Abstract
Objective
This study aims to evaluate the effectiveness of medication therapy combined with transcranial Direct Current Stimulation (tDCS) in improving problem-solving and emotion regulation abilities of patients with bipolar disorder (BD) type I.
Methods
This is a randomized clinical trial conducted on 30 patients with BD I, randomly assigned into two groups of Medication (n = 15, receiving mood stabilizers including 2−5 tablets of lithium 300 mg, sodium valproate 200 mg, and carbamazepine 200 mg) and Medication + tDCS (n = 15, receiving mood stabilizers plus tDCS with 2 mA intensity over the right dorsolateral prefrontal cortex for 10 days, two sessions per day each for 20 minutes). The Tower of London (TOL) test and Emotion Regulation Questionnaire (ERQ) were used for assessments before, immediately, and 3 months after interventions.
Results
There was a significant difference between groups in total ERQ (p = 0.001) and its cognitive reappraisal domain (p = 0.000) which were increased, but the difference was not significant in its expressive suppression domain (p > 0.05). After 3 months, their level decreased. In examining problem-solving variable, the combined therapy could significantly reduce only the total number of errors under TOL test (p = 0.00), but it remained unchanged after 3 months.
Conclusion
Medication therapy plus tDCS is effective in improving problem-solving and emotional regulation (cognitive reappraisal) skills of patients with BD I.
Keywords: Pharmacotherapy, Transcranial direct current stimulation, Emotion regulation, Bipolar disorder
INTRODUCTION
Bipolar disorder (BD) is a chronic and recurrent psychiatric disorder with sudden mood swings that can cause significant impairment in a person’s social and occupational functions [1]. In the United States, 46.6 million adults suffer from mental illness, and more than 6.1 million suffer from BD [2]. The average age for onset of BD is 20 years old [3]. There are two main types of BD; BD I and BD II. According to the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5) [4], BD I (the most severe form) involves episodes of severe mania and depression. Manic episodes are characterized by a decreased need for sleep, rapid thinking, flight of ideas and etc. [5]. Depressive episodes are characterized by an increased demand for sleep, loss of interest in activities, difficulty thinking, and etc. [6]. Globally, the lifelong prevalence rate of BD is 0.3−1.5%; 0.6% for BD I, 0.4% for BD II [7]. In Iran, its prevalence is 0.04% for BD I and 0.3% for BD II [8].
BD is associated with other mental and physical problems and an increased risk of suicide [9]. At least 25−50% of people with BD attempt suicide at least once and it reduces about 9.2 years of the life expectancy [10]. With each additional mood episode, BD patients tend to experience an increased severity of symptoms and an increased risk for recurrence [11]. In patients with BD, extreme mood changes in every episode can affect their perception and thinking process, thus affect their flexibility and ability to solve problems. Patients could have trouble adapting as a result of having less cognitive flexibility and having trouble solving their everyday problems. This cognitive disability can affect social function, resulting in psychosocial disability, because cognitive function is also related to functional and emotional domain [10]. Cognitive impairment in BD is significantly associated with impaired psychosocial function and poor quality of life [12]. About 40−60% of patients with BD have some cognitive impairment across working memory, attention and executive functions during periods of remission [13,14]. Associations between cognitive impairments, severe period of illness and poor functional outcomes has been found in BD patients, suggesting that deficits are linked with the illness progression [15]. However, the temporal progression of cognitive dysfunction in BD remains unclear [16]. Disruptions in emotion regulation have been proposed as critical predictors of the etiology and maintenance of BD [17,18]. Individuals with remitted BD tend to use more maladaptive emotion regulation strategies known to amplify emotional distress, including suppres-sion and rumination [19,20]. Remitted BD individuals also tend to engage in maladaptive emotion-related impulsivity, which is associated with increased manic symptom severity and poorer global functioning [21]. Inad-equate emotion regulation is a central part of various psychiatric disorders, including BD [22].
There are different approaches to treat BD including psychotherapy and pharmacotherapy, where the latter is the standard approach; however, it has some disadvan-tages including side effects, patients’ resistance to medication, and medication use restrictions of some patients. Therefore, there is a need for a safe and more effective method with fewer side effects such as non-invasive brain stimulation have including transcranial Direct Current Stimulation (tDCS). In this method, a weak direct electrical current (2 mA) is applied over the scalp using two electrodes (one anode and one cathode) to modulate the cortical excitability; anodal tDCS increases cortical excitability by depolarization of neurons, while cathodal tDCS reduces cortical excitability by neuronal hyperpolariza-tion [23]. Its effects are related to the mechanisms of synaptic plasticity, including long-term potentiation and long- term depression [24].
The use of tDCS can be a good treatment option for patients who experience many side effects after taking medications or for patients who are resistant to medication therapy [25]. To our knowledge, no clinical trial have examined the effectiveness of tDCS combined with pharmacotherapy in improving problem solving and emotion regulation of BD patients. In this regard, this study aims to examine the effect of tDCS plus medication on problem solving and emotion regulation skills of patients with BD I. We hypothesized that:
∙Combination of tDCS with medication therapy improve problem-solving ability of patients with BD I compared to when medication therapy is used alone;
∙Combination of tDCS with medication therapy improve emotion regulation of patients with BD I compared to when medication therapy is used alone.
