Transcranial magnetic stimulation in borderline personality disorder –  case series

Summary

Aim:

We present the results of a case series study of individual­ly navigated repetitive transcranial magnetic stimulation (rTMS) in four patients with borderline personality disorder (BPD).

Patients and methods:

Four patients with BPD performed a Go/ NoGo task dur­­ing functional MRI (fMRI) designed for observ­­ing behavioural inhibition neural cor­relates. The site within the right dorsolateral prefrontal cortex with the largest dif­ference in BOLD signal between the NoGo and Go conditions was as­signed as a target for rTMS in each patient. Four patients underwent 15 ses­sions of individual­ly navigated 10-Hz rTMS treatment at 110% of their individual rest­­ing motor threshold for 3 weeks (one ses­sion per work­­ing day). One ses­sion contained 1,500 pulses delivered in 15 trains by 10 s, lead­­ing to a total of 22,500 pulses dur­­ing the treatment.

Results:

The treatment was very well tolerated without any serious side ef­fects. After the treatment, the patients reported that they felt better self-control of their emotions, especial­ly anger; that their urges for self-harm and suicidal thoughts decreased or disappeared; and that their derealisation/ depersonalisation episodes disappeared. Patients also showed less depres­sion symp­toms after the treatment.

Conclusion:

rTMS with neuronavigation individualised by a fMRI Go/ NoGo task is a promis­­ing tool for reduc­­ing impulsive behaviour and enhanc­­ing emotion regulation in BPD patients. Double-blind placebo-control­led studies in larger samples are neces­sary to draw further conclusions about rTMS ef­fectiveness in BPD.

Key words

repetitive transcranial magnetic stimulation – rTMS – borderline personality disorder – impulsivity – emotion regulation – Go/NoGo task – neuronavigation

---

边缘性人格障碍的经颅磁刺激 - 病例系列

目的:

我们报告了4例边缘性人格障碍(BPD)患者的个体化导航重复经颅磁刺激(rTMS)病例研究结果。

患者和方法:

4例BPD患者在功能磁共振成像(fMRI)中进行了Go/ NoGo任务，以观察行为抑制神经相关。将NoGo和Go条件下BOLD信号差异最大的右侧背外侧前额叶皮质区域作为每个患者的rTMS靶点。4名患者接受了15次10赫兹rTMS治疗，每次治疗时间为3周(每天1次)，每次治疗时间为其静息运动阈值的110%。其中一个疗程包括15列火车在10秒内发出的1500次脉冲，治疗期间总共产生了22,500次脉冲。

结果:

这种疗法耐受性很好，没有任何严重的副作用。治疗后，患者报告说，他们感觉更好地控制自己的情绪，尤其是愤怒;他们对自我伤害和自杀想法的冲动减少或消失了;他们的去人格化/去人格化症状消失了。治疗后患者的抑郁症状也减少了。

结论:

功能磁共振Go/ NoGo任务个性化神经导航rTMS是一种很有前途的工具，可以减少BPD患者的冲动行为，增强情绪调节。为了进一步研究rTMS对BPD的疗效，需要对更大样本进行双盲安慰剂对照研究。

关键字

重复经颅磁刺激- rTMS -边缘性人格障碍-冲动-情绪调节- Go/NoGo任务-神经导航

Introduction

Borderline personality disorder (BPD) is a devastat­­ing pervasive mental il­lness with an estimated prevalence between 1 and 2% in the general population, up to 10% in psychiatric outpatients, and up to 20% in psychiatric inpatients [1]. The core elements in BPD include marked impulsivity and impaired emotional proces­sing [2]. Patients have increased emotional reactivity with longer time needed for their emotions to return to baseline [3]. At the same time, BPD patients have decreased abilities to regulate emotions [4]. Impulsivity in BPD occurs most often under the influence of emotions and manifests in various forms of risky (self-) des­tructive behaviour (e. g., drug abuse, risky sexual behaviour, binge eating, aggres­sion, and self-harm, includ­­ing frequent suicide attempts [1,5,6]). More than 10% of patients with BPD com­mit suicide, which is about 50 times more than in the general population [7]. Thus, target­­ing emotional regulation and behavioural inhibition appears crucial for prevent­­ing dangerous impulsive behaviour and its consequences in BPD patients [3,8].

