**3. Transcranial magnetic stimulation in borderline personality disorder**

According to DSM-V, BPD is characterized by a pervasive pattern of instability in interpersonal relationships, self-image, and affects, and marked impulsivity that begins by early adulthood and is present in a variety of contexts. BPD patients also have a high risk of mortality due to suicidal behavior. Up to 10% of BPD patients commit suicide; this rate is almost 50 times higher than in the general population [52]. BPD symptoms severely reduce patients' quality of life and impair their psychosocial functioning [49, 53]. The median prevalence of BPD is estimated from 1.6% up to 5.9% in the general population, up to 10% in psychiatric outpatients, and up to 20% in psychiatric inpatients [28, 54, 55]. BPD is about five times more common among first-degree biological relatives of those with the disorder than in the general population and it is also diagnosed predominantly (about 75%) in women [55]. One of the core elements of BDP is impaired emotion processing and impulsivity. BPD patients have impaired emotion-regulation abilities combined with emotional vulnerability characterized by marked sensitivity to emotional stimuli (low threshold) and unusually strong reactions (high amplitude) that abnormally slowly return to baseline (long duration) [56]. As mentioned earlier, impulsivity in BPD patients often appears under the emotional influence and usually manifests in various dangerous and (self-) destructive behavior.

#### **3.1. Neurobiology and neurophysiology of impulsivity in BPD**

BPD patients show impairment across various frontal regions and fronto-limbic connections crucial for behavioral inhibition, decision making, and emotion regulation. Functionally, patients with BPD show increased amygdala reactivity and altered PFC responses including in the DLPFC and ACC and sensorial processing areas, including the superior temporal gyrus in face processing and the visual cortex in response to emotional stimuli, as compared to healthy people [49, 56–58]. Anatomically, patients with BPD were found to have reduced gray matter volume in the amygdala, insula, DLPFC, and orbitofrontal cortex (OFC) compared with healthy controls [49, 59]. Positron Emission Tomography (PET) studies have revealed altered baseline metabolism in the prefrontal regions in BPD patients [60–62]. Disinhibited impulsive aggression in BPD patients has been associated with serotonergic neurotransmission, which is also affected by the PFC [62]. In conclusion, neuroimaging studies indicate that hyperactivity in the amygdala could be a consequence of weak inhibitory control of limbic emotion reactivity by PFC areas.

Some studies tried to use TMS for assessing cortical neurophysiology in BPD, including cortical excitability and inhibitory and excitatory mechanisms [63]. From this point of view, impulsivity could stem from increased or decreased excitability in some brain structures. BPD patients were found to have shorter cortical silent periods (CSP) in the right hemisphere than healthy controls [64, 65]. It is assumed that CSP measures GABAB inhibitory activity [66]. A similar reduction of CSP was also found in ADHD [67] and in patients with tic disorder [68]. Some authors hypothesized that the GABA neurotransmitter is the main inhibition neurotransmitter and the reduction of GABA activity could result in impulsive behavior and affective instability [64]. Another hypothesis is that intracortical inhibition is more linked with shifts in cortical glutamate and glutamine concentrations than with GABA neurotransmitter levels. But glutamate probably specifically interacts with GABAB receptors, so the higher glutamate and glutamine concentrations seem to be linked to the higher levels of receptor activity revealed by proton magnetic resonance spectroscopy [69]. Further studies to examine these neurophysiology markers in BPD and how they could be used for therapeutic rTMS would be appropriate.

#### **3.2. Review of rTMS treatment studies in BPD**

regulated by a prefrontal-limbic negative coupling which represents top-down cognitive emotion control. Specifically, the decrease in amygdala activity has been shown to be associated with increases in various lateral and medial PFC areas [42–45]. Patients with emotion-regulation deficits show exaggerated amygdala response to emotional stimuli and disrupted amygdalaprefrontal connectivity [46–49]. Further, real-time fMRI neurofeedback studies showed that successful regulation of amygdala activity increases connectivity between the amygdala and DLPFC or VLPFC [50, 51], representing an increase in cognitive emotion-regulation abilities.

