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Transcranial direct current stimulation for the treatment of generalized anxiety disorder: A randomized clinical trial
Journal of Affective Disorders 259 (2019) 31–37
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research paper
Transcranial direct current stimulation for the treatment of generalized anxiety disorder: A randomized clinical trial
T
Ana Lucia de Limaa, Francisco Moisés Azevedo Bragab, Rodrigo Maciel Medeiros da Costab, ⁎ Elihab Pereira Gomesb, André Russowsky Brunonic,d, Rodrigo Pegadoa, a
Graduate Program in Rehabilitation Science, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil Universidade Potiguar, Rio Grande do Norte, Brazil c Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil d Department of Internal Medicine, University of São Paulo, São Paulo, Brazil b
A R T I C LE I N FO
A B S T R A C T
Keywords: Noninvasive brain stimulation Dorsolateral prefrontal cortex Depression Affectivity Stress
Background: Generalized anxiety disorder (GAD) is a common condition with current treatments being only moderately effective. Non-invasive brain stimulation techniques might provide a novel approach for treating GAD. Transcranial direct current stimulation (tDCS) has shown promising efficacy and tolerability for major depression but has not been investigated for GAD yet. Thus, we investigated the effects of tDCS on patients with GAD. Methods: We conducted a pilot, double-blind, randomized, sham-controlled trial on 30 GAD patients. Five sessions of tDCS (2 mA, 20 min, anode over the left dorsolateral prefrontal cortex and cathode over the right supraorbital cortex) were performed. Anxiety was the primary outcome and it was measured by the Hamilton Anxiety Rating Scale and the Beck Anxiety Inventory. Secondary outcomes were accessed by the Lipp Inventory of Stress Symptoms for Adults, Positive and Negative Affect Schedule, and the Beck Depression Inventory (BDI). Data were examined at baseline, after the 5th day of intervention, and at 1-week follow-up. Results: Thirty patients finished the study. There were no significant improvements in anxiety, mood symptoms of stress, affectivity or depression. Anodal stimulation of the left DLPFC showed significant improvements in physical symptoms of stress in GAD patients. Limitations: Additional tDCS sessions could have resulted in larger tDCS effects. Conclusion: Five sessions of anodal tDCS over the DLPFC did not improve the main outcomes for GAD patients, although physical symptoms of stress were improved. The role of tDCS in GAD should be explored in larger patient samples using different parameters.
1. Introduction Generalized anxiety disorder (GAD) is a prevalent psychiatric disorder with a worldwide prevalence estimated at 7.3% (Stein et al., 2017). The condition is characterized by deficits in emotional expressivity and self-regulation and is associated with impairments in quality of life (Carnevali et al., 2019; Locke et al., 2015). Its symptoms include persistent excessive anxiety and worry, sleep disturbances, tremors, muscle tension, fatigue, restlessness, irritability, palpitations, dizziness and epigastric discomfort (Locke et al., 2015; Stein et al., 2017). Although the prevalence of GAD is higher in high-income countries, its clinical course is more persistent in lower- and middleincome countries (Ruscio et al., 2017). Physical activity, selective
⁎
serotonin reuptake inhibitors, antidepressants, and psychotherapy are recommended interventions, but low adherence and adverse effects are barriers to treatment (Locke et al., 2015). The underlying mechanisms of GAD suggest a persistent activation of brain areas associated with ruminative mental activity and introspective thinking (Locke et al., 2015). Patients with GAD also exhibit autonomic dysfunction, a decrease in vagally-mediated heart rate variability, and neurostructural abnormalities of the left rostral anterior cingulate cortex, left medial orbitofrontal cortex, and right isthmus cingulate gyrus (Carnevali et al., 2019). Anxiety disorders might result from a maladaptive neuroplasticity of the prefrontal and limbic regions, with hypoactivation of the dorsolateral prefrontal cortex (DLPFC) (Ironside et al., 2018) and abnormalities in amygdala processing
Corresponding author: Faculty of Health Science of Trairi, Federal University of Rio Grande do Norte, Trairí St. 59200-000, Santa Cruz-RN, Brazil. E-mail address: [email protected] (R. Pegado).
https://doi.org/10.1016/j.jad.2019.08.020 Received 3 June 2019; Received in revised form 8 August 2019; Accepted 13 August 2019 Available online 15 August 2019 0165-0327/ Published by Elsevier B.V.
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Fig. 1. CONSORT flowchart for the study.
(Carnevali et al., 2019; Vicario et al., 2019). These findings have also been observed during symptom provocation or negative emotional processing in patients with posttraumatic stress disorder, anxiety disorders, and obsessive-compulsive disorder (Etkin and Wager, 2007). Non-pharmacological and non-invasive interventions are novel approaches that might be a feasible strategy for treatment of mental disorders (Kar and Sarkar, 2016). Recent research has focused on the mood and physical effects of transcranial direct current stimulation (tDCS) over the DLPFC, particularly to treat psychiatric disorders such as depression (Ironside et al., 2016). Recent reviews have suggested some efficacy of tDCS for acute depressive disorder and inconsistent results for anxiety disorders (Palm et al., 2016; Vicario et al., 2019). tDCS could act in mood and anxiety disorders via modulation of DLPFC activity and plasticity (Vicario et al., 2019). Stimulation of the left DLPFC might counteract the maladaptive plasticity of the cortico‑mesolimbic network in GAD by acting on mechanisms sub-served by these regions for emotional outcomes (Vicario et al., 2019). Excitatory stimulation of the left DLPFC might upregulate positive reactions to positive emotional stimuli and downregulate negative reactions to emotional stimuli (Vicario et al., 2019). The application of tDCS over the DLPFC has been suggested to work by increasing prefrontal regulation of limbic responses to negative stimuli including negative emotional processing (Ironside et al., 2016). DLPFC activity has been negatively correlated with anxiety in neuroimaging studies (Bishop et al., 2004). Despite the promising evidence regarding tDCS use in psychiatric disorders, there is no previous randomized controlled trial, to the best of our knowledge, that evaluated the use of anodal tDCS over the left DLFPC to treat GAD. In this context, we hypothesized that this montage could reduce anxiety and associated symptoms in GAD patients. We tested the effects of five consecutive sessions of tDCS using a randomized, sham-controlled trial in 30 patients with GAD. The primary aim of this study was to evaluate the effect of anodal tDCS over DLPFC on anxiety. The secondary aims were to evaluate the effect of the intervention on the level of stress, depression, and positive and negative affectivity.
Table 1 Sociodemographic and clinical variables. Variable
Active-tDCS
Sham-tDCS
p value
Age HAM-A BAI PA NA BDI ISSL Alert Resistance Exhaustion Physical symptoms Mood symptoms Total score Gender Female Male Marital status (n) Single Married Income* 1 Minimum Wage 2 –3 Minimum wage 4 Minimum wage or more Unreported Education (n) Elementary Secondary University
32.07 ± 6.5 31.47 ± 14.2 32.27 ± 17.85 21.67 ± 7.64 30.2 ± 11.6 36.87 ± 24.43
29 ± 5.05 26.93 ± 13.2 24.67 ± 11.64 24.07 ± 5.65 23.4 ± 9.22 21.53 ± 16.77
0.160 0.372 0.178 0.336 0.086 0.054
5.06 ± 3.32 5.53 ± 4.2 5.46 ± 4.51 9.2 ± 6.76 6.86 ± 5.98 28.46 ± 11.98
6.4 ± 3.29 5.8 ± 3.38 6.2 ± 4.85 10.07 ± 6.37 8.26 ± 4.83 25.33 ± 10.5
0.279 0.849 0.671 0.720 0.486 0.453 0.705
10 5
9 6
7 8
11 4
4 8 2 1
6 7 2 0
2 9 4
2 7 6
0.136
0.69
0.57
Clinical variables described with mean and standard deviation. Hamilton Anxiety Rating Scale (HAM-A); Beck Anxiety Inventory (BAI); Positive affect (PA); Negative affect (NA); Beck Depression Inventory (BDI); Lipp Inventory of Stress Symptoms for Adults (ISSL). ⁎ Brazilian National Minimum Wage, US$ 257 per month.