On the neural level, emotion regulation and behavioural inhibition are as­sociated with functional impairment of the prefrontal-limbic network [4,9]. In the limbic system, the amygdala has been shown to be hyperactive when proces­s­­ing emotional stimuli; this has been found to be as­sociated with impulsive reactions [3,10– 12]. Several authors as­sociate impulsive behaviour with altered activity in other frontal regions (primarily the orbitofrontal cortex, ventromedial cortex and dorsolateral prefrontal prefrontal cortex (DLPFC) [12– 14]). The DLPFC plays an important role in cognitive emotion top-down regulation and in decision making [15,16]. In light of the crucial role of impaired prefrontal areas in BPD patients, repetitive transcranial magnetic stimulation (rTMS) is a promis­­ing treatment tool because these regions are easily acces­sed by rTMS coils.

We present our pilot results with rTMS treatment of BPD at the Department of Psychiatry of the University Hospital Brno. To our knowledge, rTMS treatment has not been used in BPD patients in the Czech Republic; five articles [17– 21] about rTMS and BPD are available in the literature. We introduce individual neuronavigation of rTMS to the right DLPFC (rDLPFC) us­­ing indi­vidual results from a Go/ NoGo (GNG) task in functional MRI (fMRI) with the aim of find­­ing the most individual­ly suitable target for treat­­ing self-control dif­ficulties for the fist time.

Patients and methods

Research sample

Four patients who met the criteria for BPD accord­­ing to the International Clas­sification of Dis­eases, 10^th Revision [22], were recruited in our case series study (3 women; average age 22 ± 3.9 years; average years of education 11.75 ± 1.89). Three patients were outpatients dur­­ing the treatment and one patient was hospitalised at the Department of Psychiatry of the University Hospital Brno dur­­ing the treatment. All patients had to be on stable medication from 6 weeks before the stimulation until the end of the stimulation. The exclusion criteria were ad­diction, acute psychotic state, severe depres­sion, and contraindications prevent­­ing MRI or rTMS.

Magnetic resonance imaging

Prior to treatment, the patients underwent fMRI with 3T machines Siemens Magnetom Prisma (Siemens Healthcare GmbH, Erlangen, Germany) at the Central European Institute of Technology (CEITEC) in Brno, Czech Republic. Dur­­ing fMRI, the patients performed a GNG task (TR = 2.280 ms; TE = 35 ms; res. 3 × 3 × 3 m­m). The sti­m­ulation coil was targeted at the site with the individual­ly highest activation in the NoGo > Go contrast, represent­­ing a crucial point for patients’ behavioural inhibition.

Go/ NoGo task

The GNG task design was adapted from Albares et al. [23] (Fig. 1). Each trial in the GNG task consisted of a fixation point last­­ing between 2 and 6 s, fol­lowed by either the Go or NoGo stimulus for 0.2 s, fol­lowed by a post-trial black screen for 2 s. White letters A and B on a black background were used as the Go and NoGo stimuli. In 2/ 3 of cases, the fixation point was a red cros­s; 1/ 3 of the cros­ses were green. The patients were instructed that either a Go or NoGo stimulus would appear after the red cros­s, while the green cross would always be fol­lowed by a Go stimulus. Patients were further instructed to press a button as quickly as pos­sible whenever the Go stimulus appeared, but not to press the button when the NoGo stimulus appeared (i.e., to perform behavioural inhibition). The task contained 4 blocks of 54 trials each.