METHODS
Participants
This is a single-blind randomized clinical trial (Parallel, ID: IRCT20191229045931N1) conducted in April 2020. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975. Written informed consent was obtained from all patients for being included in the study. This study has an ethical approval from the Re-search Ethics Committee of Zanjan University of Medical Sciences (Code: IR.ZUMS.REC.1398.452). Participants were 30 outpatients with BD I (depressive episode) who were selected using a purposive sampling method from among those referred to Sohravardi Clinic in Shahid Beheshti Hospital in Zanjan, Iran. The inclusion criteria for them were: consent to participate, having BD I diagnosed by a psychiatrist based on the DSM-5 criteria, age 18−50 years, at least a middle school education, no severe psychiatric disorders such as psychotic disorders and cognitive impairment, no history of epileptic seizures and head injuries, no cardiac disease, no substance and alcohol use, no history of allergy to drugs, systolic blood pressure > 125 mmHg, and receiving no psychological and technological intervention at least one month before study. Exclusion criteria were: unwillingness to continue participation, absence from more than two intervention sessions, suicidal thoughts during the intervention, need for electrical shock during the intervention, and preg-nancy. Using the Random Number Generator program, patients were divided into two parallel groups of medication (n = 15) and medication + tDCS (n = 15) after obtaining written informed consent from them. The allocation and assignment of participants to their groups were done by the researcher. The sample size was determined 14 for each group using GPower software given α = 0.05, error probability of 0.95, and an effect size of 0.6. Con-sidering a 10% sample drop, it was increased to 15 for each group, according to our previous study [26]. Figure 1 plots the flowchart of sampling and allocation.
Fig. 1.
Flowchart of sampling and allocation.
tDCS, transcranial Direct Current Stimulation.
Measures
At baseline, demographic information of patients (age, sex, education, and marital status) were recorded. Then, they completed the Emotion Regulation Question-naire (ERQ) and underwent the Tower of London (TOL) test. The ERQ has 10 items developed by Gross and John [27] to measure two emotion regulation strategies including cognitive reappraisal (CR; 6 items) and expressive suppression (ES; 4 items). Participants answer the questionnaire on a 7-point Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree), with higher scores representing higher usage of that strategy. Gross and John [27] reported a Cronbach’s alpha of 0.79 for CR and 0.73 for ES, a test-retest reliability of 0.69 across three months for the whole questionnaire. We used the Persian version of ERQ which was prepared by Foroughi et al. [28] which has good validity and reliability. They reported a Cronbach’s alpha coefficient of 0.76 for ER and 0.72 for ES.
The TOL test is a computerized tool that is widely used to measure planning ability and aspects of problem solving. It was administered using a personal computer and a mouse. The subject was asked to move three colored disks (green, blue, and red) and place them in the right place using the minimum number of moves at three at-tempts. The subject was then asked to match 12 patterns of disks using the minimum number of moves at three attempts. After each success, the next problem was given to the person to solve. In this test, the subject obtains 3 points for each problem solved at the first attempt, 2 points at the second, 1 point at the third, and zero if it is not solved (total score = 36). Finally, the total planning-solving time, total execution time as well as latency time and total number of errors were recorded.
Interventions
After conducting pretest assessments, patients in the medication group were asked to uptake mood stabilizers (2−5 tablets of lithium 300 mg, sodium valproate 200 mg, and carbamazepine 200 mg) orally two times per day or more (depending on their ability to control the acute symptoms in patients). It should be noted that the dosage of lithium ranged 600−1,500 mg; dosage of sodium valproate ranged 400−1,500 mg, and dosage of carbamazepine ranged 400−800 mg. The second group received tDCS, in addition to uptake of mood stabilizers with a pattern similar to that in the medication group. The tDCS using a Food and Drug Administration (FDA)-approved device (Oasis Pro; Mind Alive Inc.) was applied by placing two electrodes (positive anode and negative cathode) covered by a sponge soaked in saline over the subjects’ head in the right dorsolateral prefrontal cortex (anode position over F3 and cathode over F4 according to the EEG 10−20 International System) with a 2-mA intensity, ramp-like fade-in time of 15 seconds and fade-out time of 30 seconds for 20 minutes, 10 consecutive days, two sessions per day. The number of sessions was determined according to our previous study [26]. Patients completed ERQ and performed TOL test again immediately and three months after the intervention. The pre- and post-intervention assessments and tDCS intervention were performed by an expert and one health care provider, respectively who were blind to the results and allocations.
Statistical Analysis
Descriptive statistics (mean, standard deviation, frequency, and percentage) were used to describe the data, and statistical tests including multivariate ANCOVA, repeated measures ANOVA, independent ttest, and chi- square test were used to analyze them. Kolmogorov–Smirnov test results showed the normality of data distribution (p > 0.05) and Levene’s test results reported the equality of variances (p > 0.05). The statistical analyses were carried out in SPSS v.20 software (IBM Co.), considering a significance level of p < 0.05.