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2. Methods
Table 2 Result of the ANOVAs performed for each outcome measure. Variable HAM-A Time x Group Time Group BAI Time x Group Time Group PA Time x Group Time Group NA Time x Group Time Group BDI Time x Group Time Group ISSL Alert Time x Group Time Group Resistance Time x Group Time Group Exhaustion Time x Group Time Group Physical Symptoms Time x Group Time Group Mood Symptoms Time x Group Time Group Total Score Time x Group Time Group
Df
F
p
Power
pn2
2 2 1
1.400 21.050 0.03
0.255 0.0001* 0.85
0.288 1.0 0.54
0.04 0.42 0.001
2 2 1
1.462 16.897 0.493
0.24 0.0001* 0.488
0.27 0.998 0.104
0.05 0.376 0.017
2 2 1
1.077 1.541 0.06
0.337 0.223 0.809
0.207 0.280 0.056
0.037 0.052 0.002
2 2 1
2.634 15.604 0.617
0.093 0.0001* 0.439
0.996 0.449 0.118
0.358 0.086 0.022
2 2 1
1679 9.640 3.628
0.196 0.0001* 0.06
0.976 0.339 0.452
0.256 0.057 0.115
2 2 1
2.190 13.314 0.132
0.135 0.0001* 0.719
0.372 0.987 0.064
0.073 0.322 0.005
2 2 1
2.001 9.391 0.123
0.145 0.0001* 0.728
0.396 0.973 0.063
0.067 0.251 0.004
2 2 1
0.619 10.473 0.008
0.496 0,001* 0.928
0.148 0.952 0.051
0.022 0.272 0.0001
2 2 1
3.468 13.822 0.208
0,0001* 0.038* 0.652
0.99 0.552 0.073
0.33 0.11 0.007
2 2 1
1.370 16.435 0.003
0.261 0,0001* 0.958
0.248 0.997 0.0001
0.047 0.370 0.05
2 2 1
2.202 19.025 0.079
0.136 0,0001* 0.780
0.365 0.999 0.059
0.073 0.405 0.003
2.1. Participants and study design This study followed CONSORT recommendations (Schulz et al., 2010). From June 2018 to February 2019, patients were recruited in two outpatient clinics (Santa Cruz and Mossoro) located in the northeast of Brazil and treated at the Federal University of Rio Grande do Norte or the Climaf Clinic. The study was conducted by the Faculty of Health Science of Trairí, Federal University of Rio Grande do Norte and has received human study approval by the local institutional Ethical Committee (approval number 2.413.722). It has been carried out in accordance with the Declaration of Helsinki and resolution No. 466/12 of the National Health Council. The study was registered on Rebec (Brazilian platform of clinical trials) with the identifier RBR-5QJG9T. All participants provided written informed consent. Patients were selected from specialized outpatient services. Eligibility criteria were: (1) clinical diagnosis of GAD according to DSM5 (Craske et al., 2017), (2) not going through psychotherapy at the time when the study was conducted, (3) aged from 20 to 40 years, (4) not breastfeeding, (5) no history of brain surgery or brain tumor, and (6) no contraindications for tDCS, such as intracranial metal implantation. Exclusion criteria were (1) patients presenting with a history of dizziness or seizures, (2) pregnancy, and (3) signs of severity and/or indications for hospitalization or psychotherapy according to psychiatric evaluation. Patients were randomized (1:1) through a numerical sequence generated by an allocated computer using appropriate software (www. randomization.com) to assign each participant to either the active-tDCS (a-tDCS) group or the sham-tDCS group by an independent researcher who was not involved with either stimulation or assessments. Both participants and researchers involved in assessments and interventions were blinded to group allocation throughout the trial.
2.2. Interventions tDCS was delivered using a continuous electric stimulator with three energy batteries (9 V) connected in parallel. Similar devices have been used in previous studies (Okano et al., 2013; Silva-filho et al., 2018). The maximum energy output was 10 mA and was controlled by a professional digital multimeter (DT832, WeiHua Electronic Co., Ltd., China) with a standard error of ± 1.5%. Electrodes were placed into a 35 cm2 (5 cm × 7 cm) square sponge soaked in saline solution (150 mM NaCl in Milli-Q water). Rubber bandages were used to hold the
Hamilton Anxiety Rating Scale (HAM-A); Beck Anxiety Inventory (BAI); Positive affect (PA); Negative affect (NA); Beck Depression Inventory (BDI); Lipp Inventory of Stress Symptoms for Adults (ISSL). ⁎ Statistical significance result.
Fig. 2. (A): Changes in Hamilton Anxiety Rating Scale (HAM-A) over time in the 2 treatment groups. *Indicate significant difference between baseline for both groups. (B): Beck Anxiety Inventory (BAI) over time in the 2 treatment groups with significant difference in active group when compare baseline with day 5 (p = 0.002)** and follow-up (p = 0.0001)**. Variables described with mean and standard deviation. 33
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Fig. 3. Lipp Inventory of Stress Symptoms for Adults (ISSL) domains. *Denote significant difference in active group when compare with baseline. Variables described with mean and standard deviation.
described any differences between the conditions, and both groups reported experiencing the same sensation during the 30 s period. Patients rested in an armchair in a quiet and illuminated room during the sessions with no interference from the researchers.
electrodes in place for the duration of the stimulation. For electrode placement, the 10/20 EEG system with an anode electrode was used, placed over F3 for stimulation of the DLPFC, and the cathode electrode was placed over the contralateral supraorbital area (Fp2). The direct current applied was 2 mA for 20 min (2 mA/5 cm × 7 cm = 0.057 mA/ cm2). We applied 5 tDCS sessions, one per day, from Monday to Friday. For sham-tDCS, electrodes were placed at the same position as for the a-tDCS, but the current was turned off after 30 s of stimulation following previously established methods of clinical studies of brain stimulation (Gandiga et al., 2006; Lefaucheur, 2016). These methods provide the same initial sensory feelings of a-tDCS conditions, specifically, itching and tingling feelings on the scalp for the first few seconds of tDCS (Gandiga et al., 2006; Lefaucheur, 2016). No participants
2.3. Outcomes All measurements were determined while both the subject and raters were blinded to the intervention. Variables were measured one week before the beginning of the intervention (baseline), after the 5th day of intervention (T2), and 1 week after the end of the intervention period (T3). Sociodemographic characteristics (sex, age, education level, profession, marital status, and race) and clinical data (anxiety, 34
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bothered by each symptom over the past week. Responses are rated on a 4-point Likert scale and range from 0 (not at all) to 3 (severely) (Julian, 2011).