According to existing literature on neural correlates of impulsivity, the most suitable targets for rTMS impulsivity treatment seem to be the right lateral PFC areas, mainly the DLPFC or VLPFC. High frequency (HF) rTMS is used over these regions with the aim of the treatment should be to promote activity in the prefrontal areas. Lateral PFC activity, especially in the right hemisphere, has been consistently shown to be associated with successful behavioral inhibition, less impulsive decision making, and better emotion regulation. All of the areas mentioned could be improved through the application of HF rTMS treatment over the (right) DLPFC or VLPFC. Another promising candidate for rTMS application is SMA/pre-SMA that appears to

**3. Transcranial magnetic stimulation in borderline personality** 

usually manifests in various dangerous and (self-) destructive behavior.

**3.1. Neurobiology and neurophysiology of impulsivity in BPD**

According to DSM-V, BPD is characterized by a pervasive pattern of instability in interpersonal relationships, self-image, and affects, and marked impulsivity that begins by early adulthood and is present in a variety of contexts. BPD patients also have a high risk of mortality due to suicidal behavior. Up to 10% of BPD patients commit suicide; this rate is almost 50 times higher than in the general population [52]. BPD symptoms severely reduce patients' quality of life and impair their psychosocial functioning [49, 53]. The median prevalence of BPD is estimated from 1.6% up to 5.9% in the general population, up to 10% in psychiatric outpatients, and up to 20% in psychiatric inpatients [28, 54, 55]. BPD is about five times more common among first-degree biological relatives of those with the disorder than in the general population and it is also diagnosed predominantly (about 75%) in women [55]. One of the core elements of BDP is impaired emotion processing and impulsivity. BPD patients have impaired emotion-regulation abilities combined with emotional vulnerability characterized by marked sensitivity to emotional stimuli (low threshold) and unusually strong reactions (high amplitude) that abnormally slowly return to baseline (long duration) [56]. As mentioned earlier, impulsivity in BPD patients often appears under the emotional influence and

BPD patients show impairment across various frontal regions and fronto-limbic connections crucial for behavioral inhibition, decision making, and emotion regulation. Functionally, patients

**2.5. Possible targets for rTMS treatment of impulsivity**

be a crucial area for behavioral inhibition.

46 Transcranial Magnetic Stimulation in Neuropsychiatry

**disorder**

We searched for relevant studies through the PubMed (http://www.ncbi.nlm.nih.gov/ pubmed/), Web of Science (https://apps.webofknowledge.com/), and Scopus (https://www. scopus.com/) databases published before August 13, 2017. The following terms were used to search for publication titles: (borderline OR BPD) AND (TMS OR rTMS OR "transcranial magnetic stimulation"). We found seven (PubMed), six (Web of Science), and seven (Scopus) publications. After excluding duplicates and nonrelevant contributions (e.g. theoretical articles), five studies were included in the review [70–74].

The first rTMS study in BPD [70] was a case report published in 2013. A 22-year-old female BPD patient received high frequency (HF) 10 Hz stimulation over her left DLPFC at 100% of her individual motor threshold (MT). The trains lasted 5 s and intertrain intervals were 55 s; the whole protocol had 10 sessions (1500 pulses per session, one session per day). The results revealed a decrease in depression levels (Beck Depression Inventory score from 20 to 7 to 2),2 negative affect experiences (Positive and Negative Affect Schedule score from 38 to 36 to 22), impulsivity (Barratt Impulsiveness Scale score from 71 to 67 to 61), and BPD symptom score

<sup>2</sup> The effects are presented from before the stimulation, immediately after the stimulation, and 1 month after the stimulation.

(SCID-II score from 13 to 11 to 6) directly after the treatment and 1 month after the treatment, respectively. Reassessment after 3 months showed regression in the symptoms. According to the patient's reports, the rTMS therapy led to decreased sleep duration, increased emotional control and stability, behavioral self-awareness, increased motivation for change, sociability, self-esteem, happiness, attention to the behavior of others, and planning ability.

pulses in one session. The BDI-II score of the third patient was reduced from 29 to 10 points. The stimulation was well tolerated without any adverse events. Two of the patients described a mild headache at the point of stimulation. All three of them subjectively described better