RESULTS
Characteristics of Participants
In the medication group, 10 were male and 5 were female (mean age = 30.33 ± 8.63 years), where most of them were single with a high school diploma. In the combined therapy group, there were 3 males and 12 females (mean age = 32.06 ± 9.43 years) where majority of them were married and had a high school diploma (Table 1). Independent ttest results showed no significant difference between the two groups in terms of age (p > 0.05) at baseline, while chi-square test reported a statistically significant difference in sex (p < 0.05), but not in educational level and marital status (Table 1).
Table 1.
Demographic characteristics of participants in two study groups
| Demographic factors | Medication (n =15) | Medication + tDCS (n = 15) | p value | |
|---|---|---|---|---|
| Sex | Male | 10 (66.7) | 3 (20) | 0.01a |
| Female | 5 (33.3) | 12 (80) | ||
| Marital status | Married | 7 (46.7) | 8 (53.3) | 0.71a |
| Single | 8 (53.3) | 7 (46.7) | ||
| Educational level | Lower than high school | 2 (13) | 2 (13.3) | 0.90a |
| High school diploma | 9 (60) | 10 (66.7) | ||
| Bachelor’s degree | 4 (26.7) | 3 (20) | ||
| Age (yr) | 30.33 ± 8.63 | 32.06 ± 9.43 | 0.60b | |
Values are presented as number (%) or mean ± standard deviation.
aChi-square test, bIndependent ttest.
Comparing Groups in Terms of Emotion Regulation Ability
Regarding the mean score of ERQ and its subscales at three evaluation phases, the results of independent-test showed no significant difference between the two groups in terms of pretest ERQ scores and its subscales (p > 0.05). A can be seen from Figure 2, the total ERQ score was increased immediately after intervention, where the group received medication alone showed more increase (41.93 ± 12.69 vs. 52.93 ± 9.84) than the group received both medication and tDCS (42.80 ± 10 vs. 44.26 ± 8.68). In both groups, however, the total score decreased 3 months after intervention. Regarding subscale scores, the CR score of patients in both groups was increased immediately after intervention, where the group received both medication and tDCS showed more increase (25.93 ± 9.16 vs. 34.33 ± 3.97) than the group received medication alone (27.93 ± 6.67 vs. 29 ± 4.58). In both groups, however, their ability decreased 3 months after intervention. The ES score of patients decreased in both groups immediately after intervention, where the group received both medication and tDCS showed more reduction (18.60 ± 3.71 vs. 11.30 ± 2.10) than the group received medication alone (15.46 ± 6.11 vs. 15.26 ± 5.59). In both groups, the decrease in ES continued in the follow-up period. According to multivariate ANCOVA results shown in Table 2, after controlling covariates (pretest score and sex), the difference in total ERQ score (F(1,24) = 19.41, p = 0.000 and < 0.05) and CR (F(1,24) = 20.75, p = 0.000 and < 0.05) between groups were statistically significant, while in the ES subscale, the difference was not statistically significant (F(1,24) = 3.807, p = 0.63 and > 0.05). The obtained effect size (h2) indicated that 44.7% of total ERQ changes and 46.4% of CR changes in the groups were due to the effect of combined intervention. To measure the effect of time factor, within-subject effects for emotion regulation variable were measured by using repeated-measures ANOVA with Greenhouse–Geisser cor-rection. The results (Table 3) revealed a significant difference in total ERQ score (with interaction effect, p = 0.000) and CR subscale score (with both main and interaction effects, p = 0.042 and 0.000) between three different time points of pretest, posttest, and follow-up, but the difference in the mean ES score was not significant at any time points (p > 0.05). Pairwise comparison using Bonferroni test (Table 4) showed that, in combined therapy group, there was a significant difference in total ERQ and CR subscale scores between pretest and posttest (p = 0.001 and 0.000), and between pretest and follow-up phases (p = 0.012 and 0.028), but no significant differences between posttest and follow-up phases (p > 0.05). In the medication group, the difference in total ERQ and CR subscale scores was significant between pretest and follow-up phases (p = 0.002 and 0.009), and between posttest and follow-up (p = 0.015 and 0.011) phases, but no significant differences between pretest and posttest phases (p > 0.05). No significant difference in ES was reported in any groups between any time points (p > 0.05).
Fig. 2.
Trend of changes in mean scores of study variables over time in two study groups.
TET, total execution time (sec); LT, latency time (sec); TPST, total planning-solving time (sec); TNE, total number of errors; tDCS, transcranial Direct Current Stimulation; ES, expressive suppression; CR, cognitive reappraisal; ERQ, Emotion Regulation Questionnaire; TOL, The Tower of London.
Table 2.
