High-frequency repetitive transcranial magnetic stimulation (rTMS) improves neurocognitive function in bipolar disorder

Journal of Affective Disorders 246 (2019) 851–856

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research paper

High-frequency repetitive transcranial magnetic stimulation (rTMS) improves neurocognitive function in bipolar disorder

T

Yang Lin-Lina,b,1, Zhao Dongc,1, Kong Lan-Lana,b, Sun Ya-Qia,b, Wang Zi-Yanga,b, ⁎⁎ ⁎ Gao Yuan-Yuana,b, Li Naa,b, Lu Lind, , Shi Led, Wang Xue-Yia,b, Wang Yu-Meia,b, a

Institute of Mental Health, Hebei Medical University, Shijiazhuang, 050031, China Department of Psychiatry, First Hospital of Hebei Medical University, Shijiazhuang, 050031, China c Department of Psychiatry, Eighth Hospital of Shijiazhuang, Shijiazhuang, 050080, China d Institute of Mental Health, National Clinical Research Center for Mental Disorders, Key Laboratory of Mental Health and Peking University Sixth Hospital, Peking University, Beijing, 100191, China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Bipolar disorder Repetitive transcranial magnetic stimulation Cognitive function

Background: Patients with bipolar disorder (BD) present widespread and significant neurocognitive impairments during all stages of the disorder. Repetitive transcranial magnetic stimulation (rTMS) has been used to improve clinical outcomes in common psychiatric diseases, such as depression, anxiety disorders, schizophrenia, and BD. Whether rTMS can improve cognitive function in BD patients remains unclear. The present study explored the regulatory effects of rTMS on cognitive function in patients with BD. Methods: Fifty-two eligible subjects with BD were randomly assigned to receive active or sham rTMS via highspeed magnetic stimulator with a figure-of-eight coil for 10 consecutive days. In the active rTMS group, a total of 25,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of the motor threshold. The sham group received corresponding sham stimulation. Clinical manifestations and cognitive functions were assessed using a modified 24-item Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS), and the MATRICS Consensus Cognitive Battery (MCCB). Results: Ten consecutive days of high-frequency active rTMS improved scores on the Wechsler Memory Scale-III Spatial Span, and the MCCB Category Fluency subtest, without intolerable adverse effects. No significant differences in HDRS or YMRS scores were found between groups. Limitations: No follow-up after the intervention. The effect of the drug on cognitive function in subjects was not excluded. Conclusions: Short-term rTMS can improve cognitive function in BD patients.

1. Introduction Bipolar disorder (BD) is a recurrent and highly disabling affective disorder that ranks first among the 20 leading medical causes of disability (World Health Organization, 2011). The main characteristics of BD are mood swings and cognitive disturbances (Lima et al., 2017). Previous studies have consistently found that individuals with BD exhibit widespread neurocognitive dysfunction during acute episodes of mania (Clark et al., 2001) and depression (Borkowska and Rybakowski, 2001), including impairments in cognitive speed, attention, working memory, verbal memory, and executive function. Even

during the euthymic mood state, BD patients present significant deficits in working memory and delayed verbal memory compared with health controls (Volkert et al., 2016). The severity of impairments in executive function (Martinez-Aran et al., 2000; Rubinsztein et al., 2000), declarative memory (Martinez-Aran et al., 2000; Krabbendam et al., 2000; Zubieta et al., 2001), and sustained attention (Clark et al., 2002; Harmer et al., 2002) is comparable between acute and remission phases, indicating that dysregulations of cognitive function and mood state exist independently. Cognitive impairments may be the core pathophysiology of the illness rather than occurring secondary to mood symptoms (Glahn et al., 2004; Mur et al., 2007). Poor cognitive

⁎ Corresponding author at: Institute of Mental Health, Brain Aging and Cognitive Neuroscience Laboratory, Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, China ⁎⁎ Co-corresponding author. E-mail addresses: [email protected] (L. Lu), [email protected] (Y.-M. Wang). 1 These authors contributed equally to this work.

https://doi.org/10.1016/j.jad.2018.12.102 Received 6 August 2018; Received in revised form 9 December 2018; Accepted 24 December 2018 Available online 25 December 2018 0165-0327/ © 2018 Elsevier B.V. All rights reserved.