2.3.2. Secondary outcomes measures Stress was assessed per the Lipp Inventory of Stress Symptoms for Adults–ISSL (Lipp, 2000). This questionnaire aims to identify the characteristic frames of stress, making it possible to diagnose stress in adults and the stage at which the person currently is at (alert, resistance, near-exhaustion, total exhaustion). It is based on a four-phase model and proposes a method of stress evaluation that emphasizes somatic and psychological symptomatology (Lipp, 2000). Positive affect (PA) and negative affect (NA) were measured using a Positive and Negative Affect Schedule. This questionnaire has 20 items, 10 for PA and 10 for NA, and participants respond to each item on a 5point Likert-type scale (1: very slightly or not at all, 2: a little, 3: moderately, 4: quite a bit, and 5: extremely). The period adopted in this study was in ‘general’. The scores ranged from 10 to 50 for both the PA and NA (Galinha and Pais-Ribeiro, 2005; Watson and Clark, 1999). Depression was evaluated using the Beck Depression Inventory (BDI). This is a widely used self-report measure of depressive symptoms in adults and is administered across a wide range of psychological disorders (Weeks and Heimberg, 2005). BDI demonstrated good psycho-metric properties in a non-elderly adult sample of patients with GAD (Weeks and Heimberg, 2005). This is a self-report questionnaire composed of 21 items referring to cognitive symptoms and attitudes. In each item the patient chooses one or more statements that best describe how he felt in the last week (Weeks and Heimberg, 2005). The maximum score is 63 points and higher scores indicate more severe levels of depression. We monitored adverse events by asking patients about any after each session of stimulation and during the follow-up period.
2.4. Statistical analysis The sample size was determined a priori using the G-Power 3.1.9.2 (F tests ANOVA: repeated measures, within-between interactions). Sample size was estimated based on the assumption of significance of 0.05, power of 95%, and 0.35 effect size. The sample size calculation indicated 24 participants were necessary. We decided to add six additional patients to account for attrition. Thus, 30 patients were recruited and randomized into two groups of 15 patients. All subjects completed the intervention period and follow-up, i.e., there were no dropouts. Analyses were performed using Graph Pad Prism 5 and SPSS software (V.19.0, Chicago, USA). Data were expressed as means and standard deviations. The Shapiro–Wilk and Levene's test were applied to assess the normality of the distribution and homogeneity of variance of the data, respectively. Mauchly's test of sphericity was used to validate the correlation of the repeated measures, and if the assumption of sphericity was violated, the Greenhouse–Geisser correction was applied. Unpaired t tests, Mann–Whitney and Chi square tests were used to compare sociodemographic and clinical characteristics at baseline. A mixed ANOVA model was used to compare the effects of tDCS between groups on anxiety and secondary outcomes. The independent fixed variables were time (baseline, day 5, and follow-up), group of stimulation (active and sham), and the interaction term. When appropriate, post-hoc comparisons were carried out using Bonferroni correction for multiple comparisons. Partial η2 were calculated as measures of effect size in the ANOVA results (main effects and interaction effects). Partial η2 was used to calculate the effect size, where η2 = 0.01 was considered small, η2 = 0.06 moderate, and η2 = 0.14 a large effect. Statistical significance was set at p ≤ 0.05.
Fig. 4. (A) Positive affect (PA). (B) Negative affect (NA). (C) Beck Depression Inventory (BDI). *Significant difference between baseline with day 5 and follow-up only in active group.
depression, affectivity, and stress) were collected at baseline. 2.3.1. Primary outcome measure The Hamilton Anxiety Rating Scale (HAM-A), which was the primary outcome measure, and the Beck Anxiety Inventory (BAI) were used to measure anxiety symptoms. The HAM-A scale consists of 14 elements, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is scored on a basic numeric scale of 0 (not present) to 4 (severe) with a total score range of 0–56, where <17 indicates mild severity, 18–24 mild to moderate severity, and 25–30 moderate to severe (Hamilton, 1959). The BAI is a brief measure of anxiety with a focus on somatic symptoms of anxiety that was developed as a measure adept at discriminating between anxiety and depression (Julian, 2011). The BAI is administered via self-report and includes assessment of symptoms with a total of 21 items. Respondents indicate how much they have been 35
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3. Results
GAD (Shiozawa et al., 2014a). The authors performed 15 consecutive daily tDCS sessions with the cathode positioned over the right DLPFC and the anode over the contralateral deltoid with a current of 2 mA for 30 min (Shiozawa et al., 2014b). It was found there was a significant improvement of anxiety during the 15-day treatment course and a discrete improvement in depression (Shiozawa et al., 2014b). The DLPFC was chosen considering that this area is associated with mood regulation, anxiety, and emotional pain (Ironside et al., 2018). This brain area has a potential role in top-down control processes involved in mood disturbances (Ironside et al., 2016). However, although tDCS is usually employed to modulate cortical excitability in a target region, it also induces changes in interconnected regions and corticosubcortical circuits (Todder et al., 2018). Therefore, future studies could use electric simulation modeling to identify which critical target areas should be modulated in GAD to improve clinical outcomes. Stress was evaluated by ISSL and a significant improvement in physical symptoms of stress was found only in active tDCS. The study of anxiety in the context of real-life is difficult and its negative impacts extend beyond aversive feelings or mood disturbance and involve disruptions in regards to physical aspects (Locke et al., 2015). Physical symptoms, such as sleep disturbance, restlessness, muscle tension, gastrointestinal symptoms, and chronic headaches can negatively impact a patient's quality of life and disrupt important activities of daily living (Locke et al., 2015). It has been suggested that DLPFC stimulation could modulate emotional reactivity, psychological flexibility, and social engagement (Sgoifo et al., 2015). Prefrontal cortical areas, including the orbitofrontal cortex and medial prefrontal cortex, tonically inhibit the amygdala and neuromodulation could improve this inhibition (Sgoifo et al., 2015). This is important for balancing the stress response because anxiety and depression are associated with prefrontal cortex hypoactivity and lack of inhibitory neural mechanisms (Sgoifo et al., 2015). The enhancement of physical symptoms of stress could be associated with autonomic responses including behavioral modulation in the face of stress (Mcklveen et al., 2016). Improvements in physical aspects of stress in GAD can improve life satisfaction, cognitive function, and psychological well-being (Locke et al., 2015). The results of this study should encourage additional clinical trials, including long-term tDCS treatment (e.g., 10 to 20 sessions) and different brain targets including the right DLPFC. Neuroimaging indicates that tDCS over DLPFC alters functional activation and connectivity in brain regions that support cognitive function, including regions distal from the stimulating electrodes such as cortical-striatal and limbic circuits (Ironside et al., 2018). It is hypothesized that prefrontal stimulation increases cortical activity, which increases top-down attentional control of connected limbic structures (Ironside et al., 2018). tDCS could increase the cortical activation of DLPFC and decrease amygdala activation. These effects can improve anxiety symptoms by a direct causal inhibitory role of the prefrontal cortex on the amygdala (Ironside et al., 2018). Some limitations of the present study must be acknowledged. First, the results of this study might be biased due to the limited sample size. On the other hand, the use of this technique in this population could provide guidance for selecting symptom measures to determine the power and sample size necessary for future trials with GAD. Second, the study performed only five sessions of tDCS. The number of sessions was not effective to show significant differences in GAD mood symptoms. Likewise the tDCS protocol for depression, the recommendation of 10 or more sessions should be considered in future investigations aiming the possible therapeutic effects of tDCS. Future studies with a larger sample size and a longer treatment period could induce therapeutic gains for GAD that are refractory to conventional treatments. It is worth noting that our study considered only the short-term effects of tDCS for GAD. Long-term effects should also be investigated to provide more details about the clinical and social benefits of tDCS for patients with GAD.