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49

The last study is from Reyes-López et al. [74]. They stimulated 29 BPD patients divided into two groups with two stimulation designs. One stimulation group received 1 Hz stimulation to the right DLPFC (15 patients), 900 pulses per session. The second group received 5 Hz stimulation to the left DLPFC, trains lasted 10 s, intertrain intervals were also 10 s, 1500 pulses per session (14 patients). The whole stimulation had 15 sessions (1 session per day); the DLPFC was targeted as 5 cm above the maximum stimulation point in the motor area and patients were stimulated on 100% of their individual MT. There was a significant reduction in the Clinical Global Impression Scale for BPD (CGI-BPD) score from baseline after rTMS, with a 29.4% change for 1 Hz group and 28.7% for 5 Hz group. The Borderline Evaluation of Severity over Time (BEST) scores were also reduced for both groups (1 Hz group: 20.4% reduction from baseline; 5 Hz group: 36.9% reduction from baseline). Scores in BIS were also reduced significantly (1 Hz group: 18.96% reduction from baseline; 5 Hz group: 11.83% reduction from baseline). The reduction in BDI scores was 49% for 1 Hz group and 60% for 5 Hz group. Lastly, the Hamilton Anxiety Rating Scale (HAM-A) score was also reduced by 60.3% for 1 Hz group and by 58.7% for 5 Hz group. These results show that both stimulation protocols were effective in reducing BPD symptoms,

control of emotional and behavior impulses and better emotional regulation.

such as fear of abandonment, impulsivity, emotional instability, and anger.

have been found to have opposite effects [80].

**3.3. Conclusions and future directions of rTMS treatment paradigms in BPD**

Most existing studies used rTMS targeted to the left or right DLPFC or DMPFC; one study targeted the cerebellum. Both high and low-frequency protocols were used. Many authors connected the BPD symptoms with hypometabolism in the prefrontal regions and hyperactivation of the amygdala. Current studies have reported various effects of rTMS treatment, mostly after HF treatment in BPD patients, including improved self-control, emotion regulation, mood, anxiety, and executive functions. Some studies also reported effects after sham stimulation. Consequently, it is difficult to make any recommendation regarding rTMS targeting and protocol parameters. We might also speculate that targeting any PFC region by rTMS could improve BPD symptoms thanks to the rich cortico-cortical and cortico-limbic projections from the prefrontal regions. The low-frequency stimulation of the cerebellum could be also used to reduce BPD symptoms based on the cerebellothalamocortical tracts. One question is the laterality of rTMS treatment in BPD patients. Neuroimaging studies of impulsivity usually find a greater association with action control with the right prefrontal regions. Differences in the CSP between patients with BPD and healthy controls were found, especially in the right hemisphere [64]. However, current studies show effects for both right and left prefrontal stimulation protocols. Another question was raised by the study by Reyes-López et al. [74]. They used low-frequency rTMS in the right DLPFC and found similar effects as after high-frequency rTMS over the same area. These findings contradict previous findings and theoretical underpinnings about hypometabolism in PFC in BPD patients and about the effect of low-frequency rTMS. For example, low and high-frequency rTMS over the left DLPFC in depressed patients

Cailhol et al. [71] performed a randomized controlled stimulation of 10 BPD patients by HF 10 Hz rTMS over the right DLPFC. Five patients received active stimulation, and five patients received sham stimulation. One patient was excluded. The right DLPFC was targeted as 6 cm anterior to M1, stimulation was done at 80% intensity of individual MT, trains lasted 5 s and intertrain intervals lasted 25 s (2000 per session, 10 sessions in total). The response rate was defined as a 30% reduction in the Borderline Personality Severity Index (BPDSI) after the stimulation; this was reached by two patients from the active group and one patient from the sham group. BPDSI scores were significantly lower for the active rTMS group than for the sham stimulation group after 3 months of affective instability and anger. Performance in the Tower of London test improved only in the rTMS active group. The stimulation was well tolerated without any adverse events. The authors hypothesized that PFC activity could be increased by rTMS neuromodulation and thereby downregulate the subcortical structures. The effect of rTMS on anger and affect instability in BPD patients could be explained by this hypothesis.