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The study was approved by the Ethics Committee of the First Hospital of Hebei Medical University. Before the experiments, all of the participants were informed about the purpose of the study and all of them signed consent forms. The antipsychotic and mood-stabilizing drug profiles for the active and sham groups (25 and 27, respectively) were the following: amisulpride (0 and 1, respectively), aripiprazole (5 and 4, respectively), lithium (6 and 7, respectively), olanzapine (5 and 3, respectively), quetiapine (9 and 15, respectively), peridone (3 and 3, respectively), valproate (9 and 9, respectively), valproic acid magnesium (8 and 14, respectively), paliperidone (0 and 1, respectively), and ziprasidone (1 and 0, respectively).

function decreases a patient's quality of life and has a negative impact on clinical treatment (Latalova et al., 2011). Cognitive impairment in patients with BD may continue to worsen as the disease progresses and is a susceptibility factor for BD recurrence (Brissos et al., 2008; Robinson and Ferrier, 2006). These cognitive impairments should be treated; nonetheless, the increased number of studies investigating new pharmacological and nonpharmacological treatments over the past decade did not provide any robust evidence for therapeutic interventions targeting cognitive deficits. Consequently, further research is urgently needed to draw firm conclusions. Special, cognitive remediation appears as a good long-term option to ameliorate psychosocial outcomes in bipolar patients, however clinical trials for BD (Solé et al., 2017) are still lacking. Repetitive transcranial magnetic stimulation (rTMS) has been used to treat affective disorders, such as depression and BD, and to ameliorate mood symptoms. Compared with pharmacological therapy, rTMS is noninvasive, well tolerated, and relatively safe. Even though accumulating evidence indicates that rTMS affects spontaneous activity in the brain and higher cognitive function in general population (McKinley et al., 2012), patients with mild cognitive impairment (Rabey et al., 2013), and schizophrenia patients (Mittrach et al., 2010; Klein et al., 1999), no specific enhancing effects have been observed on some of cognitive tasks in studies of rTMS treatment (Cristea et al., 2018). Some previous studies have indicated that rTMS can improve depressive symptoms (Dell'Osso et al., 2009) and manic symptoms (Praharaj et al., 2009). It can also be used to effectively treat patients with comorbid physical illness, patients who cannot tolerate the side effects of drug therapy, and refractory BD patients (Dell'Osso et al., 2009; Zendjidjian et al., 2014). However, only few studies have explored the effect of rTMS on cognitive function in BD patients. The purpose of this study was to explore the efficacy and safety of rTMS in improving cognitive function in patients with BD.

2.3. Interventions Experiment equipment is a Rapid2 machine manufactured by Magstim, UK. The participants were randomly assigned to receive a course of active or sham rTMS via high-speed magnetic stimulator with a figure-of-eight coil. The motor threshold (MT) was determined on a daily basis (Pridmore et al., 1998) and was defined at the point of maximal stimulation for the right abductor pollucisbrevis or other hand muscles upon visual detection with the paddle axis oriented laterally. The treatment site (left dorsolateral prefrontal cortex [DLPFC]) was defined as 5 cm anterior to this point. Over 10 consecutive days (starting from Monday), the participants received fifty 5-s, 10-Hz trains delivered at 110% of the MT at 30-s inter-train intervals. For active treatment, the coil was tangentially placed on the scalp with the paddle axis oriented toward the bridge of the nose. For sham treatment, a false coil was placed in the same position as the active treatment. The sham treatment produced the same vibration as the true stimulus but no magnetic field and thus no therapeutic effect. 2.4. Sample size estimate

2. Materials and methods The significant level was bilaterally α = 0.05, the test efficacy was 1-β = 80%, and the enrolled subjects were followed up for 2 weeks. After reviewing the literature, assuming a hazard ratio (HR) of 0.692, the control group and the experimental group were 1:1. Taking into account the proportion of the group, and the side effects caused by accidental factors and recurrence of symptoms, it was expected that 30% of the test group and the control group would be included in the test (Chow et al., 2003).

2.1. Trial design This study was a single-blind randomized controlled trial in which participants were divided into intervention and control groups. While participants did not know to which group they were assigned before the end of the trial, the researchers did. Participants were numbered according to the order of enrollment, where odd numbers were assigned to interventions, and even numbers were assigned to controls.

