Combining Transcranial Magnetic Stimulation With Emotion Regulation Skills Training in Borderline Personality Disorder

Emotion dysregulation has long been established as the core characteristic feature of borderline personality disorder (BPD). Large scale mediation analyses have identified emotion dysregulation as a key driver of the most impairing effects of this disorder, including interpersonal difficulties, self-harm and suicidality.1 Further, emotion dysregulation has been found to have a transactional relationship with overall BPD symptoms, with significant bi-directional relationships between severity of emotion regulation difficulties and severity of BPD symptoms, suggesting emotion dysregulation goes hand in hand with BPD. Thus, effectively improving emotion regulation (ER) skills is crucial to ameliorating the devastating experience and deleterious effects of this disorder.

For the past decade, we have been studying emotion regulation both on the behavioral level and on the level of neurocircuit function. These studies have primarily focused on bipolar disorder (BD) rather than BPD. However, there is significant overlap in the experience and negative effects of emotion dysregulation between the two disorders, and they are often diagnostically indistinguishable. The specific focus on emotion dysregulation rather than symptoms means these studies are likely relevant to both disorders. This is supported by findings in the BPD literature that overlap with our prior studies. Key takeaways from these studies thus far are: 1) Response to behavior-based ER skills training alone (e.g. CBT) is limited by impaired baseline functioning of ER neurocircuitry, with weaker functional connectivity predicting poorer outcomes. Similar findings have been shown in BPD, with weaker baseline functioning of ER neurocircuit regions predicting poorer outcomes to DBT specifically and psychotherapy in general. 2) Functional connectivity deficits between key nodes in ER neurocircuitry (anterior insula, inferior parietal lobule) distinguish BD from healthy controls, and is significantly related to severity of emotion dysregulation. Similar findings have been shown in studies of BPD patients, which found similar weak functional connectivity between anterior insula and ER circuit regions including the IPL, significantly associated with ER deficits. 3) Modulation of this ER circuit pathway using transcranial magnetic stimulation (TMS) improves ER functional connectivity and behavioral performance on a laboratory task. We have been able to demonstrate both increased AI-IPL functional connectivity and improved performance on an ER behavioral task following IPL stimulation in patients with BD. Given the existing overlap in findings related to ER in both disorders, we hypothesize similar results to be found in patients with BPD.

Thus, taken together, behavioral ER skills training may be a viable approach to improving emotion dysregulation, but is limited by intrinsic ER neurocircuit function. Directly modulating ER neurocircuitry improves ER neurocircuit function and performance on a laboratory analogue of ER behavior, but the effects on real-world ER skills is unknown. Importantly, focusing on ER related neurocircuit function in isolation from the behavioral and psychological processes involved in ER, and vice versa, may not be sufficient to provide relief to those individuals struggling with severe emotion dysregulation, as there is an important bidirectional relationship between these neurocircuit and behavioral components. It remains an open question, therefore, whether improving neurocircuit function supporting emotion regulation while simultaneously addressing the psychological and behavioral processes driving emotion dysregulation can provide synergistic relief to the devastating impact of emotion dysregulation.

Existing approaches to improving ER in BPD Dialectical Behavioral Therapy (DBT) has long been the gold standard for treating individuals with BPD. However, whereas DBT can be a powerful and effective intervention, outcomes are hampered by the extensive length of treatment (one year for a full course of DBT), leading to treatment dropout rates as high as 58% in outpatient settings. This has led to the development of brief versions of DBT (e.g. 12 sessions, 6-month protocols) focused on teaching mindfulness and emotion regulation skills. However, response to these briefer versions have been discouraging, with over 50% of patients showing no clinically significant decrease in symptoms, and sometimes further deterioration. Further, evidence suggests individuals with BPD who show greater baseline deficits in emotion regulation neurocircuit function benefit less from treatment. This suggests two great needs for the field of BPD treatment: 1) briefer efficacious behavioral protocols focused on emotion regulation skills training, and 2) interventions that can strengthen ER neurocircuit function.