Another stimulation design was presented by De Vidovich et al. [72], who stimulated the left cerebellum in BPD patients. This cerebellar stimulation was used based on cerebellar projections to the PFC through the ventrolateral thalamic nucleus (VL), which was observed in animal studies [75, 76]. Further, one tractography study in humans found that about 40% of fiber tracts from the cerebellum through the superior cerebellar peduncle actually reach the PFC through the VL [77]. In the study itself, eight patients with BPD and eight healthy controls received 1 Hz stimulation on 80% of MT for 10 min over the left lateral cerebellum (1 cm inferior and 3 cm left to the union). The effect of the rTMS was measured by the Affective Go No-Go task (AGN), using two categories of words (positive/negative and fruits/insect). The first and second block of the task included only the first category; the third and fourth part included both categories. BPD patients generally scored worse than healthy controls in AGN, especially in the latter category before the stimulation. After rTMS, their performance became equivalent to the healthy control performance. The stimulation was well tolerated, with no adverse events. These data support previous findings that inhibition performance in BPD patients is impaired when cognitive demands are high, and the situation requires complex associative capacities [78, 79]. The results suggest that LF cerebellar rTMS could have a facilitating effect on the PFC.

Feffer et al. [73] stimulated three women (39, 32, and 42 years old) with BPD and depression comorbidity. The severity of depression symptoms was measured by Beck Depression Inventory II (BDI-II). Two patients received bilateral intermittent (iTBS) stimulation of the DMPFC targeted by neuronavigation; the stimulation had 20 sessions (1 session per day), 1200 pulses per session (600 pulses to each hemisphere). The BDI-II score of the first patient was reduced from 56 to 16 points; the score of the second patient was reduced from 20 to 12 points. The third patient received 20 sessions (1 session per day) of 20 Hz bilateral stimulation to the DMPFC localized by neuronavigation. The duration of the train was 2.5 s and the duration of the intertrain interval was 10 s. Stimulation of each hemisphere contained 1500 pulses in one session. The BDI-II score of the third patient was reduced from 29 to 10 points. The stimulation was well tolerated without any adverse events. Two of the patients described a mild headache at the point of stimulation. All three of them subjectively described better control of emotional and behavior impulses and better emotional regulation.

(SCID-II score from 13 to 11 to 6) directly after the treatment and 1 month after the treatment, respectively. Reassessment after 3 months showed regression in the symptoms. According to the patient's reports, the rTMS therapy led to decreased sleep duration, increased emotional control and stability, behavioral self-awareness, increased motivation for change, sociability,

Cailhol et al. [71] performed a randomized controlled stimulation of 10 BPD patients by HF 10 Hz rTMS over the right DLPFC. Five patients received active stimulation, and five patients received sham stimulation. One patient was excluded. The right DLPFC was targeted as 6 cm anterior to M1, stimulation was done at 80% intensity of individual MT, trains lasted 5 s and intertrain intervals lasted 25 s (2000 per session, 10 sessions in total). The response rate was defined as a 30% reduction in the Borderline Personality Severity Index (BPDSI) after the stimulation; this was reached by two patients from the active group and one patient from the sham group. BPDSI scores were significantly lower for the active rTMS group than for the sham stimulation group after 3 months of affective instability and anger. Performance in the Tower of London test improved only in the rTMS active group. The stimulation was well tolerated without any adverse events. The authors hypothesized that PFC activity could be increased by rTMS neuromodulation and thereby downregulate the subcortical structures. The effect of rTMS on anger and affect instability in BPD patients could be explained by this hypothesis.

Another stimulation design was presented by De Vidovich et al. [72], who stimulated the left cerebellum in BPD patients. This cerebellar stimulation was used based on cerebellar projections to the PFC through the ventrolateral thalamic nucleus (VL), which was observed in animal studies [75, 76]. Further, one tractography study in humans found that about 40% of fiber tracts from the cerebellum through the superior cerebellar peduncle actually reach the PFC through the VL [77]. In the study itself, eight patients with BPD and eight healthy controls received 1 Hz stimulation on 80% of MT for 10 min over the left lateral cerebellum (1 cm inferior and 3 cm left to the union). The effect of the rTMS was measured by the Affective Go No-Go task (AGN), using two categories of words (positive/negative and fruits/insect). The first and second block of the task included only the first category; the third and fourth part included both categories. BPD patients generally scored worse than healthy controls in AGN, especially in the latter category before the stimulation. After rTMS, their performance became equivalent to the healthy control performance. The stimulation was well tolerated, with no adverse events. These data support previous findings that inhibition performance in BPD patients is impaired when cognitive demands are high, and the situation requires complex associative capacities [78, 79]. The

results suggest that LF cerebellar rTMS could have a facilitating effect on the PFC.