Test of between-subject effects (dependent variable: posttest emotion regulation)
| Source | Sum of squares | df | Mean square | F | Sig. | Partial eta squared |
|---|---|---|---|---|---|---|
| Intercept | ||||||
| ES | 116.293 | 1 | 116.293 | 6.138 | 0.021 | 0.204 |
| CR | 639.908 | 1 | 639.908 | 59.191 | 0.000 | 0.712 |
| ERQ | 1,018.708 | 1 | 1,018.708 | 26.539 | 0.000 | 0.525 |
| Pretest | ||||||
| ES | 4.017 | 1 | 4.017 | 0.212 | 0.649 | 0.009 |
| CR | 9.438 | 1 | 9.438 | 0.873 | 0.359 | 0.035 |
| ERQ | 19.826 | 1 | 19.826 | 0.517 | 0.479 | 0.021 |
| Sex | ||||||
| ES | 78.971 | 1 | 78.971 | 4.168 | 0.052 | 0.148 |
| CR | 6.877 | 1 | 6.877 | 0.636 | 0.433 | 0.026 |
| ERQ | 141.677 | 1 | 141.677 | 3.691 | 0.067 | 0.133 |
| Group | ||||||
| ES | 72.135 | 1 | 72.135 | 3.807 | 0.063 | 0.137 |
| CR | 224.341 | 1 | 224.341 | 20.751 | 0.000 | 0.464 |
| ERQ | 745.188 | 1 | 745.188 | 19.413 | 0.000 | 0.447 |
| Error | ||||||
| ES | 454.752 | 24 | 18.948 | |||
| CR | 259.463 | 24 | 10.811 | |||
| ERQ | 921.251 | 24 | 38.385 |
ES, expressive suppression; CR, cognitive reappraisal; ERQ, Emotion Regulation Questionnaire; Sig., significant.
Table 3.
Test of within-subject effects for emotion regulation variable (Greenhouse–Geisser test)
| Component | Source | Sum of squares | df | Mean square | F | Sig. | Partial eta squared |
|---|---|---|---|---|---|---|---|
| ES | Time | 24.711 | 1.967 | 12.565 | 0.755 | 0.473 | 0.027 |
| Time*Group | 43.883 | 1.967 | 22.314 | 1.341 | 0.270 | 0.047 | |
| Error | 883.845 | 54 | 16.368 | ||||
| CR | Time | 131.883 | 1.735 | 76.022 | 3.576 | 0.042 | 0.117 |
| Time*Group | 563.035 | 1.735 | 324.551 | 15.267 | 0.000 | 0.361 | |
| Error | 995.722 | 46.840 | 21.258 | ||||
| Total | Time | 281.485 | 1.863 | 151.069 | 3.855 | 0.030 | 0.125 |
| Time*Group | 1,035.833 | 1.863 | 555.918 | 14.186 | 0.000 | 0.344 | |
| Error | 1,971.467 | 50.309 | 39.187 |
ES, expressive suppression; CR, cognitive reappraisal; Sig., significant.
Table 4.
Pairwise comparison for emotion regulation variable
| Group | Measure | Time (I) | Time (J) | Mean difference (I−J) | Standard error | Sig. | 95% Confidence interval | |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Lower bound | Upper bound | |||||||
| tDCS + medication | ES | Pretest | Posttest | −1.133 | 1.534 | 1.000 | −5.345 | 3.078 |
| Follow-up | −0.333 | 1.213 | 1.000 | −3.664 | 2.997 | |||
| Posttest | Pretest | 1.133 | 1.534 | 1.000 | −3.078 | 5.345 | ||
| Follow-up | 0.800 | 1.082 | 1.000 | −2.171 | 3.771 | |||
| Follow-up | Posttest | 0.333 | 1.213 | 1.000 | −2.997 | 3.664 | ||
| Follow-up | −0.800 | 1.082 | 1.000 | −3.771 | 2.171 | |||
| CR | Pretest | Posttest | −8.400* | 1.783 | 0.001 | −13.297 | −3.503 | |
| Follow-up | −7.600* | 2.170 | 0.012 | −13.559 | −1.641 | |||
| Posttest | Pretest | 8.400* | 1.783 | 0.001 | 3.503 | 13.297 | ||
| Follow-up | 0.800 | 0.954 | 1.000 | −1.820 | 3.420 | |||
| Follow-up | Pretest | 7.600* | 2.170 | 0.012 | 1.641 | 13.559 | ||
| Posttest | −0.800 | 0.954 | 1.000 | −3.420 | 1.820 | |||
| Total | Pretest | Posttest | −11.000* | 1.663 | 0.000 | −15.568 | −6.432 | |
| Follow-up | −8.400* | 2.751 | 0.028 | −15.955 | −0.845 | |||
| Posttest | Pretest | 11.000* | 1.663 | 0.000 | 6.432 | 15.568 | ||
| Follow-up | 2.600 | 2.232 | 0.795 | −3.529 | 8.729 | |||
| Follow-up | Pretest | 8.400* | 2.751 | 0.028 | 0.845 | 15.955 | ||
| Posttest | −2.600 | 2.232 | 0.795 | −8.729 | 3.529 | |||
| Medication | ES | Pretest | Posttest | 0.200 | 1.429 | 1.000 | −3.725 | 4.125 |
| Follow-up | 3.333 | 1.757 | 0.241 | −1.491 | 8.158 | |||
| Posttest | Pretest | −0.200 | 1.429 | 1.000 | −4.125 | 3.725 | ||
| Follow-up | 3.133 | 1.621 | 0.226 | −1.318 | 7.585 | |||