A total of 51 individuals were screened for eligibility. Twenty-one individuals were excluded for not meeting the inclusion criteria. Thirty patients were randomized to each group (active or sham) and all patients completed the entire experimental procedure. No complications were observed during the study period among patients who completed the treatment protocols and patients tolerated the tDCS treatments well. Few adverse effects occurred. The most frequent adverse effects were headache (active: 30%; sham: 35% with p = 0.45), tingling (active: 60%; sham: 55% with p = 0.47) and sleepiness (active: 90%; sham: 20% with p = 0.001). Patients were treated according to the guideline's recommendations for management of GAD and medication intake remained constant throughout the trial. There were no significant differences between treatment groups regarding medication use (Fig. 1). There were no significant differences in sociodemographic and clinical variables at baseline between the groups (Table 1). The mixed ANOVA results are shown in Table 2. Anxiety was assessed using HAM-A and BAI at three time points (baseline, day 5- and 1-week follow-up). A mixed ANOVA model indicated no significant interaction between group and time for anxiety evaluated using HAM-A (p = 0.255) and BAI (p = 0.24). A decrease in anxiety levels throughout the trial (effect of time) was observed in the two treatment groups (p = 0.0001). Intragroup analyses showed a significant difference between baseline, day 5, and follow-up in the sham and active group (Fig. 2A). When compared to baseline with follow-up, the active group showed a reduction of 48.7% and sham of 33.6%. Significant time vs group interactions were observed only for physical symptoms of stress (p = 0.03) with a main effect of time (p = 0.0001). Post-hoc analysis showed a significant difference between baseline for day 5 (p = 0.004) and follow-up (p = 0.0001) in the active group. Effects of time were observed for all scales except the PA (Table 2) (Figs. 3 and 4.). 4. Discussion To the best of our knowledge, the present study is the first randomized controlled trial assessing the short-term effects of tDCS for GAD. We performed five consecutive days of anodal tDCS over the left DLPFC at 2 mA for 20 min. Contrary to our hypotheses, no differences were found for the primary and secondary outcomes. Nonetheless, we found a significantly greater improvement in the active group of the physical symptoms of stress. Several articles have suggested the therapeutic efficacy of non-invasive brain stimulation for treating neurological conditions and psychiatric disorders, such as depression, addiction, stroke, and pain (Lefaucheur, 2016; Vicario et al., 2019). Particularly for the treatment of acute depression, meta-analyses have suggested the efficacy of tDCS with a moderate effect size (Palm et al., 2016). Some of these clinical trials have conducted stimulation of the left DLPFC and inhibitory stimulation over the right orbit (Lefaucheur, 2016). Therefore, considering the overlap between depressive and anxiety symptoms, we performed anodal stimulation over the DLPFC in GAD patients. Nonetheless, although intragroup analyses showed decreases in anxiety, stress, negative affectivity, and depression scales, no intergroup comparison showed significant differences in these outcomes with a F3-SO montage. In hindsight, perhaps five sessions of tDCS was insufficient to ameliorate anxiety symptoms. This number of sessions was chosen considering initial tDCS studies for Major Depressive Disorder (MDD) demonstrating tDCS efficacy with only five sessions (Fregni et al., 2006). However, later meta-analyses have suggested that this number of sessions might be insufficient (Brunoni et al., 2016). These issues could be further clarified in future studies using more prolonged protocols. To date, only a case study was published about the use of tDCS for 36
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5. Conclusion
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Transcranial direct current stimulation for generalized anxiety disorder: a case study. Biol. Psychiatry. 75, e17–e18. https://doi.org/10.1016/j. biopsych.2013.07.014. Shiozawa, P., Leiva, A.P.G., Castro, C.D.C., Enokibara, M., Cordeiro, Q., Fregni, F., Brunoni, A.R., 2014b. Transcranial direct current stimulation for generalized anxiety disorder_ a case study. Biol. Psychiatry 75, e17–e18. https://doi.org/10.1016/j. biopsych.2013.07.014. Silva-filho, E., Okano, A.H., Morya, E., Albuquerque, J., Cacho, E., Unal, G., Bikson, M., Pegado, R., 2018. Neuromodulation treats Chikungunya arthralgia: a randomized controlled trial. Sci. Rep. 8, 16010. https://doi.org/10.1038/s41598-018-34514-4. Stein, D.J., Scott, K.M., de Jonge, P., Kessler, R.C., 2017. Epidemiology of anxiety disorders: from surveys to nosology and back. Dialogues Clin. Neurosci. 19, 127–136. Todder, D., Gershi, A., Perry, Z., Kaplan, Z., Levine, J., Avirame, K., 2018. Immediate effects of transcranial direct current stimulation on obsession-induced anxiety in refractory obsessive-compulsive disorder: a pilot study. J. ECT 34, e51–e57. https:// doi.org/10.1097/YCT.0000000000000473. Vicario, C.M., Salehinejad, M.A., Felmingham, K., Martino, G., Nitsche, M.A., 2019. A systematic review on the therapeutic effectiveness of non-invasive brain stimulation for the treatment of anxiety disorders. Neurosci. Biobehav. Rev. 96, 219–231. https://doi.org/10.1016/j.neubiorev.2018.12.012. Watson, D., Clark, L.A., 1999. The Panas-X manual for the positive and negative affect schedule—Expanded form. Order A. J. Theory Ordered Sets Its Appl. 277, 1–27. https://doi.org/10.17077/48vt-m4t2. Weeks, J.W., Heimberg, R.G., 2005. Evaluation of the psychometric properties of the beck depression inventory in a non-elderly adult sample of patients with generalized anxiety disorder. Depress. Anxiety. 22, 41–44. https://doi.org/10.1002/da.20068.
