Cognitive improvements from adjunct therapy with transcranial magnetic stimulation are short-lived in patients with remitted bipolar disorder
Ying Wanga, Chuanxin Liub, Tao Fangc, Xiaodong Lind, Deguo Jiangd, Jingjing Zhud, Chunjun Zhuoac, Jiaen Yed
a Tianjin Anding Hospital, Department of Psychiatric-Neuroimaging-Genetics and Comorbidity Laboratory;
b School of Mental Health, Jining Medical University Department of Biological Psychiatry;
c The Fourth Center Hospital of Tianjin, Department of Radiology;
d Wenzhou Seventh People’s Hospital, Department of Psychiatry and Neuroimaging Centre, Wenzhou, China.
Background: Repetitive transcranial magnetic stimulation (rTMS) has been used as an adjunct therapy to improve the cognitive abilities of patients with remitted bipolar disorder (BPD). This is accomplished through functional brain activity alterations. However, there is limited information about the duration and persistence of cognitive improvements. In the current study, we investigated the long-term (four weeks) cognitive effects of adjunct treatment with rTMS in patients with remitted BPD.
Methods: Twenty-one patients with remitted BDP were enrolled in the study. rTMS was used in patients for four weeks. Global functional connectivity density (gFCD) was used to assess the alterations in brain activity before and after rTMS. The MATRICS Consensus Cognitive Battery (MCCB) was used to evaluate the cognitive abilities of patients before and after rTMS.
Results: Compared to the baseline, cognitive improvements were detected in patients at the end of two weeks of treatment, as determined through increased MCCB scores. Increases in gFCD were observed in the frontal cortex, inferior temporal lobe, and parietal lobe. However, the MCCB scores remained stable during the third week of treatment and began to decline by four weeks post-treatment. Similarly, the increased gFCD values also declined to nearly baseline values by the fourth week post-treatment.
Conclusions: High frequency rTMS can improve the cognitive abilities of patients with remitted BPD rapidly; however, the beneficial effects are short-lived and begin to disappear by three weeks after treatment. The brain activity alterations induced by rTMS also increased initially, followed by substantial declines, suggesting that desensitization or exhaustion may play a role. Further studies are needed to determine the optimal method for maintaining long-term cognitive improvements in patients with remitted BPD.
Keywords: Bipolar disorder, transcranial magnetic stimulation, global functional connectivity, cognitive function, desensitization, exhaustion
Patients with bipolar disorder (BPD) display a wide array of cognitive impairments, ranging from delayed processing speeds to impeded visual and verbal learning . However, none of the cognitive impairments found in patients with BPD have been associated with the state of the disease. For example, cognitive impairment profiles are similar between symptomatic and non-symptomatic patients with BPD, as well as between patients with different types of BPD, such as type 1 and type 2 BPD [2, 3]. The prevalence of cognitive impairment in BP is high, with executive function impairments being the most prevalent at 5-58%, followed by attention/working memory impairments at 10-52%, speed/reaction time impairments at 23-44%, verbal memory impairments at 8-42%, and visual memory impairments at 12-33% [4, 5]. Cognitive impairments have also been found to increase the progression of other disease symptoms in patients with BPD [6, 7]. Considering the deleterious effects of cognitive impairments, researchers have aimed to improve the cognitive abilities of patients through adjunct therapy with repetitive transcranial magnetic stimulation (rTMS) .
In previous reports, rTMS has been associated with improvements in the cognitive functioning of patients with BPD [9, 10]. In addition, cognitive improvements have been linked to specific brain activity alterations. For example, bilateral rTMS was previously found to decrease the functional activity of the default mode network (DMN) and sensorimotor network (SMN), leading to the improvement of executive functioning and verbal memory . In another study, rTMS was found to improve the cognitive control processing circuit . Recently, Thomas-Ollivier et al. reported that rTMS could improve the verbal fluency and psychomotor retardation of patients with BPD . In another study, Yang et al. found that rTMS could improve the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, commonly known as the MCCB, category fluency subtest . In combination, these previous demonstrate that rTMS may improve the cognitive functioning of patients with BPD by stimulating the bilateral or left dorsolateral prefrontal cortex (PFC). In general, high frequency rTMS stimulation of the dorsolateral PFC yielded substantial improvements in the cognitive functioning and psychomotor retardation of patients with BPD, with minimal safety concerns . The cognitive improvements from rTMS may be due to altered brain activity in the cognitive- and memory-related functional networks, such as the DMN and central executive network (e.g., prefrontal lobe, insular lobe, temporal lobe, and hippocampus) [14, 15].