| Follow-up | Pretest | −3.333 | 1.757 | 0.241 | −8.158 | 1.491 | ||
| Posttest | −3.133 | 1.621 | 0.226 | −7.585 | 1.318 | |||
| CR | Pretest | Posttest | −1.067 | 1.161 | 1.000 | −4.254 | 2.121 | |
| Follow-up | 4.133* | 1.127 | 0.009 | 1.039 | 7.228 | |||
| Posttest | Pretest | 1.067 | 1.161 | 1.000 | −2.121 | 4.254 | ||
| Follow-up | 5.200* | 1.536 | 0.015 | 0.982 | 9.418 | |||
| Follow-up | Pretest | −4.133* | 1.127 | 0.009 | −7.228 | −1.039 | ||
| Posttest | −5.200* | 1.536 | 0.015 | −9.418 | −0.982 | |||
| Total | Pretest | Posttest | −1.467 | 2.013 | 1.000 | −6.994 | 4.061 | |
| Follow-up | 6.800* | 1.490 | 0.002 | 2.707 | 10.893 | |||
| Posttest | Pretest | 1.467 | 2.013 | 1.000 | −4.061 | 6.994 | ||
| Follow-up | 8.267* | 2.342 | 0.011 | 1.836 | 14.697 | |||
| Follow-up | Pretest | −6.800* | 1.490 | 0.002 | −10.893 | −2.707 | ||
| Posttest | −8.267* | 2.342 | 0.011 | −14.697 | −1.836 | |||
ES, expressive suppression; CR, cognitive reappraisal; tDCS, transcranial Direct Current Stimulation; Sig., significant.
*The mean difference is significant at p < 0.05.
Comparing Groups in Terms of Problem Solving Ability
Regarding the mean scores of TOL test, a significant difference was found at baseline between the two groups only in the pretest total score (p = 0.039). As can be seen from Figure 2, in both groups, the total planning-solving time (sec), total execution time (sec), and total number of errors were highly reduced immediately after intervention, while their total TOL score increased. The latency time (sec) decreased in the medication group, and increased in the combined group. After 3 months, the reduction in the total planning-solving time, total execution time and latency time continued in both groups while the total number of errors remained unchanged in the combined group. The increase in the total TOL score continued after 3 months. After controlling covariates (pretest scores and sex), the ANCOVA results (Table 5) showed a significant difference between groups only in terms of the total number of errors (F = 17.50, p = 0.00 and < 0.05) indicating that the combination of medication with tDCS could reduce the total number of errors under TOL test in BD patients compared to when only medication therapy was used. The obtained effect size indicated that 44.3% of changes in the total number of errors under TOL test in the groups were due to the effect of combined intervention. To measure the effect of the time factor, within-subject effects was assessed by using repeated-measures ANOVA with Greenhouse–Geisser correction. The results (Table 6) showed a significant difference only in the total number of errors between the three time points (with interaction effect only, p = 0.001). There was no main effect of time on any domains of TOL test (p > 0.05). Pairwise comparison using Bonferroni test (Table 7) showed that, in the combined therapy group, there was a significant difference in total execution time and total TOL test score only between pretest and follow-up phases (p = 0.003 and 0.005). In total planning-solving time and total number of errors, the difference was significant between pretest and posttest (p = 0.025 and 0.00), and between pretest and follow-up (p = 0.006 and 0.000) phases. No significant difference in latency time was reported between any time points (p > 0.05). In the medication group, the difference in total execution time, total planning-solving time, total number of errors, and total TOL test score was significant only between pretest and follow-up phases (p < 0.05). No significant difference in latency time was reported between any time points (p > 0.05).
Table 5.