The main results of this placebo-controlled study indicate that five sessions of anodal tDCS over the DLPFC did not improve anxiety and mood symptoms in patients with GAD. Nonetheless, the protocol showed improvements in the physical symptoms of stress. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Ana Lucia de Lima: Conceptualization, Writing - original draft, Investigation, Methodology, Writing - review & editing. Francisco Moisés Azevedo Braga: Investigation, Methodology. Rodrigo Maciel Medeiros da Costa: Investigation, Methodology. Elihab Pereira Gomes: Investigation, Methodology. André Russowsky Brunoni: Writing - original draft, Formal analysis. Rodrigo Pegado: Conceptualization, Data curation, Writing - original draft, Formal analysis. Declaration of Competing Interest All authors have read this protocol, agree with the Journal of Affective Disorders policy and declare no conflicts of interest including any financial, personal or other relationships with other people or organizations. We also state that this manuscript is not under consideration elsewhere. Acknowledgments None. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2019.08.020. References Bishop, S., Duncan, J., Brett, M., Lawrence, A.D., 2004. Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat. Neurosci. 7, 184–188. https://doi.org/10.1038/nn1173. Brunoni, A.R., Moffa, A.H., Fregni, F., Palm, U., Padberg, F., Blumberger, D.M., Daskalakis, Z.J., Bennabi, D., Haffen, E., Alonzo, A., Loo, C.K., 2016. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br. J. Psychiatry 208, 522–531. https://doi.org/10.1192/bjp. bp.115.164715. Carnevali, L., Mancini, M., Koenig, J., Makovac, E., Watson, D.R., Meeten, F., Critchley, H.D., Ottaviani, C., 2019. Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder. Auton. Neurosci. Basic Clin. 217, 41–48. https://doi. org/10.1016/j.autneu.2019.01.001. Craske, M.G., Stein, M.B., Eley, T.C., Milad, M.R., Holmes, A., Holmes, A., Rapee, R.M., Wittchen, H.U., 2017. Anxiety disorders. Nat. Rev. Dis. Primers 3, 17100. https://doi. org/10.1038/nrdp.2017.24. Etkin, A., Wager, T.D., 2007. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488. https://doi.org/10.1182/blood-2010-06-290668. Fregni, F., Boggio, P.S., Nitsche, M.A., Rigonatti, S.P., Pascual-Leone, A., 2006. Treatment of major depression with transcranial direct current stimulation ephedrine-induced emergence of bipolar symptoms. Bipolar Disord. 8, 203–204. https://doi.org/10. 1111/j.1399-5618.2006.00291.x. Galinha, I.C., Pais-Ribeiro, J.L., 2005. Contribuição para o estudo da versão portuguesa da positive and negative affect schedule (PANAS): II—Estudo psicométrico. Análise
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Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research paper
Transcranial direct current stimulation for the treatment of generalized anxiety disorder: A randomized clinical trial
T
Ana Lucia de Limaa, Francisco Moisés Azevedo Bragab, Rodrigo Maciel Medeiros da Costab, ⁎ Elihab Pereira Gomesb, André Russowsky Brunonic,d, Rodrigo Pegadoa, a
Graduate Program in Rehabilitation Science, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil Universidade Potiguar, Rio Grande do Norte, Brazil c Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil d Department of Internal Medicine, University of São Paulo, São Paulo, Brazil b
A R T I C LE I N FO
A B S T R A C T
Keywords: Noninvasive brain stimulation Dorsolateral prefrontal cortex Depression Affectivity Stress
Background: Generalized anxiety disorder (GAD) is a common condition with current treatments being only moderately effective. Non-invasive brain stimulation techniques might provide a novel approach for treating GAD. Transcranial direct current stimulation (tDCS) has shown promising efficacy and tolerability for major depression but has not been investigated for GAD yet. Thus, we investigated the effects of tDCS on patients with GAD. Methods: We conducted a pilot, double-blind, randomized, sham-controlled trial on 30 GAD patients. Five sessions of tDCS (2 mA, 20 min, anode over the left dorsolateral prefrontal cortex and cathode over the right supraorbital cortex) were performed. Anxiety was the primary outcome and it was measured by the Hamilton Anxiety Rating Scale and the Beck Anxiety Inventory. Secondary outcomes were accessed by the Lipp Inventory of Stress Symptoms for Adults, Positive and Negative Affect Schedule, and the Beck Depression Inventory (BDI). Data were examined at baseline, after the 5th day of intervention, and at 1-week follow-up. Results: Thirty patients finished the study. There were no significant improvements in anxiety, mood symptoms of stress, affectivity or depression. Anodal stimulation of the left DLPFC showed significant improvements in physical symptoms of stress in GAD patients. Limitations: Additional tDCS sessions could have resulted in larger tDCS effects. Conclusion: Five sessions of anodal tDCS over the DLPFC did not improve the main outcomes for GAD patients, although physical symptoms of stress were improved. The role of tDCS in GAD should be explored in larger patient samples using different parameters.
1. Introduction Generalized anxiety disorder (GAD) is a prevalent psychiatric disorder with a worldwide prevalence estimated at 7.3% (Stein et al., 2017). The condition is characterized by deficits in emotional expressivity and self-regulation and is associated with impairments in quality of life (Carnevali et al., 2019; Locke et al., 2015). Its symptoms include persistent excessive anxiety and worry, sleep disturbances, tremors, muscle tension, fatigue, restlessness, irritability, palpitations, dizziness and epigastric discomfort (Locke et al., 2015; Stein et al., 2017). Although the prevalence of GAD is higher in high-income countries, its clinical course is more persistent in lower- and middleincome countries (Ruscio et al., 2017). Physical activity, selective
⁎
serotonin reuptake inhibitors, antidepressants, and psychotherapy are recommended interventions, but low adherence and adverse effects are barriers to treatment (Locke et al., 2015). The underlying mechanisms of GAD suggest a persistent activation of brain areas associated with ruminative mental activity and introspective thinking (Locke et al., 2015). Patients with GAD also exhibit autonomic dysfunction, a decrease in vagally-mediated heart rate variability, and neurostructural abnormalities of the left rostral anterior cingulate cortex, left medial orbitofrontal cortex, and right isthmus cingulate gyrus (Carnevali et al., 2019). Anxiety disorders might result from a maladaptive neuroplasticity of the prefrontal and limbic regions, with hypoactivation of the dorsolateral prefrontal cortex (DLPFC) (Ironside et al., 2018) and abnormalities in amygdala processing
Corresponding author: Faculty of Health Science of Trairi, Federal University of Rio Grande do Norte, Trairí St. 59200-000, Santa Cruz-RN, Brazil. E-mail address: [email protected] (R. Pegado).
https://doi.org/10.1016/j.jad.2019.08.020 Received 3 June 2019; Received in revised form 8 August 2019; Accepted 13 August 2019 Available online 15 August 2019 0165-0327/ Published by Elsevier B.V.
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Fig. 1. CONSORT flowchart for the study.
(Carnevali et al., 2019; Vicario et al., 2019). These findings have also been observed during symptom provocation or negative emotional processing in patients with posttraumatic stress disorder, anxiety disorders, and obsessive-compulsive disorder (Etkin and Wager, 2007). Non-pharmacological and non-invasive interventions are novel approaches that might be a feasible strategy for treatment of mental disorders (Kar and Sarkar, 2016). Recent research has focused on the mood and physical effects of transcranial direct current stimulation (tDCS) over the DLPFC, particularly to treat psychiatric disorders such as depression (Ironside et al., 2016). Recent reviews have suggested some efficacy of tDCS for acute depressive disorder and inconsistent results for anxiety disorders (Palm et al., 2016; Vicario et al., 2019). tDCS could act in mood and anxiety disorders via modulation of DLPFC activity and plasticity (Vicario et al., 2019). Stimulation of the left DLPFC might counteract the maladaptive plasticity of the cortico‑mesolimbic network in GAD by acting on mechanisms sub-served by these regions for emotional outcomes (Vicario et al., 2019). Excitatory stimulation of the left DLPFC might upregulate positive reactions to positive emotional stimuli and downregulate negative reactions to emotional stimuli (Vicario et al., 2019). The application of tDCS over the DLPFC has been suggested to work by increasing prefrontal regulation of limbic responses to negative stimuli including negative emotional processing (Ironside et al., 2016). DLPFC activity has been negatively correlated with anxiety in neuroimaging studies (Bishop et al., 2004). Despite the promising evidence regarding tDCS use in psychiatric disorders, there is no previous randomized controlled trial, to the best of our knowledge, that evaluated the use of anodal tDCS over the left DLFPC to treat GAD. In this context, we hypothesized that this montage could reduce anxiety and associated symptoms in GAD patients. We tested the effects of five consecutive sessions of tDCS using a randomized, sham-controlled trial in 30 patients with GAD. The primary aim of this study was to evaluate the effect of anodal tDCS over DLPFC on anxiety. The secondary aims were to evaluate the effect of the intervention on the level of stress, depression, and positive and negative affectivity.