Determin­­ing the stimulation point

Data analysis was performed in SPM12 (The FIL Methods Group, London, United King­dom). In our previous analysis, we found that the behavioural inhibition network was more activated dur­­ing the NoGo condition after the red cross (NoGoRed) than dur­­ing the Go condition after the red cross (GoRed). Based on these results, the site with the maximum BOLD signal within the rDLPFC in NoGoRed > GoRed contrast was found and used as the rTMS target. The individual rDLPFC mask was derived from the Destrieux Atlas [24] from FreeSurfer software (The General Hospital Corporation, Boston, MA, USA) [25], combin­­ing areas from the sulcus frontalis inferior and sulcus frontalis superior to gyrus frontalis medius. The individual rDLPFC mask was obtained by proces­s­­ing anatomical images of each patient us­­ing the FreeSurfer 5.3.0 software [25]. The stimulation coil was subsequently targeted to the highest point of NoGoRed > GoRed contrast in the patient’s rDLPFC by Brainsight software TMS neuronavigation, ver. 2.2 (Rogue Research Inc., Montreal, QC, Canada).

Repetitive transcranial magnetic stimulation protocol

Repetitive transcranial magnetic stimulation was performed by DuoMag XT (Rogue Resolutions Ltd, Cardif­f, United Kingdom) with a 70BF cool coil. Patients underwent 15 stimulation ses­sions at 110% of their individual rest­­ing motor threshold (MT) over a period of 3 weeks with one ses­sion each work­­ing day. Patients received 1,500 pulses dur­­ing one ses­sion (total 22,500 pulses dur­­ing the whole procedure) with 10 Hz frequency. Train lasted 10 s with inter-train interval of 30 s. The MT was measured before the first stimulation ses­sion; it was defined as the lowest pos­sible intensity induc­­ing at least five motor responses from 10 pulses in the primary motor cortex above 50 μV measured from the abductor pol­licis brevis muscle (measured by EMG, a component of the DuoMag XT stimulator).

Rat­­ing scales and semi-structured interview

Patients were as­ses­sed us­­ing the Mont­gomery-Åsberg Depres­sion Rat­­ing Scale (MADRS), Clinical Global Impres­sions (CGI), and semi-structured interviews. This battery was presented to patients before and after the rTMS treatment. MADRS [26] as­ses­ses the presence and severity of depres­sive symp­toms. High-frequency stimulation of rDLPFC could cause depres­sion [27] or have a positive or negative ef­fect on mood [28,29]. This scale was included to monitor any worsen­­ing of patient mood. CGI scales are measures of symp­tom severity, treatment response, and treatment ef­ficacy in patients with mental disorders [30]. The ef­fect of rTMS on impulsive symp­toms and emotion regulation was captured by semi-structured interviews focused on the patient’s individual symp­toms.

These four patients were part of a larger open study for evaluat­­ing the neural ef­fects of rTMS in BPD patients; they were as­ses­sed by an unblinded rater.

Results

The average Montreal Neurological Institute and Hospital coordinate of the stimulated point in the rDLPFC area was: x = 26.49 ± 2.92; y = 60.89 ± 13.65; z = 57.01 ± 9.23. Treatment with rTMS was very well tolerated without any serious side ef­fects. Two patients reported headaches at the stimulation coil site last­­ing about 2 h that spontaneously resolved. The fol­low­­ing results constitute qualitative case reports based on semi-structured interviews completed with MADRS and CGI before and after the stimulation protocol.

Case study 1

The first patient (20-year-old woman) was medicated with 50 mg sertraline daily. She was treated as an outpatient and had never been hospitalised. She was self-harm­­ing by scratch­­ing and cutt­­ing herself at a frequency of approximately once in 30– 40 days; had long-term suicidal thoughts, but had never attempted suicide; felt social withdrawal and increased fear of people in social situations; and experienced frequent bursts of anger towards others.

After the rTMS treatment, the patient reported that her ability to recognise her emotions increased, and she was thus better able to regulate emotions. She reported that especial­ly when she was upset in social situations or when she had the urge to hurt herself, she was able to stop and think about what she wanted to do about her urgency or emotional state. She did not harm herself dur­­ing the treatment and reported fewer emotional outbursts. Moreover, she reported markedly improved attention. Her mood, as rated by MADRS, improved from 19 to 14 points and the CGI was improved from markedly ill (5) to mildly ill (3). Her il­lness was much improved (2) after the treatment.