Feffer et al. [73] stimulated three women (39, 32, and 42 years old) with BPD and depression comorbidity. The severity of depression symptoms was measured by Beck Depression Inventory II (BDI-II). Two patients received bilateral intermittent (iTBS) stimulation of the DMPFC targeted by neuronavigation; the stimulation had 20 sessions (1 session per day), 1200 pulses per session (600 pulses to each hemisphere). The BDI-II score of the first patient was reduced from 56 to 16 points; the score of the second patient was reduced from 20 to 12 points. The third patient received 20 sessions (1 session per day) of 20 Hz bilateral stimulation to the DMPFC localized by neuronavigation. The duration of the train was 2.5 s and the duration of the intertrain interval was 10 s. Stimulation of each hemisphere contained 1500

self-esteem, happiness, attention to the behavior of others, and planning ability.

48 Transcranial Magnetic Stimulation in Neuropsychiatry

The last study is from Reyes-López et al. [74]. They stimulated 29 BPD patients divided into two groups with two stimulation designs. One stimulation group received 1 Hz stimulation to the right DLPFC (15 patients), 900 pulses per session. The second group received 5 Hz stimulation to the left DLPFC, trains lasted 10 s, intertrain intervals were also 10 s, 1500 pulses per session (14 patients). The whole stimulation had 15 sessions (1 session per day); the DLPFC was targeted as 5 cm above the maximum stimulation point in the motor area and patients were stimulated on 100% of their individual MT. There was a significant reduction in the Clinical Global Impression Scale for BPD (CGI-BPD) score from baseline after rTMS, with a 29.4% change for 1 Hz group and 28.7% for 5 Hz group. The Borderline Evaluation of Severity over Time (BEST) scores were also reduced for both groups (1 Hz group: 20.4% reduction from baseline; 5 Hz group: 36.9% reduction from baseline). Scores in BIS were also reduced significantly (1 Hz group: 18.96% reduction from baseline; 5 Hz group: 11.83% reduction from baseline). The reduction in BDI scores was 49% for 1 Hz group and 60% for 5 Hz group. Lastly, the Hamilton Anxiety Rating Scale (HAM-A) score was also reduced by 60.3% for 1 Hz group and by 58.7% for 5 Hz group. These results show that both stimulation protocols were effective in reducing BPD symptoms, such as fear of abandonment, impulsivity, emotional instability, and anger.

#### **3.3. Conclusions and future directions of rTMS treatment paradigms in BPD**

Most existing studies used rTMS targeted to the left or right DLPFC or DMPFC; one study targeted the cerebellum. Both high and low-frequency protocols were used. Many authors connected the BPD symptoms with hypometabolism in the prefrontal regions and hyperactivation of the amygdala. Current studies have reported various effects of rTMS treatment, mostly after HF treatment in BPD patients, including improved self-control, emotion regulation, mood, anxiety, and executive functions. Some studies also reported effects after sham stimulation. Consequently, it is difficult to make any recommendation regarding rTMS targeting and protocol parameters. We might also speculate that targeting any PFC region by rTMS could improve BPD symptoms thanks to the rich cortico-cortical and cortico-limbic projections from the prefrontal regions. The low-frequency stimulation of the cerebellum could be also used to reduce BPD symptoms based on the cerebellothalamocortical tracts. One question is the laterality of rTMS treatment in BPD patients. Neuroimaging studies of impulsivity usually find a greater association with action control with the right prefrontal regions. Differences in the CSP between patients with BPD and healthy controls were found, especially in the right hemisphere [64]. However, current studies show effects for both right and left prefrontal stimulation protocols.

Another question was raised by the study by Reyes-López et al. [74]. They used low-frequency rTMS in the right DLPFC and found similar effects as after high-frequency rTMS over the same area. These findings contradict previous findings and theoretical underpinnings about hypometabolism in PFC in BPD patients and about the effect of low-frequency rTMS. For example, low and high-frequency rTMS over the left DLPFC in depressed patients have been found to have opposite effects [80].