Table 1 Sociodemographic and clinical variables. Variable
Active-tDCS
Sham-tDCS
p value
Age HAM-A BAI PA NA BDI ISSL Alert Resistance Exhaustion Physical symptoms Mood symptoms Total score Gender Female Male Marital status (n) Single Married Income* 1 Minimum Wage 2 –3 Minimum wage 4 Minimum wage or more Unreported Education (n) Elementary Secondary University
32.07 ± 6.5 31.47 ± 14.2 32.27 ± 17.85 21.67 ± 7.64 30.2 ± 11.6 36.87 ± 24.43
29 ± 5.05 26.93 ± 13.2 24.67 ± 11.64 24.07 ± 5.65 23.4 ± 9.22 21.53 ± 16.77
0.160 0.372 0.178 0.336 0.086 0.054
5.06 ± 3.32 5.53 ± 4.2 5.46 ± 4.51 9.2 ± 6.76 6.86 ± 5.98 28.46 ± 11.98
6.4 ± 3.29 5.8 ± 3.38 6.2 ± 4.85 10.07 ± 6.37 8.26 ± 4.83 25.33 ± 10.5
0.279 0.849 0.671 0.720 0.486 0.453 0.705
10 5
9 6
7 8
11 4
4 8 2 1
6 7 2 0
2 9 4
2 7 6
0.136
0.69
0.57
Clinical variables described with mean and standard deviation. Hamilton Anxiety Rating Scale (HAM-A); Beck Anxiety Inventory (BAI); Positive affect (PA); Negative affect (NA); Beck Depression Inventory (BDI); Lipp Inventory of Stress Symptoms for Adults (ISSL). ⁎ Brazilian National Minimum Wage, US$ 257 per month.
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2. Methods
Table 2 Result of the ANOVAs performed for each outcome measure. Variable HAM-A Time x Group Time Group BAI Time x Group Time Group PA Time x Group Time Group NA Time x Group Time Group BDI Time x Group Time Group ISSL Alert Time x Group Time Group Resistance Time x Group Time Group Exhaustion Time x Group Time Group Physical Symptoms Time x Group Time Group Mood Symptoms Time x Group Time Group Total Score Time x Group Time Group
Df
F
p
Power
pn2
2 2 1
1.400 21.050 0.03
0.255 0.0001* 0.85
0.288 1.0 0.54
0.04 0.42 0.001
2 2 1
1.462 16.897 0.493
0.24 0.0001* 0.488
0.27 0.998 0.104
0.05 0.376 0.017
2 2 1
1.077 1.541 0.06
0.337 0.223 0.809
0.207 0.280 0.056
0.037 0.052 0.002
2 2 1
2.634 15.604 0.617
0.093 0.0001* 0.439
0.996 0.449 0.118
0.358 0.086 0.022
2 2 1
1679 9.640 3.628
0.196 0.0001* 0.06
0.976 0.339 0.452
0.256 0.057 0.115
2 2 1
2.190 13.314 0.132
0.135 0.0001* 0.719
0.372 0.987 0.064
0.073 0.322 0.005
2 2 1
2.001 9.391 0.123
0.145 0.0001* 0.728
0.396 0.973 0.063
0.067 0.251 0.004
2 2 1
0.619 10.473 0.008
0.496 0,001* 0.928
0.148 0.952 0.051
0.022 0.272 0.0001
2 2 1
3.468 13.822 0.208
0,0001* 0.038* 0.652
0.99 0.552 0.073
0.33 0.11 0.007
2 2 1
1.370 16.435 0.003
0.261 0,0001* 0.958
0.248 0.997 0.0001
0.047 0.370 0.05
2 2 1
2.202 19.025 0.079
0.136 0,0001* 0.780
0.365 0.999 0.059
0.073 0.405 0.003
2.1. Participants and study design This study followed CONSORT recommendations (Schulz et al., 2010). From June 2018 to February 2019, patients were recruited in two outpatient clinics (Santa Cruz and Mossoro) located in the northeast of Brazil and treated at the Federal University of Rio Grande do Norte or the Climaf Clinic. The study was conducted by the Faculty of Health Science of Trairí, Federal University of Rio Grande do Norte and has received human study approval by the local institutional Ethical Committee (approval number 2.413.722). It has been carried out in accordance with the Declaration of Helsinki and resolution No. 466/12 of the National Health Council. The study was registered on Rebec (Brazilian platform of clinical trials) with the identifier RBR-5QJG9T. All participants provided written informed consent. Patients were selected from specialized outpatient services. Eligibility criteria were: (1) clinical diagnosis of GAD according to DSM5 (Craske et al., 2017), (2) not going through psychotherapy at the time when the study was conducted, (3) aged from 20 to 40 years, (4) not breastfeeding, (5) no history of brain surgery or brain tumor, and (6) no contraindications for tDCS, such as intracranial metal implantation. Exclusion criteria were (1) patients presenting with a history of dizziness or seizures, (2) pregnancy, and (3) signs of severity and/or indications for hospitalization or psychotherapy according to psychiatric evaluation. Patients were randomized (1:1) through a numerical sequence generated by an allocated computer using appropriate software (www. randomization.com) to assign each participant to either the active-tDCS (a-tDCS) group or the sham-tDCS group by an independent researcher who was not involved with either stimulation or assessments. Both participants and researchers involved in assessments and interventions were blinded to group allocation throughout the trial.
2.2. Interventions tDCS was delivered using a continuous electric stimulator with three energy batteries (9 V) connected in parallel. Similar devices have been used in previous studies (Okano et al., 2013; Silva-filho et al., 2018). The maximum energy output was 10 mA and was controlled by a professional digital multimeter (DT832, WeiHua Electronic Co., Ltd., China) with a standard error of ± 1.5%. Electrodes were placed into a 35 cm2 (5 cm × 7 cm) square sponge soaked in saline solution (150 mM NaCl in Milli-Q water). Rubber bandages were used to hold the
Hamilton Anxiety Rating Scale (HAM-A); Beck Anxiety Inventory (BAI); Positive affect (PA); Negative affect (NA); Beck Depression Inventory (BDI); Lipp Inventory of Stress Symptoms for Adults (ISSL). ⁎ Statistical significance result.
Fig. 2. (A): Changes in Hamilton Anxiety Rating Scale (HAM-A) over time in the 2 treatment groups. *Indicate significant difference between baseline for both groups. (B): Beck Anxiety Inventory (BAI) over time in the 2 treatment groups with significant difference in active group when compare baseline with day 5 (p = 0.002)** and follow-up (p = 0.0001)**. Variables described with mean and standard deviation. 33
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Fig. 3. Lipp Inventory of Stress Symptoms for Adults (ISSL) domains. *Denote significant difference in active group when compare with baseline. Variables described with mean and standard deviation.
described any differences between the conditions, and both groups reported experiencing the same sensation during the 30 s period. Patients rested in an armchair in a quiet and illuminated room during the sessions with no interference from the researchers.
electrodes in place for the duration of the stimulation. For electrode placement, the 10/20 EEG system with an anode electrode was used, placed over F3 for stimulation of the DLPFC, and the cathode electrode was placed over the contralateral supraorbital area (Fp2). The direct current applied was 2 mA for 20 min (2 mA/5 cm × 7 cm = 0.057 mA/ cm2). We applied 5 tDCS sessions, one per day, from Monday to Friday. For sham-tDCS, electrodes were placed at the same position as for the a-tDCS, but the current was turned off after 30 s of stimulation following previously established methods of clinical studies of brain stimulation (Gandiga et al., 2006; Lefaucheur, 2016). These methods provide the same initial sensory feelings of a-tDCS conditions, specifically, itching and tingling feelings on the scalp for the first few seconds of tDCS (Gandiga et al., 2006; Lefaucheur, 2016). No participants
2.3. Outcomes All measurements were determined while both the subject and raters were blinded to the intervention. Variables were measured one week before the beginning of the intervention (baseline), after the 5th day of intervention (T2), and 1 week after the end of the intervention period (T3). Sociodemographic characteristics (sex, age, education level, profession, marital status, and race) and clinical data (anxiety, 34
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bothered by each symptom over the past week. Responses are rated on a 4-point Likert scale and range from 0 (not at all) to 3 (severely) (Julian, 2011).