2.5. Assessments 2.2. Participants A standard clinical protocol was used to monitor progress in all of the participants who underwent rTMS. The participants underwent baseline clinical assessments and follow-up clinical assessments that were performed using a modified 25-item HDRS, the YMRS, the Pittsburgh Sleep Quality Index (PSQI), and the MATRICS Consensus Cognitive Battery (MCCB). Adverse effects were recorded on a daily basis. The MCCB was developed for clinical trials estimating cognition in schizophrenia (Nuechterlein et al., 2008; Kern et al., 2008; Nuechterlein et al., 2004; Green and Nuechterlein, 2004). Previous studies have confirmed that the MCCB is an appropriate measure of neurocognition in BD (Sperry et al., 2015; Burdick et al., 2011; Burdick et al., 2014). The present study used the Chinese version of the MCCB, revised by Zou et al (Zhou et al., 2009). All of the subtests and composite scores of the MCCB were significantly correlated with the Wisconsin Card Sorting Test (WCST), Raven's Standard Progressive Matrices, and Stroop scores (r = 0.54–0.55, p < 0.05), thus demonstrating good concurrent validity of the MCCB. The MCCB includes seven cognitive domains and 10 subtests: (i)attention/vigilance(Continuous Performance Test-Identical Pairs); (ii)working memory(University of Maryland Letter-Number Span and Wechsler Memory ScaleIII [WMS-III] Spatial Span); (iii)verbal learning(revised Hopkins Verbal

Participants were recruited form outpatients at the First Hospital of Hebei Medical University. The inclusion criteria were the following: (i) 18–55 years of age, (ii) diagnosis of bipolar I or II disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4thedition, text revision (DSM-IV-TR), (iii) stable antipsychotic and mood-stabilizing treatment, and (iv) at least 3 months of clinical remission before entering the randomization phase, Young Mania Rating Scale (YMRS) score ≤ 6 (Young et al., 1978) and a modified 24-item Hamilton Depression Rating Scale(HDRS) score ≤ 8 (Mazure et al., 1986). The exclusion criteria included the following:(i) patients who met the criteria for a diagnosis of substance or alcohol abuse; (ii) history of significant neurologic illness, such as seizures or head trauma; (iii) electroencephalography (EEG)abnormalities that were suggestive of an epileptic predisposition; (iv) significant, unstable medical illnesses; (v) electroconvulsive therapy or rTMS within the past year; and (vi) participation in any structured psychological intervention, such as psychoeducation or cognitive remediation, within the past 2 years,(vii) comorbidities in structured clinical interview for DSM-IV (SCID) (Spitzer and Wakefield, 1999). 852

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3.2. Emotional symptoms

Learning Test), (iv)visual learning(revised Brief Visuospatial Memory Test); (v)speed of processing(Category Fluency, Trail Making A, and Brief Assessment of Cognition in Schizophrenia[BACS] Symbol Coding, vi)reasoning and problem solving(Neuropsychological Assessment Battery[NAB] Mazes); and (vii)social cognition Mayer Salovey Caruso Emotional Intelligence Test [MSCEIT] Managing Emotions).

The data were analyzed using a 2 × 2 repeated-measures ANOVA, with treatment group (active rTMS vs. sham stimulation) as the between-participants factor and time of MCCB test (baseline vs. followup) as the within-participants factor. No differences in HDRS scores (F1,50 = 0.577, p = 0.451) or YMRS scores (F1,50 = 0.657, p = 0.422) were found between groups at baseline and follow-up. Further data are presented in Table 2.

2.6. Statistical analysis The data were analyzed using SPSS 18 software. The data are expressed as mean ± standard deviation (SD) and values of p < 0.05were considered statistically significant. Independent sample ttest and chi-square test were used for the general demographic data. Data on emotional symptoms were analyzed using a 2 × 2 repeatedmeasures ANOVA, with treatment group (active rTMS vs. sham stimulation) as the between-participants factor and time of MCCB test (baseline vs. follow-up) as the within-participants factor. Although the mood changes in the two groups before and after treatment were not significant, we included HDRS and YMRS as covariates in the analyses in order to consider the potential impact of these covariates. The covariance analysis was used to calculate the changes of MCCB factors before and after treatment. The independent variable was the reduction rate of each factor of MCCB, and the covariates were the reduction rate of HDRS and YMRS. Reduction rate = (baseline - follow-up) / baseline.