Test of between-subject effects (dependent variable: posttest problem-solving)
| Source | Dependent variable | Sum of squares | df | Mean square | F | Sig. | Partial eta squared |
|---|---|---|---|---|---|---|---|
| Intercept | TET | 7,779.509 | 1 | 7,779.509 | 0.170 | 0.684 | 0.008 |
| LT | 408.355 | 1 | 408.355 | 0.041 | 0.842 | 0.002 | |
| TPST | 2,691.359 | 1 | 2,691.359 | 0.125 | 0.727 | 0.006 | |
| TNE | 4.653 | 1 | 4.653 | 0.103 | 0.752 | 0.005 | |
| Total | 279.977 | 1 | 279.977 | 19.961 | 0.000 | 0.476 | |
| Pretest | TET | 45.606 | 1 | 45.606 | 0.001 | 0.975 | 0.000 |
| LT | 74,851.188 | 1 | 74,851.188 | 7.445 | 0.012 | 0.253 | |
| TPST | 634.364 | 1 | 634.364 | 0.030 | 0.865 | 0.001 | |
| TNE | 468.380 | 1 | 468.380 | 10.327 | 0.004 | 0.319 | |
| Total | 8.483 | 1 | 8.483 | 0.605 | 0.445 | 0.027 | |
| Sex | TET | 45,457.944 | 1 | 45,457.944 | 0.994 | 0.330 | 0.043 |
| LT | 14,042.647 | 1 | 14,042.647 | 1.39 | 0.250 | 0.060 | |
| TPST | 9,613.695 | 1 | 9,613.695 | 0.447 | 0.511 | 0.020 | |
| TNE | 52.729 | 1 | 52.729 | 1.16 | 0.293 | 0.050 | |
| Total test score | 9.589 | 1 | 9.589 | 0.684 | 0.417 | 0.030 | |
| Group | TET | 118,286.390 | 1 | 118,286.390 | 2.58 | 0.122 | 0.105 |
| LT | 1,794.726 | 1 | 1,794.726 | 0.179 | 0.677 | 0.008 | |
| TPST | 75,836.633 | 1 | 75,836.633 | 3.52 | 0.074 | 0.138 | |
| TNE | 793.944 | 1 | 793.944 | 17.50 | 0.000 | 0.443 | |
| Total | 55.303 | 1 | 55.303 | 3.94 | 0.060 | 0.152 | |
| Error | TET | 1,006,603.658 | 22 | 45,754.712 | |||
| LT | 221,189.998 | 22 | 10,054.091 | ||||
| TPST | 472,964.619 | 22 | 21,498.392 | ||||
| TNE | 997.786 | 22 | 45.354 | ||||
| Total | 308.582 | 22 | 14.026 |
TET, total execution time; LT, latency time; TPST, total planning-solving time; TNE, total number of errors; Sig., significant.
Table 6.
Test of within-subject effects for problem-solving variable (Greenhouse–Geisser test)
| Component | Source | Sum of squares | df | Mean square | F | Sig. | Partial eta squared |
|---|---|---|---|---|---|---|---|
| TET | Time | 68,030.889 | 1.876 | 36,263.109 | 1.301 | 0.280 | 0.046 |
| Time*Group | 36,739.958 | 1.876 | 19,583.826 | 0.702 | 0.491 | 0.025 | |
| Error | 1,412,298.150 | 50.653 | 27,881.845 | ||||
| LT | Time | 9,102.758 | 1.920 | 4,741.769 | 0.612 | 0.540 | 0.022 |
| Time*Group | 36,739.958 | 1.876 | 19,583.826 | 0.702 | 0.491 | 0.025 | |
| Error | 401,382.946 | 51.832 | 7,743.950 | ||||
| TPST | Time | 30,096.375 | 1.637 | 18,380.990 | 1.081 | 0.337 | 0.038 |
| Time*Group | 29,965.612 | 1.637 | 18,301.128 | 1.076 | 0.338 | 0.038 | |
| Error | 751,828.056 | 44.209 | 17,006.286 | ||||
| TNE | Time | 161.231 | 1.876 | 85.941 | 2.736 | 0.078 | 0.092 |
| Time*Group | 486.608 | 1.876 | 259.377 | 8.257 | 0.001 | 0.234 | |
| Error | 1,591.102 | 50.654 | 31.411 | ||||
| Total test score | Time | 4.007 | 1.847 | 2.169 | 0.209 | 0.795 | 0.008 |
| Time*Group | 9.842 | 1.847 | 5.329 | 0.513 | 0.587 | 0.019 | |
| Error | 517.783 | 49.870 | 10.383 |
TET, total execution time; LT, latency time; TPST, total planning-solving time; TNE, total number of errors; Sig., significant.
Table 7.