2.3.2. Secondary outcomes measures Stress was assessed per the Lipp Inventory of Stress Symptoms for Adults–ISSL (Lipp, 2000). This questionnaire aims to identify the characteristic frames of stress, making it possible to diagnose stress in adults and the stage at which the person currently is at (alert, resistance, near-exhaustion, total exhaustion). It is based on a four-phase model and proposes a method of stress evaluation that emphasizes somatic and psychological symptomatology (Lipp, 2000). Positive affect (PA) and negative affect (NA) were measured using a Positive and Negative Affect Schedule. This questionnaire has 20 items, 10 for PA and 10 for NA, and participants respond to each item on a 5point Likert-type scale (1: very slightly or not at all, 2: a little, 3: moderately, 4: quite a bit, and 5: extremely). The period adopted in this study was in ‘general’. The scores ranged from 10 to 50 for both the PA and NA (Galinha and Pais-Ribeiro, 2005; Watson and Clark, 1999). Depression was evaluated using the Beck Depression Inventory (BDI). This is a widely used self-report measure of depressive symptoms in adults and is administered across a wide range of psychological disorders (Weeks and Heimberg, 2005). BDI demonstrated good psycho-metric properties in a non-elderly adult sample of patients with GAD (Weeks and Heimberg, 2005). This is a self-report questionnaire composed of 21 items referring to cognitive symptoms and attitudes. In each item the patient chooses one or more statements that best describe how he felt in the last week (Weeks and Heimberg, 2005). The maximum score is 63 points and higher scores indicate more severe levels of depression. We monitored adverse events by asking patients about any after each session of stimulation and during the follow-up period.
2.4. Statistical analysis The sample size was determined a priori using the G-Power 3.1.9.2 (F tests ANOVA: repeated measures, within-between interactions). Sample size was estimated based on the assumption of significance of 0.05, power of 95%, and 0.35 effect size. The sample size calculation indicated 24 participants were necessary. We decided to add six additional patients to account for attrition. Thus, 30 patients were recruited and randomized into two groups of 15 patients. All subjects completed the intervention period and follow-up, i.e., there were no dropouts. Analyses were performed using Graph Pad Prism 5 and SPSS software (V.19.0, Chicago, USA). Data were expressed as means and standard deviations. The Shapiro–Wilk and Levene's test were applied to assess the normality of the distribution and homogeneity of variance of the data, respectively. Mauchly's test of sphericity was used to validate the correlation of the repeated measures, and if the assumption of sphericity was violated, the Greenhouse–Geisser correction was applied. Unpaired t tests, Mann–Whitney and Chi square tests were used to compare sociodemographic and clinical characteristics at baseline. A mixed ANOVA model was used to compare the effects of tDCS between groups on anxiety and secondary outcomes. The independent fixed variables were time (baseline, day 5, and follow-up), group of stimulation (active and sham), and the interaction term. When appropriate, post-hoc comparisons were carried out using Bonferroni correction for multiple comparisons. Partial η2 were calculated as measures of effect size in the ANOVA results (main effects and interaction effects). Partial η2 was used to calculate the effect size, where η2 = 0.01 was considered small, η2 = 0.06 moderate, and η2 = 0.14 a large effect. Statistical significance was set at p ≤ 0.05.
Fig. 4. (A) Positive affect (PA). (B) Negative affect (NA). (C) Beck Depression Inventory (BDI). *Significant difference between baseline with day 5 and follow-up only in active group.
depression, affectivity, and stress) were collected at baseline. 2.3.1. Primary outcome measure The Hamilton Anxiety Rating Scale (HAM-A), which was the primary outcome measure, and the Beck Anxiety Inventory (BAI) were used to measure anxiety symptoms. The HAM-A scale consists of 14 elements, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is scored on a basic numeric scale of 0 (not present) to 4 (severe) with a total score range of 0–56, where <17 indicates mild severity, 18–24 mild to moderate severity, and 25–30 moderate to severe (Hamilton, 1959). The BAI is a brief measure of anxiety with a focus on somatic symptoms of anxiety that was developed as a measure adept at discriminating between anxiety and depression (Julian, 2011). The BAI is administered via self-report and includes assessment of symptoms with a total of 21 items. Respondents indicate how much they have been 35
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3. Results
GAD (Shiozawa et al., 2014a). The authors performed 15 consecutive daily tDCS sessions with the cathode positioned over the right DLPFC and the anode over the contralateral deltoid with a current of 2 mA for 30 min (Shiozawa et al., 2014b). It was found there was a significant improvement of anxiety during the 15-day treatment course and a discrete improvement in depression (Shiozawa et al., 2014b). The DLPFC was chosen considering that this area is associated with mood regulation, anxiety, and emotional pain (Ironside et al., 2018). This brain area has a potential role in top-down control processes involved in mood disturbances (Ironside et al., 2016). However, although tDCS is usually employed to modulate cortical excitability in a target region, it also induces changes in interconnected regions and corticosubcortical circuits (Todder et al., 2018). Therefore, future studies could use electric simulation modeling to identify which critical target areas should be modulated in GAD to improve clinical outcomes. Stress was evaluated by ISSL and a significant improvement in physical symptoms of stress was found only in active tDCS. The study of anxiety in the context of real-life is difficult and its negative impacts extend beyond aversive feelings or mood disturbance and involve disruptions in regards to physical aspects (Locke et al., 2015). Physical symptoms, such as sleep disturbance, restlessness, muscle tension, gastrointestinal symptoms, and chronic headaches can negatively impact a patient's quality of life and disrupt important activities of daily living (Locke et al., 2015). It has been suggested that DLPFC stimulation could modulate emotional reactivity, psychological flexibility, and social engagement (Sgoifo et al., 2015). Prefrontal cortical areas, including the orbitofrontal cortex and medial prefrontal cortex, tonically inhibit the amygdala and neuromodulation could improve this inhibition (Sgoifo et al., 2015). This is important for balancing the stress response because anxiety and depression are associated with prefrontal cortex hypoactivity and lack of inhibitory neural mechanisms (Sgoifo et al., 2015). The enhancement of physical symptoms of stress could be associated with autonomic responses including behavioral modulation in the face of stress (Mcklveen et al., 2016). Improvements in physical aspects of stress in GAD can improve life satisfaction, cognitive function, and psychological well-being (Locke et al., 2015). The results of this study should encourage additional clinical trials, including long-term tDCS treatment (e.g., 10 to 20 sessions) and different brain targets including the right DLPFC. Neuroimaging indicates that tDCS over DLPFC alters functional activation and connectivity in brain regions that support cognitive function, including regions distal from the stimulating electrodes such as cortical-striatal and limbic circuits (Ironside et al., 2018). It is hypothesized that prefrontal stimulation increases cortical activity, which increases top-down attentional control of connected limbic structures (Ironside et al., 2018). tDCS could increase the cortical activation of DLPFC and decrease amygdala activation. These effects can improve anxiety symptoms by a direct causal inhibitory role of the prefrontal cortex on the amygdala (Ironside et al., 2018). Some limitations of the present study must be acknowledged. First, the results of this study might be biased due to the limited sample size. On the other hand, the use of this technique in this population could provide guidance for selecting symptom measures to determine the power and sample size necessary for future trials with GAD. Second, the study performed only five sessions of tDCS. The number of sessions was not effective to show significant differences in GAD mood symptoms. Likewise the tDCS protocol for depression, the recommendation of 10 or more sessions should be considered in future investigations aiming the possible therapeutic effects of tDCS. Future studies with a larger sample size and a longer treatment period could induce therapeutic gains for GAD that are refractory to conventional treatments. It is worth noting that our study considered only the short-term effects of tDCS for GAD. Long-term effects should also be investigated to provide more details about the clinical and social benefits of tDCS for patients with GAD.