While some reports have demonstrated that rTMS may improve the cognitive functioning of patients of BPD, the majority of these studies observed short-term cognitive effects. To the best of our knowledge, no studies have assessed the persistent or long-term therapeutic effects of rTMS on the cognitive functioning of patients with BPD. In addition, the brain activity alterations associated with cognitive improvements have not been studied in these patients. Hence, in this pilot study, we aim to assess the persistent therapeutic effects of high frequency rTMS in patients with BPD, while also characterizing alterations in brain activity associated with the cognitive improvements. We hypothesize that high frequency rTMS can improve the cognitive functioning of patients with BPD for several weeks, and that cognitive improvements may be associated with specific functional brain alterations.
Material and methods
For this study, 30 patients with BPD (type I) in clinical remission were obtained from Wenzhou Seventh Hospital Outpatient Center between July 2016 and December 2016. The average patient age was 30.8 ± 3.4 years (range: 22-36 years) and consisted of 60% males (n=18) and 40% females (n=12). Patient selection as accomplished using the inclusion and exclusion criteria outlined in Table 1. This study was approved by the Wenzhou Seventh People’s Hospital’s Ethics Committee (IRB date: 2016-01-20). Prior to the study, written informed consent was obtained from all of the participants. The clinicodemographic data of the patients were recorded.
Each patient received one daily session of rTMS for four consecutive weeks. At the baseline and after each session, the patients were immediately evaluated for their cognitive abilities using the MCCB. In addition, magnetic resonance imaging (MRI) was performed after the second week of treatment. To ensure consistency between the patients, the dosages of mood stabilizers and other therapeutic agents were fixed during the study. Patients who experienced severe episodes of mania or depression that required immediate intervention were discarded from the study.
The rTMS was carried out in accordance with safety guidelines from previous studies [8-16]. The scalp locations of the abductor pollicis brevis and 5-cm site were found and traced on the swim cap with previously published movement visualization techniques [15,16]. Briefly, rTMS was applied over the left dorsolateral prefrontal cortex (DLPFC) using a figure-eight-shaped coil, which induced a maximum electrical field that peaks beneath the intersection of the two windings. The Magstim high-speed stimulator (Magstim Company Limited, Wales, UK) was used for delivering the treatment. The left DLPFC stimulation site was defined as the region 5-cm anterior from the area of the optimal site for the primary motor cortex of the left hemisphere, also known as the Pascual-Leone method. This method was previously reported to accurately target the DLPFC area. The motor threshold (MT) was determined for each patient prior to treatment. The stimulation intensity was 110% of the motor threshold of the right abductor pollicis brevis muscle, and the stimulation frequency was constant at 10 Hz. The other stimulation parameters were: 45 trains with 3 sec duration and divided into three blocks, with an inter-train interval of 10 sec for each block. The inter-block interval was 20 sec, resulting in 1,350 pulses/session for approximately 10.5 min/day. Each treatment session was performed at the same time each day (9:00 am UTC+8) .
MRI data acquisition
The 3.0-Tesla MR system (Discovery MR750, General Electric, Milwaukee, WI, USA) was used in this study. Functional magnetic resonance imaging (fMRI) was performed using the GE Healthcare Discovery MR750 3T MRI system (General Electric, Milwaukee, WI, USA), with an eight-channel phased-array head coil. The patients were required to lay in a supine position and asked to restrict thoughts and head movements during the imaging session. The imaging parameters were: 2,000 msec repetition time (TR), 45 msec echo time (TE), 32 slices, 4-mm slice thickness, 0.5-mm gap, field of view (FOV), 64 × 64 acquisition matrix, and 90° flip angle. SENSitivity encoding (SENSE), with a SENSE factor of two and parallel imaging, were used for all of the scans. The high-resolution and 3-dimensional turbo-fast echo T1-weighted sequence was with the following parameters: 8.2/3.2 msec TR/TE, 188 slices, 1-mm thickness, no gap, FOV= 256 × 256, acquisition matrix= 256 × 256, and 12° flip angle .