Pairwise comparison for problem solving variable
| Group | Measure | Time (I) | Time (J) | Mean difference (I−J) | Standard error | Sig. | 95% Confidence interval | |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Lower bound | Upper bound | |||||||
| tDCS + medication | TET | Pretest | Posttest | 180.133 | 68.421 | 0.062 | −7.745 | 368.012 |
| Follow-up | 252.867* | 58.863 | 0.003 | 91.232 | 414.501 | |||
| Posttest | Pretest | −180.133 | 68.421 | 0.062 | −368.012 | 7.745 | ||
| Follow-up | 72.733 | 30.399 | 0.098 | −10.740 | 156.207 | |||
| Follow-up | Pretest | −252.867* | 58.863 | 0.003 | −414.501 | −91.232 | ||
| Posttest | −72.733 | 30.399 | 0.098 | −156.207 | 10.740 | |||
| LT | Pretest | Posttest | −18.867 | 31.512 | 1.000 | −105.397 | 67.664 | |
| Follow-up | 23.400 | 20.101 | 0.796 | −31.795 | 78.595 | |||
| Posttest | Pretest | 18.867 | 31.512 | 1.000 | −67.664 | 105.397 | ||
| Follow-up | 42.267 | 22.415 | 0.246 | −19.283 | 103.817 | |||
| Follow-up | Pretest | −23.400 | 20.101 | 0.796 | −78.595 | 31.795 | ||
| Posttest | −42.267 | 22.415 | 0.246 | −103.817 | 19.283 | |||
| TPST | Pretest | Posttest | 165.067* | 53.184 | 0.025 | 19.025 | 311.108 | |
| Follow-up | 203.600* | 52.337 | 0.006 | 59.887 | 347.313 | |||
| Posttest | Pretest | −165.067* | 53.184 | 0.025 | −311.108 | −19.025 | ||
| Follow-up | 38.533 | 22.814 | 0.345 | −24.113 | 101.180 | |||
| Follow-up | Pretest | −203.600* | 52.337 | 0.006 | −347.313 | −59.887 | ||
| Posttest | −38.533 | 22.814 | 0.345 | −101.180 | 24.113 | |||
| TNE | Pretest | Posttest | 12.200* | 1.549 | 0.000 | 7.948 | 16.452 | |
| Follow-up | 12.200* | 2.133 | 0.000 | 6.344 | 18.056 | |||
| Posttest | Pretest | −12.200* | 1.549 | 0.000 | −16.452 | −7.948 | ||
| Follow-up | 0.000 | 1.335 | 1.000 | −3.666 | 3.666 | |||
| Follow-up | Pretest | −12.200* | 2.133 | 0.000 | −18.056 | −6.344 | ||
| Posttest | 0.000 | 1.335 | 1.000 | −3.666 | 3.666 | |||
| Total test score | Pretest | Posttest | −2.400 | 1.244 | 0.227 | −5.815 | 1.015 | |
| Follow-up | −3.667* | 0.935 | 0.005 | −6.233 | −1.100 | |||
| Posttest | Pretest | 2.400 | 1.244 | 0.227 | −1.015 | 5.815 | ||
| Follow-up | −1.267 | 1.020 | 0.709 | −4.068 | 1.534 | |||
| Follow-up | Pretest | 3.667* | 0.935 | 0.005 | 1.100 | 6.233 | ||
| Posttest | 1.267 | 1.020 | 0.709 | −1.534 | 4.068 | |||
| Medication | TET | Pretest | Posttest | 109.533 | 66.220 | 0.366 | −72.302 | 291.369 |
| Follow-up | 245.533* | 51.407 | 0.001 | 104.372 | 386.694 | |||
| Posttest | Pretest | −109.533 | 66.220 | 0.366 | −291.369 | 72.302 | ||
| Follow-up | 136.000 | 68.834 | 0.209 | −53.013 | 325.013 | |||
| Follow-up | Pretest | −245.533* | 51.407 | 0.001 | −386.694 | −104.372 | ||
| Posttest | −136.000 | 68.834 | 0.209 | −325.013 | 53.013 | |||
| LT | Pretest | Posttest | 25.800 | 25.530 | 0.992 | −44.303 | 95.903 | |
| Follow-up | 60.467 | 42.990 | 0.549 | −57.580 | 178.513 | |||
| Posttest | Pretest | −25.800 | 25.530 | 0.992 | −95.903 | 44.303 | ||
| Follow-up | 34.667 | 39.797 | 1.000 | −74.614 | 143.947 | |||
| Follow-up | Pretest | −60.467 | 42.990 | 0.549 | −178.513 | 57.580 | ||
| Posttest | −34.667 | 39.797 | 1.000 | −143.947 | 74.614 | |||
| TPST | Pretest | Posttest | 84.400 | 46.807 | 0.284 | −44.129 | 212.929 | |
| Follow-up | 185.000* | 40.338 | 0.002 | 74.235 | 295.765 | |||
| Posttest | Pretest | −84.400 | 46.807 | 0.284 | −212.929 | 44.129 | ||
| Follow-up | 100.600 | 38.246 | 0.062 | −4.423 | 205.623 | |||
| Follow-up | Pretest | −185.000* | 40.338 | 0.002 | −295.765 | −74.235 | ||
| Posttest | −100.600 | 38.246 | 0.062 | −205.623 | 4.423 | |||
| TNE | Pretest | Posttest | 1.133 | 1.895 | 1.000 | −4.071 | 6.337 | |
| Follow-up | 6.600* | 2.205 | 0.031 | 0.544 | 12.656 | |||
| Posttest | Pretest | −1.133 | 1.895 | 1.000 | −6.337 | 4.071 | ||
| Follow-up | 5.467 | 2.634 | 0.175 | −1.767 | 12.700 | |||
| Follow-up | Pretest | −6.600* | 2.205 | 0.031 | −12.656 | −0.544 | ||
| Posttest | −5.467 | 2.634 | 0.175 | −12.700 | 1.767 | |||
| Total test score | Pretest | Posttest | −1.200 | 1.153 | 0.951 | −4.366 | 1.966 | |
| Follow-up | −3.667* | 0.728 | 0.001 | −5.665 | −1.668 | |||
| Posttest | Pretest | 1.200 | 1.153 | 0.951 | −1.966 | 4.366 | ||
| Follow-up | −2.467 | 1.130 | 0.144 | −5.569 | 0.636 | |||
| Follow-up | Pretest | 3.667* | 0.728 | 0.001 | 1.668 | 5.665 | ||
| Posttest | 2.467 | 1.130 | 0.144 | −0.636 | 5.569 | |||
TET, total execution time; LT, latency time; TPST, total planning-solving time; TNE, total number of errors; Sig., significant.