#### **3.4. Summary of rTMS treatment in BPD**

The existing studies suggest that rTMS is a well-tolerated treatment in patients with BPD and is a potentially highly useful tool for reducing BPD symptoms including impulsivity and emotion regulation. There is a lack of double-blind randomized controlled studies with sufficient sample sizes. Current studies differ substantially in both rTMS cortical targets and stimulation protocols. Most studies have found an effect of high-frequency rTMS over the right DLPFC, but there are also studies that found low-frequency DLPFC, left-sided DLPFC, and cerebellar rTMS effective. More double-blind placebo-controlled studies and studies directly comparing different stimulation protocols in BPD are needed, and the duration of the therapeutic effects should be assessed.

ADHD is characterized by a delay in cortical maturation, which is most substantial in the prefrontal regions [88]. Earlier neuroimaging studies described structural and functional abnormalities in patients with ADHD, suggesting a hypofunction of catecholamine projection from the basal ganglia into the PFC. This dysfunction manifests as a relative hypoactivity of the cortical dopamine system with a relative hyperactivity of striatal dopamine [89]. A metaanalysis of functional studies showed hypoactivity in the frontal regions (DLPFC, inferior PFC, OFC), anterior cingulum, superior parietal regions, caudate nucleus, and thalamus [90]. Duerden et al. [91] also observed that adolescents with ADHD had a significantly greater cortical thickness in the pre-supplementary motor area (SMA) than controls. Further, impaired functional connectivity between the frontal and parietal cortex and between the frontal and cerebellar cortex have been found in patients with ADHD during interference control tasks and time discrimination tasks [92] associated with interference control, activity timing, and time predictions. Striatal hypoactivation in ADHD can lead to the insufficient detection of behaviorally important stimuli, inability to orientate one's activities to long-term goals, and

Repetitive Transcranial Magnetic Stimulation Treating Impulsivity in Borderline Personality…

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Several studies used TMS to investigate neurophysiological parameters in ADHD. A metaanalysis by Dutra et al. [96] identified no significant differences between ADHD and control groups in CSP, resting MT, and motor-evoked potential. However, there was a consistent finding in reduced short intracortical inhibition (SICI) in both children with ADHD [97–100] and adult ADHD patients [67]. SICI is a subthreshold conditioning stimulus followed by a suprathreshold test stimulus with an interstimulus interval of 1–6 ms. The motor-evoked potential which was evoked by the second suprathreshold stimulus should be reduced by 50–90% [101]. The SICI is described as probably measuring GABAA-mediated cortical inhibition [66, 102]. A study by Hasan et al. [103] also reported increased intracortical facilitation (ICF) in adult ADHD patients compared to healthy controls when considering an interstimulus interval of 7 ms between paired pulses applied to the left hemisphere. ICF is measured by TMS when the magnetic evoked potential generated by the suprathreshold is usually facilitated at an interstimulus interval of 8–30 ms [101]. However, there are too few studies to make a more robust conclusion.

We searched for relevant studies through the PubMed (http://www.ncbi.nlm.nih.gov/ pubmed/), Web of Science (https://apps.webofknowledge.com/), and Scopus (https://www. scopus.com/) databases published before August 13, 2017. The following terms were used to search in the publication titles: (ADHD OR "attention deficit hyperactivity disorder") AND (TMS OR rTMS OR "transcranial magnetic stimulation"). We found 20 (PubMed), 32 (Web of Science), and 25 (Scopus) articles. After excluding duplicates and nonrelevant contributions

Current studies examining the treatment of ADHD by rTMS use two main protocols. The first protocol is the low-frequency (LF) stimulation of the SMA, intended to suppress motor symptoms of hyperactivity. The other protocol uses HF rTMS over the DLPFC, intended to facilitate dopaminergic neurotransmission in the PFC and induce the release of endogenous dopamine in the nucleus caudate nucleus and NAcc [104]. This kind of stimulation could improve the symptoms of ADHD mostly in the cognitive domain (deficit of attention and impulsive cognitive style).

insufficient feedback effect from behavioral modification [93–95].

**4.2. Review of rTMS treatment studies in ADHD**

(e.g. theoretical articles), seven studies were included in the review.