Case study 2

The second patient (23-year-old man) was medicated with 10 mg of escitalopram and had been treated since the age of 20. He did not self-harm before the treatment; he had been hav­­ing suicidal thoughts once a week since the age of 21 and he had attempted suicide four times. He was easily ir­ritated with low frustration toleration. He had problems control­l­­ing anger and reported dif­ficulties in concentration.

After the rTMS, the patient reported that he experienced anger at a lower intensity and happiness as more intense, and his ir­ritability decreased, lead­­ing to calmer feelings. He also reported that he feels like he has more time to think before speak­­ing impulsively and his attention markedly increased. His MADRS score decreased from 2 to 0 points; CGI improved from moderately ill (4) to mildly ill (3). His il­lness was minimal­ly improved (3) after the treatment.

Case study 3

The third patient (18-year-old woman) had no medication, was hospitalised twice, and had been treated since the age of 16. She had suicidal thoughts last­­ing for two years with no suicide attempt, was self-harm­­ing by cutting, hitt­­ing with a meat gavel, or scratch­­ing herself to the point of bleed­­ing every day for two years. In con­nection with self-harming, she described that she had pseudo-hal­lucinatory experiences in the form of a man’s voice encourag­­ing her to harm herself and insult­­ing her. She reported that she often said things she im­mediately regretted; she had outbursts of anger, scream­­ing at people and threaten­­ing them; she had frequent episodes of derealisation; and she had abused alcohol daily for 2 years; however, she was abstinent at the begin­­­n­­ing of the rTMS treatment.

After the rTMS, the patient improved in her emotion regulation in stres­sful situations and in anger management. She experienced emotions as intense, but she could better recognise and control them. She did not experience any derealisation episodes and the voice in her head vanished and she also has managed to avoid harm­­ing herself, report­­ing decreased anxiety, improved attention, and improved sleep dur­­ing the treatment. Accord­­ing to the clinical rating, her mood improved significantly (MADRS dropped from 20 to 3 points) and her CGI decreased from severely ill (6) to mildly ill (3). She was much improved (2) after the treatment.

Case study 4

The fourth patient (27-year-old woman) had been medicated with 11 dif­ferent psychotropics (citalopram, escitalopram, sertraline, trazodone, quetiapine, chlorpro­thixene, topiramate, lithium, buspirone, promethazine, haloperidol) dur­­ing her treatment from 1998 to 2017 and underwent 6 psychiatric hospitalisations. She was medicated with lithium, quetiapine, and chlorprothixene at the time of stimulation. She had suicidal thoughts every day and had harmed herself by cutt­­ing with a razor blade and bleed­­ing from her veins every day since she was 23, and had attempted suicide 3 times by cutt­­ing her veins, had demonstrated risky sexual behaviour (approximately 80 sexual partners over 12 years, although she was mar­ried for 5 of those years). She often felt uncontrol­led anger toward people around her.

From the begin­n­­ing of the second treat­ment week, she reported spontaneous inexplicable crying, after which she felt significant relief. After the treatment, she reported reduced urges for self-harm, better anger management, especial­ly in interpersonal situations, improved attention, decreased anxiety, and improved mood (MADRS from 16 to 11). Her CGI improved from markedly ill (5) to moderately ill (4) and she was minimal­ly improved (3) after the treatment.

Discus­sion

We report the first study in the Czech Republic us­­ing individual fMRI-based navigat­­ing rTMS and examin­­ing the therapeutical potential of rTMS in BPD patients. rTMS appeared to be well tolerated without serious side ef­fects and led to reduced BPD symp­toms in individual patients. After treatment, the patients described increased emotional awarenes­s, which subsequently helped them to regulate emotions more ef­ficiently. Tendency to self-harm, vague suicidal thoughts, derealisation, and increased af­fective ir­ritation were not experienced by patients approximately from mid-treatment to the end of the treatment. Patients described improved moods and marked improvement in their attention among other ef­fects of rTMS treatment.