A total of 51 individuals were screened for eligibility. Twenty-one individuals were excluded for not meeting the inclusion criteria. Thirty patients were randomized to each group (active or sham) and all patients completed the entire experimental procedure. No complications were observed during the study period among patients who completed the treatment protocols and patients tolerated the tDCS treatments well. Few adverse effects occurred. The most frequent adverse effects were headache (active: 30%; sham: 35% with p = 0.45), tingling (active: 60%; sham: 55% with p = 0.47) and sleepiness (active: 90%; sham: 20% with p = 0.001). Patients were treated according to the guideline's recommendations for management of GAD and medication intake remained constant throughout the trial. There were no significant differences between treatment groups regarding medication use (Fig. 1). There were no significant differences in sociodemographic and clinical variables at baseline between the groups (Table 1). The mixed ANOVA results are shown in Table 2. Anxiety was assessed using HAM-A and BAI at three time points (baseline, day 5- and 1-week follow-up). A mixed ANOVA model indicated no significant interaction between group and time for anxiety evaluated using HAM-A (p = 0.255) and BAI (p = 0.24). A decrease in anxiety levels throughout the trial (effect of time) was observed in the two treatment groups (p = 0.0001). Intragroup analyses showed a significant difference between baseline, day 5, and follow-up in the sham and active group (Fig. 2A). When compared to baseline with follow-up, the active group showed a reduction of 48.7% and sham of 33.6%. Significant time vs group interactions were observed only for physical symptoms of stress (p = 0.03) with a main effect of time (p = 0.0001). Post-hoc analysis showed a significant difference between baseline for day 5 (p = 0.004) and follow-up (p = 0.0001) in the active group. Effects of time were observed for all scales except the PA (Table 2) (Figs. 3 and 4.). 4. Discussion To the best of our knowledge, the present study is the first randomized controlled trial assessing the short-term effects of tDCS for GAD. We performed five consecutive days of anodal tDCS over the left DLPFC at 2 mA for 20 min. Contrary to our hypotheses, no differences were found for the primary and secondary outcomes. Nonetheless, we found a significantly greater improvement in the active group of the physical symptoms of stress. Several articles have suggested the therapeutic efficacy of non-invasive brain stimulation for treating neurological conditions and psychiatric disorders, such as depression, addiction, stroke, and pain (Lefaucheur, 2016; Vicario et al., 2019). Particularly for the treatment of acute depression, meta-analyses have suggested the efficacy of tDCS with a moderate effect size (Palm et al., 2016). Some of these clinical trials have conducted stimulation of the left DLPFC and inhibitory stimulation over the right orbit (Lefaucheur, 2016). Therefore, considering the overlap between depressive and anxiety symptoms, we performed anodal stimulation over the DLPFC in GAD patients. Nonetheless, although intragroup analyses showed decreases in anxiety, stress, negative affectivity, and depression scales, no intergroup comparison showed significant differences in these outcomes with a F3-SO montage. In hindsight, perhaps five sessions of tDCS was insufficient to ameliorate anxiety symptoms. This number of sessions was chosen considering initial tDCS studies for Major Depressive Disorder (MDD) demonstrating tDCS efficacy with only five sessions (Fregni et al., 2006). However, later meta-analyses have suggested that this number of sessions might be insufficient (Brunoni et al., 2016). These issues could be further clarified in future studies using more prolonged protocols. To date, only a case study was published about the use of tDCS for 36
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5. Conclusion
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The main results of this placebo-controlled study indicate that five sessions of anodal tDCS over the DLPFC did not improve anxiety and mood symptoms in patients with GAD. Nonetheless, the protocol showed improvements in the physical symptoms of stress. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Ana Lucia de Lima: Conceptualization, Writing - original draft, Investigation, Methodology, Writing - review & editing. Francisco Moisés Azevedo Braga: Investigation, Methodology. Rodrigo Maciel Medeiros da Costa: Investigation, Methodology. Elihab Pereira Gomes: Investigation, Methodology. André Russowsky Brunoni: Writing - original draft, Formal analysis. Rodrigo Pegado: Conceptualization, Data curation, Writing - original draft, Formal analysis. Declaration of Competing Interest All authors have read this protocol, agree with the Journal of Affective Disorders policy and declare no conflicts of interest including any financial, personal or other relationships with other people or organizations. We also state that this manuscript is not under consideration elsewhere. Acknowledgments None. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2019.08.020. References Bishop, S., Duncan, J., Brett, M., Lawrence, A.D., 2004. Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat. Neurosci. 7, 184–188. https://doi.org/10.1038/nn1173. Brunoni, A.R., Moffa, A.H., Fregni, F., Palm, U., Padberg, F., Blumberger, D.M., Daskalakis, Z.J., Bennabi, D., Haffen, E., Alonzo, A., Loo, C.K., 2016. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br. J. Psychiatry 208, 522–531. https://doi.org/10.1192/bjp. bp.115.164715. Carnevali, L., Mancini, M., Koenig, J., Makovac, E., Watson, D.R., Meeten, F., Critchley, H.D., Ottaviani, C., 2019. Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder. Auton. Neurosci. Basic Clin. 217, 41–48. https://doi. org/10.1016/j.autneu.2019.01.001. Craske, M.G., Stein, M.B., Eley, T.C., Milad, M.R., Holmes, A., Holmes, A., Rapee, R.M., Wittchen, H.U., 2017. Anxiety disorders. Nat. Rev. Dis. Primers 3, 17100. https://doi. org/10.1038/nrdp.2017.24. Etkin, A., Wager, T.D., 2007. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488. https://doi.org/10.1182/blood-2010-06-290668. Fregni, F., Boggio, P.S., Nitsche, M.A., Rigonatti, S.P., Pascual-Leone, A., 2006. Treatment of major depression with transcranial direct current stimulation ephedrine-induced emergence of bipolar symptoms. Bipolar Disord. 8, 203–204. https://doi.org/10. 1111/j.1399-5618.2006.00291.x. Galinha, I.C., Pais-Ribeiro, J.L., 2005. Contribuição para o estudo da versão portuguesa da positive and negative affect schedule (PANAS): II—Estudo psicométrico. Análise
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