*The mean difference is significant at p < 0.05.
DISCUSSION
In patients with BD, extreme mood changes can impair their ability to solve problems [10]. They also tend to use more maladaptive emotion regulation strategies and engage in maladaptive emotion-related impulsivity [19,20]. To the best of our knowledge, this is the first clinical trial that assess the effectiveness of pharmacotherapy combined with tDCS in improving problem solving and emotion regulation in patients (adults) with BD I. The results revealed the efficacy of right anode/left cathode tDCS (2 mA, 20 minutes) over the right DLPFC combined with medication (mood stabilizers) in reducing the total number of errors under TOL test compared to the medication therapy alone, indicating its impact on the improvement of problem-solving ability. It remained unchanged after 3 months. This supports the first hypothesis of this study. According to Salvi et al. [29], tDCS to the right anterior temporal lobe facilitates insight problem-solving. Problem solving is a complex behavior that requires a network of cortical areas for all types of solving strategies and solutions. People make solution decisions about presented words more quickly when words are presented to the left visual hemifield, which projects directly to the right hemisphere, than when words are presented to the right visual hemifield, which projects to the left hemi-sphere. This suggests that the right hemisphere semantic processing is more likely than left right hemisphere semantic processing to produce lexical or semantic infor-mation that leads to the solution [30]. Metuki et al. [31] applied anodal tDCS to the left DLPFC and concluded that the executive control of this region modulates semantic processing of verbal insight problems. Our result is somehow consistent with the results of Aghajani et al. [32]. In a study in Iran using TOL test, they found that tDCS can improve problem solving skills of male high school students.
Our findings also revealed the effectiveness of medication plus tDCS and medication alone in improving emotion regulation (total ERQ score and its CR domain) of adults with BD I; no significant difference in its ES domain was reported. This supports the second hypothesis of this study. In both groups, however, the emotion regulation ability decreased 3 months after intervention. Stable results may be achieved if the number and duration of tDCS sessions increases or the stimulated area is changed. The effect of tDCS over DLPFC on emotion regulation may be due to the fact that anodal stimulation affects the cortical surface of the amygdala by increasing the appropriate rate of neuronal firing. Activity in specific areas of the frontal cortex including DLPFC covaries with amygdala activity [33,34]. Our result is consistent with the results of Feeser et al. [35]. They concluded that tDCS facilitates CR in both directions by either increasing or decreasing emotional responsiveness depending on the regulatory goal. According to them, anodal tDCS influences arousal during emotion regulation. They suggested the potential use of tDCS as a tool to modulate CR. Peña-Gómez et al. [36] applied tDCS over left DLPFC and reported that anodal tDCS reduced the perceived degree of emotional valence for negative stimuli, possibly due to an enhancement of cognitive control of emotional expression. In Pripfl and Lamm’s study [37], anodal right tDCS over the DLPFC reduced negative affect in emotion appraisal, but did not modulate the regulation of positive emotion appraisal. Anodal left stimulation did not induce any significant effects.
There were some limitation/disadvantages in the present study. We used a purposive sampling method and small sample size (due to lack of BD patients in the outpatient clinic during the COVID-19 pandemic), low number of male patients (due to their lack of cooperation), and no sham group. Furthermore, the generalizability of findings to all patients with BD 1 worldwide should be done with caution. Therefore, further studies are recommended using a larger sample size, a sham group, and objective tools (e.g., electroencephalography or functional magnetic resonance imaging). Evaluation of the effect of combining pharmacotherapy with psychotherapy or other novel therapies such as neurofeedback or repetitive Transcranial Magnetic Stimulation is recommended in BD patients.
Combination of tDCS with medication therapy is effective in improving problem solving and emotional regulation (cognitive reappraisal) abilities of patients with BD I.
Acknowledgements
This study was extracted from the master thesis of the first author. The authors would like to thank all the patients who participated in this study for their cooperation.
Funding Statement
Funding None.
Footnotes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Experiment design: Seyedeh Elnaz Mousavi, Mohsen Dadashi. Data acquisition: Parnaz Mardani, Ahmad Zolghadriha, Hossein Javdani. Data analysis: Seyedeh Elnaz Mousavi, Parnaz Mardani, Mohsen Dadashi. Writing—initial draft and literature search: Seyedeh Elnaz Mousavi, Parnaz Mardani. All authors contributed to and revised the manuscript. All authors read and approved the final manuscript.
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