Our results are in line with the exist­­ing literature, 5 articles focused on treat­­ing BPD symp­toms with rTMS [17,19– 21,31]. Individual studies reported similar outcomes in BPD patients in terms of better self-control and emotional regulation, improved mood, and decreased anxiety. Despite the similar pattern of rTMS ef­fects in BPD, studies dif­fer substantial­ly in stimulation parameters, includ­­ing stimulation brain targets.

Based on previous results, high frequency rTMS should lead to increased metabolism in the stimulated area [32,33]. This could lead to increased prefrontal-limbic con­nectivity, which represents top-down cognitive emotion regulation, but there has not been a study prov­­ing this mechanism. Such ef­fects should lead to improved af­fective stability, emotion regulation, and impulsivity symp­toms as was observed in this pilot study and previous studies. There has not yet been a study about the mechanism of the neural ef­fect of rTMS, optimal stimulation parameters, and the best area for the stimulation in BPD patients.

The limits of our study include the small pilot sample of BPD patients and the prevalence of subjective reports for ef­fects description. Future studies should test rTMS treatment in larger patient samples us­­ing protocols for results evaluation, includ­­ing question­naires and behavioural tests specifical­ly for BPD patients (like Min­nesota Borderline Personality Disorder Scale [MBPD] [34] and the Borderline Symp­tom list 23 [BSL-23] [35]). We focused primarily on the tolerability of stimulation and clinical ef­fects perceived by patients in our study, but it would be appropriate to quantify and objectivise the ef­fect with at least the above-mentioned scales. Neural ef­fects of rTMS treatment in BPD should also be as­ses­sed.

We only observed the patients dur­­ing the time of treatment. Future studies should evaluate the long-term ef­fects of rTMS in BPD, because the persistence of the ef­fect over time has not yet been examined. The literature about rTMS in depres­sion indicates that the positive ef­fect could persist for 4 to 5 months [36,37]. The maintenance treatment after this time should be further examined. One pos­sibility would be to administer rTMS twice weekly for 1 month, once weekly for 2 months, and twice monthly for 9 months (see in [38]). Because the ef­fects of rTMS in BPD were demonstrated mainly in emotional dimensions, it could be more appropriate to navigate rTMS us­­ing an emotional GNG task in future. The study lacked a control group. There are not many double-blind placebo-control­led trials of rTMS in BPD. However, rTMS protocol could pos­sibly induce placebo ef­fects. For the duration of the treatment, the patients visited our department daily and were frequently asked about their state. Double-blind placebo-control­led studies are needed to exclude the influence of placebo ef­fects of rTMS protocols in BPD patients.

Conclusion

The cur­rent literature suggests that rTMS is a wel­l-tolerated treatment without any serious side ef­fects in BPD patients and a potential­ly useful tool for reduc­­ing BPD symp­toms, includ­­ing impulsivity and emotion regulation impairment. However, double-blind placebo-control­led studies in larger samples of patients with BPD are needed to further evaluate this method of BPD treatment.

The contribution was supported by the grant of AZV MZ ČR 15-30062A and the project-specific university research of the Ministry of Education, Youth and Sports of the Czech Republic MUNI/ A/ 0976/ 2017 and by institutional support MH CZ Development of Research Organization FNBr, 65269705.

We acknowledge the core facility MAFIL of CEITEC supported by the Czech-BioImag­­ing large RI project (LM2015062 funded by MEYS CR) for their support with obtain­­ing scientific data presented in this paper.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.

Mgr. Tomas Sverak

Department of Psychiatry

Masaryk University

University Hospital Brno

Jihlavska 20

625 00 Brno

Czech Republic

e-mail: tomas.sverak@mail.muni.cz

Accepted for review: 15. 7. 2018

Accepted for print: 10. 12. 2018