fMRI data pre-processing
Resting-state fMRI scans were processed using Statistical Parametric Mapping 8 (SPM8; http://www.fil.ion.ucl.ac.uk/spm). First, the initial ten scan volumes were removed to account for scanner stabilization and patient acclimation. Next, the remaining volumes were corrected to account for slice timing and motion artifacts, of which translational and rotational motions of less than 2-mm and 2° were allowed. Six motion parameters and average blood oxygen level-dependent (BOLD) signals of the ventricles and white matter were removed from the datasets. Data with specific volume framewise displacement values that were >0.5 were excluded from the analysis. Bandpass frequencies ranging from 0.01 to 0.08 Hz were used to filter the data. Each structural image was co-registered to the average functional image, and the transformed images were co-registered to the Montreal Neurological Institute (MNI) space using linear registration. The motion-corrected functional volumes were spatially normalized to the MNI using parameters estimated during the linear co-registration. Lastly, the functional images were re-sampled into 3-mm cubic voxels for further analyses .
Brain activity assessment and global functional connectivity density (gFCD) calculation
Global functional connectivity density (gFCD) is an ideal index for assessing whole-brain activity as it reflects the entire brain connectivity, along with alterations of the baseline brain metabolism. The gFCD was calculated for each voxel using a customized Linux script. The Pearson’s linear correlation was used to explore functional connectivity between the voxels, with a correlation coefficient threshold of r > 0.6. Only voxels within the cerebral grey matter mask were used to calculate the gFCD, and the gFCD for any given voxel (x0) was calculated as the total number of functional connections [k(x0)] between x0 and all of the other voxels using a growth algorithm. This procedure was repeated for all of the voxels. To further normalize the distribution, each gFCD value was divided by the average value of all the voxels. A 6 × 6 × 6 mm3 Gaussian kernel was used to spatially smooth the gFCD maps and minimize the effects of anatomical differences among patients, ages, genders, illness durations, and education levels .
HAMD, YRMS, and MCCB assessments
The total severity of hypomanic/manic or depressive symptoms was assessed using the Hamilton Rating Scale for Depression (HAMD) or Young Manic Rating Scale (YMRS), while anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAMA). All of the scales were used to evaluate patients before and after treatment with rTMS. The cognitive abilities of patients were assessed with the MCCB. Specifically, MCCB was used to characterize the trajectory of cognitive ability alterations before and after treatment with rTMS. Lastly, the Global Assessment of Functioning (GAF) was used to assess the global functioning of patients before and after rTMS.
The paired t-test was performed in triplicate to compare the gFCD and MCCB alterations before and after treatment. The alterations at the end of the second week were compared to the baseline (pre-rTMS), while the alterations at the end of the third week were also compared to the baseline. A two-tailed p-value < 0.05 was considered to be statistically significant [20-22].
Clinicodemographic data of patients in this study
Initially, 30 patients with BPD in remissions were enrolled in this study. Although the dosage of the therapeutic agents remained constant throughout the study, five patients relapsed. In addition, four patients withdrew from the study due to self-reported adverse effects, including headache and other uncomfortable feelings. Three patients failed to undergo MRI and were excluded from the study. In total, 21 patients were included in the analysis (Figure 1). The clinicodemographic data of the patients are shown in Table 2.
In this pilot study, we have shown that adjuvant treatment with rTMS can improve the cognitive abilities of patients with remitted BPD. The cognitive improvements occured approximately two weeks after treatment, yet the effects began to weaken by three weeks after treatment. Hence, adjunct therapy with rTMS results in short-term increased brain activity, which is quickly followed by decreased brain activity in the fourth week after treatment.
