrenia [46], bipolar disorder [47], and others. Common ROS include superoxide radicals, oxygen ions, and peroxides, and these reactive species can cause oxidative damage to cellular proteins, membranes and DNA [3,11]. Under normal conditions, ROS are eliminated by various antioxidant defenses. In terms of enzymatic mechanisms, superoxide dismutase (SOD), which has powerful anti-inflammatory effects [48], catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide [14]. Although we found no difference in SOD and ROS levels between both groups, these results are not unusual, and it has been suggested that SOD plays a role when superoxide concentrations are substantially elevated [13]. According to animal studies, SOD reduces blood pressure in hypertensive rats or mice, but it has no effect on the blood pressure of normal rats or mice [12,49,50]. ROS levels are regulated by the balance between ROS-generating and antioxidant enzymes, which include SOD activity [12]. Therefore, we interpret our results that ROS and SOD activity may vary depending on state, and their levels may remain constant under stable conditions like our subjects’ condition. Further detailed studies of the effect of MBT on ROS, SODs, and other antioxidant defense systems under stressful conditions are needed. We found significant differences between the two groups with regard to BDI and BAI scores, stress levels, and levels of positive affect; these symptoms were within normal limits in both groups. In addition, high NO levels were associated with an increase in positive affect. Meditation has been found in numerous studies to increase positive affect [25,51,52]. And electrophysiology study of brain reported significant increases in left anterior side activation which was previously known to be related with positive affect, in meditators group compared with the controls [52]. In this cross sectional study, we could not know the causal relationship between biochemical variables and psychological factors, however, we could speculate that the increased levels of NO may be mediated by the elevation of
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positive affect through relaxation, and the breathing techniques associated with BWV. Nevertheless, the observed alleviation of oxidative stress may have occurred as a result of another factor, such as stress management [53]. Thus, further study is needed considering duration of training, various biochemical factors, psychological tests and other variables. Meditation has been associated with alleviation of oxidative stress and improvement in antioxidant systems. [53] These results suggest that MBT may exert therapeutic effects on various diseases associated with oxidative stress through increasing NO levels and antioxidant enzymes. In particular, the reduction in stress and the increase in positive affect through BWV would be expected to contribute to the ability of alternative and complementary therapies to reduce oxidative stress in the treatment of many diseases. However, several important limitations exist. First, this study used a crosssectional design and did not confirm the psycho-endocrine changes after training. Thus, a longitudinal study investigating the same people over a longer period of time, including both before and after starting BWV, is required to confirm our findings. And also randomized controlled study is needed to avoid self-selection bias. Second, we had no way of assessing the qualitative/quantitative data to evaluate the efficacy of the BWV. If the training period was identified, we could assess whether duration of training has any impact on the psycho-endocrine status. And use of questionnaire to check BWV frequency or assessment after scheduled training would allow for better assessment of the quality of BWV. Third, even though we tried to restrict smoking and alcohol prior to blood sampling in control group, we could not guarantee that this instruction was obeyed fully. It is important to note that numerous pathophysiologies, including cigarette smoking and drinking, are associated with a biological activity of oxidative process [12]. Thus, controlling these confounders study should be considered in the future study. Finally, mechanisms by which BWV achieves a therapeutic benefit on oxidative stress are not understood. Randomized and multifactorial researches are needed to suggest basic biochemical, psychological evidences of meditation. 5. Conclusions In conclusion, BWV which is a kind of MBT may increase NO levels, which elicit relaxation through increases in positive affect. These findings suggest that the positive affect elicited by BWV can protect the body from various diseases related to oxidative stress, thereby reflecting the close interactions between mind and body. Acknowledgment This research was supported by Grant Nos. 04-2010-0480 and 04-2012-0790 from the Seoul National University Hospital Research Funds. The Seoul National University Hospital had no further role in study design; in the collection,
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analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Liu J, Mori A. Stress, aging, and brain oxidative damage. Neurochem Res 1999;24(11):1479-97. [2] Konishi T. Brain oxidative stress as basic target of antioxidant traditional oriental medicines. Neurochem Res 2009;34(4):711-6. [3] Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch Eur J Physiol 2010;459(6):923-39. [4] Sun J, Druhan LJ, Zweier JL. Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production. Arch Biochem Biophys 2010;494(2):130-7. [5] Wolin MS. Reactive Oxygen Species and Nitric Oxide in Vascular Function. Studies on Pediatric Disorders. Springer; 2014 p.15-33. [6] Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 2013;60:1-4. [7] Khazaei M, Zarei M, Sharifi MR, Pourshanazari AA. Effect of hypertension and its reverse on serum nitric oxide concentration and vascular permeability in two-kidney one-clip hypertensive rats. Gen Physiol Biophys 2011;30(2):115. [8] d'Audiffret AC, Frisbee SJ, Stapleton PA, Goodwill AG, Isingrini E, Frisbee JC. Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease? J Appl Physiol 2010;108(5):1041-51. [9] Dusek JA, Benson H. Mind-body medicine: a model of the comparative clinical impact of the acute stress and relaxation responses. Minn Med 2009;92(5):47. [10] Derbyshire ER, Marletta MA. Biochemistry of soluble guanylate cyclase. cGMP: Generators, Effectors and Therapeutic Implications. Springer; 200917-31. [11] Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol Cell Physiol 1996;40(5):C1424. [12] Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011;15(6):1583-606. [13] Imlay JA. What biological purpose is served by superoxide reductase? J Biol Inorg Chem 2002;7(6):659-63. [14] Van Raamsdonk JM, Hekimi S. Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci 2012;109(15):5785-90. [15] Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, et al. Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res 2009;43(9):864-9. [16] Chung I-M, Kim Y-M, Yoo M-H, Shin M-K, Kim C-K, Suh SH. Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. Atherosclerosis 2010;213(1):109-14. [17] Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in meditation. Trends Cogn Sci 2008;12(4):163-9. [18] Peterson LG, Pbert L. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry 1992;149:936-43. [19] Sivasankaran S, Pollard‐Quintner S, Sachdeva R, Pugeda J, Hoq SM, Zarich SW. The effect of a six‐week program of yoga and meditation on brachial artery reactivity: Do psychosocial interventions affect vascular tone? Clin Cardiol 2006;29(9):393-8. [20] Khoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, et al. Mindfulness-based therapy: A comprehensive meta-analysis. Clin Psychol Rev 2013;33(6):763-71.
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