3.3. Cognitive function The score data of MCCB are shown in Table 3. rTMS improved cognitive function in BD participants in the WMS-III Spatial Span (F1,50 = 6.484, p = 0.014), and MCCB Category Fluency subtest (F1,50 = 4.853, p = 0.032). Fig. 1 shows the reduction ratios of the WMS-III Spatial Span and Category Fluency. 3.4. Treatment side effects No serious side effects were reported during or after treatment. Three participants (one in the rTMS group and two in the sham group) experienced mild dizziness during the first treatment. One patient in the rTMS group developed insomnia that disappeared after three treatments.

3. Results 4. Discussion 3.1. Demographic information In the present study, we evaluated the effects of 2 weeks of highfrequency rTMS over the left DLPFC, on cognitive impairment in BD participants in remission. The results showed that working memory and processing speed significantly improved in BD participants after rTMS, thus suggesting that rTMS had positive effect on cognitive function in BD participants, without causing adverse effects. rTMS is clinically safe, effective and widely used physical technology. In a previous study, researchers on high-frequency rTMS published between 1999 and 2009 have been systematically reviewed (Guse et al., 2010). These previous studies applied stimulation over the PFC in participants who suffered from psychiatric or neurological diseases and in healthy volunteers, measuring the effects on cognitive function. High-frequency rTMS (10–20 Hz) was most likely to cause significant cognitive improvement when applied over the left DLPFC within a range of 10 to 15 successive sessions and with an individual MT between 80% and 110%. The

A total of 60 participants were enrolled in the present study, eight of whom (13.3%) did not enter the randomization process for various reasons (e.g., withdrew consent, no longer met study criteria, or lost to follow-up). The remaining 52 participants were randomly assigned to the active treatment group or sham group and entered the 2-week intervention phase. The participants’ baseline clinical and demographic characteristics are summarized in Table 1. No significant differences were found between groups in age, age at illness onset of depression, number of depressive episodes, age at illness onset of manic episodes, number of manic episodes, body mass index, total number of episodes, illness duration, psychiatric symptoms, life events, recent episode type, antipsychotic class, HDRS score, YMRS score, or PSQI score (p > 0.05).The active treatment group had lower level of education than the sham group(t = 2.144, p = 0.037).

Table1 Baseline clinical and sociodemographic characteristics of euthymic participants with bipolar disorder.

Gender: Male /Female Age (years) Education (years) Age at illness onset of depression (years) Number of depressive episodes Age at illness onset of manic episodes (years) Number of manic episodes Body mass index Total number of episodes Illness duration (years) Psychiatric symptoms Life events Recent episode type Antipsychotic species HDRS score YMRS score PSQI score

Active rTMS (n = 25) Mean ± SD

Sham stimulation (n = 27) Mean ± SD

χ 2/ t

P

12/13 28.64 ± 8.05 12.89 ± 2.47 20.67 ± 5.55 4.48 ± 3.58 22.37 ± 6.74 2.88 ± 2.83 25.34 ± 3.87 5.92 ± 5.13 7.92 ± 5.74 0.36 ± 0.49 0.64 ± 0.49 0.72 ± 0.79 1.20 ± 1.08 4.80 ± 2.78 0.76 ± 1.05 4.52 ± 2.31

19/8 27.41 ± 7.08 14.20 ± 1.87 19.19 ± 4.91 3.12 ± 2.51 23.12 ± 8.23 2.96 ± 2.68 25.24 ± 4.00 7.44 ± 5.21 7.00 ± 4.15 0.52 ± 0.51 0.56 ± 0.51 0.70 ± 0.61 1.33 ± 1.00 4.85 ± 2.92 0.96 ± 1.34 4.41 ± 2.45

2.698 0.587 2.144 1.012 −1.549 0.360 −1.142 −0.110 −1.053 0.360 1.012 −0.108 0.503 −1.849 −0.065 −0.603 0.170

0.100a 0.560b 0.037 b 0.316 b 0.128 b 0.721 b 0.259 b 0.913 b 0.297 b 0.721 b 0.316 b 0.914 b 0.617 b 0.070 b 0.948 b 0.549 b 0.866 b

rTMS, repetitive transcranial magnetic stimulation; HDRS, Hamilton Depression Rating Scale; YMRS, Young Manic Rating Scale; PSQI, Pittsburgh Sleep Quality Index. p-value: a indicates the chi-square test result, while b indicates the independent sample t-test result. 853

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Table 2 Statistical analysis of HDRS and YMRS scores.