Previous studies have demonstrated that adjunct therapy with rTMS may improve the cognitive abilities in patients with remitted BPD through alterations in functional brain activity. However, the majority of previous studies have focused on the short-term effects of rTMS at 1-2 weeks post-treatment [9, 13, 23]. A few studies have reported on the relatively long-term effect of rTMS on cognition. In the present pilot study, we found that the therapeutic effects of rTMS were limited to 1-2 weeks post-treatment. Previous studies reported that rTMS could increase neural activity significantly within seven days in the frontocentral cortex [24, 25]. In addition, rTMS has been shown to improve the cognitive control function, anterior cingulate cortex activity, and reciprocal interaction of the PFC, leading to improved cognitive abilities within seven days of starting treatment [26-28].
Our pilot study also demonstrates that rTMS can induce the activation of the bilateral prefrontal and parietal lobes in 14 days, which is consistent with previous findings [8-16]. Our findings converge with previous studies to demonstrate that rTMS can regulate the functionally reciprocal interaction of the frontocentral cortex, which plays a pivotal role in cognitive processing, leading to the improved cognitive functioning of patients with BPD within one to two weeks after treatment. Unlike previous studies, we found that the cognitive improvements gradually weakened from the third week of treatment, although the illness was stable and rTMS was maintained. We postulate that this weakening of cognitive improvement may be due to cortex neuron desensitization, which is generated by the continued exposure to the rTMS stimulus. However, it could be related to the exhaustion of brain neural activity caused by continuous exposure to high frequency rTMS stimulation. This is similar to the dopamine exhaustion hypothesis in patients with treatment-refractory schizophrenia and serotonin exhaustion hypothesis in patients with treatment-refractory depression [29, 30]. Our postulation requires further investigation in the future.
Our pilot study indicated that changes in cognitive abilities induced by adjunct treatment with rTMS overlap with the gFCD trajectory. This finding supports our postulation that cortex neural activity desensitization or exhaustion may play a role in the short-lived effects of rTMS. However, the trajectory was eliminated by the sharp decrease in MCCB scores at the end of the fourth week of treatment. This phenomenon provides an important clue about how to possibly increase the duration of cognitive improvements in the future.
There are several limitations to our pilot study. First, we were unable to regress the impact of different mood stabilizers and other pharmacological agents because we could not convert them to a uniform dosage. This is unlike many schizophrenia studies that used a chlorpromazine equivalent. However, we fixed the dosages of each patient and also compared the patients before and after treatment, which would any potential bias to a large extent. Secondly, in this study, we used high frequency rTMS stimulation, yet some studies have reported that bilateral stimulation may be a better method. In future studies, we plan to explore this method to determine the optimal method. Third, this study used a small patient population, and larger studies are needed to verify our findings. In addition, this study could benefit from a drug-naive cohort of patients to better evaluate the therapeutic effects of rTMS. Finally, in this pilot study, we conducted paired t-tests in triplicate to compare gFCD and MCCB alterations before and after treatment. This may inflate type I error and may require correction of the p-levels. As an alternative option, a one-way ANOVA for repeated measures may be conducted with appropriate post-hoc tests.
High frequency rTMS can improve the cognitive abilities of patients with remitted BPD rapidly, yet the benefits are short-lived and begin to weaken by three weeks post-treatment. The functional brain activity alteration induced by rTMS verified the initial improvement in cognitive functioning, followed by a rapid decline, which may be due to desensitization or exhaustion. Hence, we plan to investigate new ways to increase the length of cognitive improvements in patients with remitted BPD in the future.
This work was supported by grants from the Project of Wenzhou Science and Technology Bureau (2017Y0797 to J.Y.), National Natural Science Foundation of China (81871052 to C.Z.), the Key Projects of the Natural Science Foundation of Tianjin, China (17JCZDJC35700 to C.Z.), the Tianjin Health Bureau Foundation (2014KR02 to C.Z.), the Zhejiang Public Welfare Fund Project (LGF18H090002 to D.J.), Tianjin Anding Hospital Scholar Award (300000 Yuan to C.Z.), and the Key Project of Wenzhou Science and Technology Bureau (ZS2017011 to X.L.).
Data availability statement
The datasets generated and analysed during the present study are available from the corresponding author on reasonable request.
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