HDRS score YMRS score

Active rTMS (n = 25) Baseline

Follow-up

Sham stimulation (n = 27) Baseline

Follow-up

F

P

4.80 ± 2.784 0.76 ± 1.052

3.20 ± 2.141 0.76 ± 0.879

4.96 ± 2.919 1.00 ± 1.356

3.81 ± 2.367 0.77 ± 0.992

0.577 0.657

0.451 0.422

The p-value is two group (active rTMS vs. sham stimulation) × 2 time (baseline vs. follow-up) repeated-measures ANOVA result. Table 3 MCCB data and statistical analysis. Active rTMS (n = 25) Baseline

Follow-up

Sham stimulation (n = 27) Baseline Follow-up

F

p

2.470 ± 0.927

2.830 ± 0.760

2.587 ± 0.823

2.768 ± 0.779

0.017

0.896

23.560 ± 3.606

24.000 ± 3.926

22.259 ± 3.415

23.407 ± 3.456

0.313

0.578

15.440 ± 4.312

18.840 ± 4.170

17.521 ± 3.857

18.814 ± 4.123

6.484

0.014

29.440 ± 4.788

29.640 ± 5.685

26.667 ± 5.588

27.333 ± 6.995

0.116

0.735

24.200 ± 6.390

29.600 ± 5.172

23.593 ± 6.535

26.444 ± 6.612

2.724

0.105

21.120 ± 4.816 44.760 ± 16.042 53.800 ± 10.054

25.080 ± 4.864 34.440 ± 12.735 56.720 ± 11.894

20.185 ± 5.031 46.222 ± 21.495 51.444 ± 12.236

21.407 ± 5.786 35.963 ± 11.227 55.741 ± 11.782

4.853 0.686 1.110

0.032 0.412 0.297

10.680 ± 5.706

14.240 ± 5.988

11.444 ± 5.337

12.778 ± 5.033

2.448

0.124

9.200 ± 1.633

9.440 ± 2.063

10.148 ± 1.994

10.000 ± 2.418

0.398

0.531

Attention/vigilance Continuous Performance Test-Identical Pairs Working memory, verbal University of Maryland Letter-Number Span Working memory, nonverbal WMS-III Spatial Span Verbal learning Hopkins Verbal Learning Test, Revised Visual learning Brief Visuospatial Memory Test, Revised Processing speed Category Fluency Trail Making A BACS Symbol Coding Reasoning and problem solving NAB Mazes Social cognition MSCEIT Managing Emotions

The p-value is the statistical result of covariance analysis; the independent variable is the reduction rate of each factor of MCCB; the covariate is the reduction rate of Hamilton Depression Rating Scale (HDRS) and Young Manic Rating Scale (YMRS).Reduction rate = (baseline - follow-up) / baseline.

Fig.1. The reduction rate [Reduction rate=(baseline - follow-up) / baseline] of WMS-III Spatial Span and Category Fluency in the MATRICS Consensus Cognitive Battery (MCCB).

prefrontal region, which mainly involved in cognitive control (Miller and Cohen, 2001) and emotional regulation (Ochsner and Gross, 2005). rTMS may improve the cognitive function of BD by exerting influence on DLPFC. There are several reasons why rTMS may promote cognitive enhancement; first, rTMS may prolong neuronal depolarization, enhance neurotransmission between cells, and alter neural loop activity (Gerschlager et al., 2002); second, rTMS may increase brain-derived neurotrophic factor mRNA expression and protein levels, which can have a neuroprotective effect (Muller et al., 2000); third, rTMS may regulate cerebral cortical function by altering cerebral cortex excitability and enhancing synaptic plasticity (Machii et al.,

enhancement of cognitive function induced by active rTMS was higher in the clinical group than in the general population and treatment effect in active rTMS was superior to sham stimulation. A previous study evaluated the cognitive effects of H1-coil (deep) transcranial magnetic stimulation (TMS) in patients with treatment-resistant BD. Forty-three patients were randomized to receive 20 sessions of active (55 trains, 18 Hz, 120% resting motor threshold intensity) or sham rTMS within a double-blind, sham-controlled trial. The results revealed cognitive improvement in all cognitive domains, that occurred regardless of intervention group and depression improvement (Myczkowski et al., 2018). Our findings were consistent with results from that study. DLPFC is a 854

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In summary, rTMS improved visual learning and processing speed in remitted BD participants without causing significant adverse effects. The present study provides evidence that neurocognitive processes can be enhanced by rTMS in BD participants in remission. rTMS is relatively safe, simple, and effective way to treat cognitive dysfunction in BD patients.

2006). In the present study, we observed no significant improvement in depressive symptoms; which was inconsistent with previous research results reported by meta-analysis of randomized, sham-controlled studies of rTMS treatment for depression (34 studies). rTMS can effectively improve mood in patients with depression, and monotherapy with rTMS has shown to be more effective than rTMS as adjunctive to antidepressant medication (Slotema et al., 2010). It is possible that most of the previous studies included patients who were in the acute phase, and thus the emotional symptoms were more significant. The participants in this study were in remission. Cognitive impairment in BD patients can be expressed as transient (state-related) or persistent (trait-related) (Clark and Goodwin, 2004). In the acute attack phase, almost every cognitive domain is negatively affected. During the depression phase, executive function is significantly compromised. This damage to stable cognitive function can be partially restored (Volkert et al., 2016; Vrabie et al., 2015), but some long-term damage can also occur, including deleterious effects on attention, learning, memory, and executive function (Bora et al., 2009), which are trait markers of BD (Bora et al., 2011; Langenecker et al., 2010). The present results suggested that some cognitive functions improve in BD participants after rTMS. However, whether the improvement in cognitive function is simply attributable to improvements in clinical symptoms remains unclear. Nonetheless, this possibility may be excluded for three reasons: first, in the present study, the participants were in remission. Therefore, their clinical symptoms were not particularly pronounced and thus did not significantly impact the findings. Second, the clinical symptoms in the two groups were not significantly different before and after rTMS. Third, emotional data were included as a control variable in the data analysis, and at the statistical level to minimize the impact of emotion on cognitive function. Therefore, the improvements in cognitive function that were caused by rTMS did not appear to depend on symptom improvement, thus suggesting that cognitive function itself improved. The level of education is a protective factor against the decline of cognitive function in the elderly (Farmer et al., 1995). The active treatment group had lower education level than the sham group, which might suggest that cognitive impairment in the intervention group is greater and more difficult to reverse than in the sham group. Therefore, this factor does not reduce the reliability of the conclusions of the trial. Cognitive dysfunction is increasingly recognized as a key feature of BD. Neurocognitive deficits persist across illness stages, including euthymic (Robinson et al., 2006), and may be more severe in patients with BD with a history of psychosis (Lewandowski et al., 2011). Currently, there are no available tools for systematical evaluation of cognitive function in BD. The MCCB was developed for clinical trials estimating cognition in schizophrenia, and it has shown to have good reliability and validity (Nuechterlein et al., 2008; Kern et al., 2008; Nuechterlein et al., 2004; Green and Nuechterlein, 2004). This study attempted to use MCCB to evaluate the cognitive function of BD. The advantage is that the MCCB contains a wide range of cognitive function, the disadvantage is the lack of social cognition (Sperry et al., 2015). None of the participants in this study experienced serious side effects, suggesting that rTMS is a safe treatment for BD participants during remission, which is a conclusion consistent with previous studies (Rossi et al., 2009). During the trial, the subject's mood did not reveal large fluctuations or recurrence, because the patients’ experienced a three-month clinical remission period before enrollment, the study duration was relatively short, and the probability of recurrence was relatively small. The present study following limitations: relatively small sample size; the intervention cycle that was relatively short; no long-term return visit tracking after the end of treatment. Also, all of the participants continued their medication regimens during the study period which means it is possible that the specific medications influenced cognitive function. Finally, there was no classification of BD participants.

Disclosure statement This was not an industry-supported study. There was no investigational or off-label use. The authors declare no conflicts of interest. This work was supported by the National Science Foundation of China (no. 81771463). The funding agency had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. Clinical trial information High-frequency repetitive transcranial magnetic stimulation (rTMS) improves neurocognitive function in bipolar disorder(ChiCTR-IPC15006566). The work was performed at the Institution of Mental Health, Hebei Medical University, and Department of Psychiatry, First Hospital of Hebei Medical University. Conflict of interest All of the authors have been personally and actively involved in substantive work leading to the report and will hold themselves jointly and individually responsible for its content. All authors approved the final version of the manuscript for publication and declare no conflict of interest. References Lima, I.M.M., Peckham, A.D., Johnson, S.L., 2017. Cognitive deficits in bipolar disorders: implications for emotion. Clinical Psychol. Rev. 59, 126–136. https://doi.org/10. 1016/j.cpr.2017.11.006. Clark, L., Iversen, S.D., Goodwin, G.M., 2001. A neuropsychological investigation of prefrontal cortex involvement in acute mania. Am. J. Psychiatry 158 (10), 1605–1611. https://doi.org/10.1176/appi.ajp.158.10.1605. Borkowska, A., Rybakowski, J.K., 2001. Neuropsychological frontal lobe tests indicate that bipolar depressed patients are more impaired than unipolar. Bipolar Disorders 3 (2), 88–94. Volkert, J., Schiele, M.A., Kazmaier, J., Glaser, F., Zierhut, K.C., Kopf, J., et al., 2016. Cognitive deficits in bipolar disorder: from acute episode to remission. Eur. Arch.Psychiatry Clinical Neurosci. 266 (3), 225–237. https://doi.org/10.1007/ s00406-015-0657-2. Martinez-Aran, A., Vieta, E., Colom, F., Reinares, M., Benabarre, A., Gasto, C., et al., 2000. Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological disturbances. Psychotherapy Psychosomatics 69 (1), 2–18. https://doi.org/10.1159/ 000012361. Rubinsztein, J.S., Michael, A., Paykel, E.S., Sahakian, B.J., 2000. Cognitive impairment in remission in bipolar affective disorder. Psychol. Med. 30 (5), 1025–1036. Krabbendam, L., Honig, A., Wiersma, J., Vuurman, E.F., Hofman, P.A., Derix, M.M., et al., 2000. Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission. Acta Psychiatrica Scandinavica 101 (4), 274–280. Zubieta, J.K., Huguelet, P., O'Neil, R.L., Giordani, B.J., 2001. Cognitive function in euthymic bipolar I disorder. Psychiatry Res. 102 (1), 9–20. Clark, L., Iversen, S.D., Goodwin, G.M., 2002. Sustained attention deficit in bipolar disorder. Br. J.Psychiatry 180, 313–319. Harmer, C.J., Clark, L., Grayson, L., Goodwin, G.M., 2002. Sustained attention deficit in bipolar disorder is not a working memory impairment in disguise. Neuropsychologia 40 (9), 1586–1590. Glahn, D.C., Bearden, C.E., Niendam, T.A., Escamilla, M.A., 2004. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disorders 6 (3), 171–182. https://doi.org/10.1111/j.13995618.2004.00113.x. Mur, M., Portella, M.J., Martinez-Aran, A., Pifarre, J., Vieta, E., 2007. Persistent neuropsychological deficit in euthymic bipolar patients: executive function as a core deficit. J.Clinical Psychiatry 68 (7), 1078–1086. Latalova, K., Prasko, J., Diveky, T., Velartova, H., 2011. Cognitive Impairment in Bipolar Disorder 155. Biomedical Papers of the Faculty of Medicine of Palacky University, Olomouc, Czech Republic, pp. 19–26. Brissos, S., Dias, V.V., Kapczinski, F., 2008. Cognitive performance and quality of life in bipolar disorder. Can. J. Psychiatry 53 (8), 517–524. https://doi.org/10.1177/

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