The current proposal seeks to address both of these needs, by collecting early Phase 1 pilot data on a combined approach using neuromodulation to strengthen ER neurocircuitry combined with an intensive, brief behavioral approach to teaching ER skills. If we can show this approach is feasible and acceptable, and preliminary evidence for efficacy, data from this trial will provide crucial preliminary evidence to support funding for a larger, randomized controlled clinical trial

What is emotion regulation? Emotion regulation has been operationally defined as the process by which individuals influence and modulate which emotions they have, when they have them, and how they experience and express them. Adaptive emotion regulation requires the detection of emotion salience (e.g. threat, reward), the evaluation of the match between the salience signal and ongoing situational demands, and the modulation of responses accordingly (e.g. attention, appraisal, behavior). Modulating attention between implicit salience signals and explicit ongoing situational, goal-directed demands is a key early component to successful emotion regulation supporting both cognitive change and response modulation.

Emotion regulation can be thought of as a broad construct that provides the scaffolding for many complex cognitive and behavioral processes necessary for adaptive functioning, including decision making, impulse control, and social/interpersonal interactions. Effective emotion regulation has been shown to lead to diminished susceptibility to cognitive and psychological biases in decision making, leading to more adaptive risk assessment (greater or lower risky decisions dependent upon context). A recent review demonstrated that the neurocircuitry involved in effective decision-making overlaps with the neurocircuitry of emotion regulation, suggesting effective decision making inherently relies upon ER-related processes (such as conscious attention shifting, explicit weighting of competing appraisals, dampening or increasing emotion arousal). Studies examining the relationship between impulsivity and emotion regulation suggest impulsivity may be the result of failure to effectively regulate responses to salience signaling and is better accounted for in BPD as a consequence of emotion dysregulation rather than as a separate construct. Studies of interpersonal effectiveness and social communication have demonstrated a significant relationship between adaptive emotion regulation skills and effective communication and social bonding. Studies in BPD show emotion dysregulation mediates responses to a social rejection task, with higher levels of emotion dysregulation associated with higher perceived threat and distress during the task. Thus, improving emotion regulation skills in BPD may not only ameliorate the negative effects of emotion dysregulation, but also provides support for improvement in a range of difficulties inherent in the disorder.

Rationale for targeting IPL to improve ER in BD. The current proposal extends our ongoing work using iTBS to the IPL to improve emotion regulation. Existing studies of healthy individuals implicate distributed cortical neurocircuitry supporting emotion regulation via modulation of limbic structures. Of these regions, the IPL plays a critical role in integrating salience signals with higher-order cognitive functions and support the modulation of attention in service of ongoing goal-directed demands. The IPL forms the intersection of the ventral attention network (VAN), the dorsal attention network (DAN), and the frontoparietal control network (FPC), crucial for voluntarily re-orienting attention and behavior in response to relevant interoceptive stimuli in order to align with ongoing goal-directed needs. Thus, the IPL is uniquely situated as a key integrative hub within the ER neurocircuitry facilitating adaptive ER through the modulation of regulatory control via both ventral and dorsal attention networks and limbic structures. We propose a key mechanism leading to ER deficits is weakened engagement of IPL-AI functional circuitry, resulting in reduced ability to regulate attention and subsequent behavior to direct attention away from irrelevant salient cues, disrupting early attentional processes crucial to the engagement of adaptive ER.

Evidence for Efficacy of ER Skills Training with the UP The ER skills training in this proposal is adapted from the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), an evidence-based, emotion regulation protocol. The UP was developed based upon evolutionary emotion science and modeled after Gross's temporal process model of ER. Core modules are designed to teach skills encompassing the specific adaptive ER processes of attention deployment, cognitive change, and response modulation. The UP consists of 6 core modules: (1) psychoeducation on the nature and function of emotions; (2) present-focused awareness training to facilitate objective awareness and identification of maladaptive conditioned emotion responses; (3) interoceptive awareness training to identify the contribution of physiological responses to maladaptive thoughts and behaviors; (4) automatic thoughts and cognitive reappraisal skills to identify and modify maladaptive automatic appraisals; (5) the identification and modification of maladaptive emotion driven behaviors; and (6) emotion exposures to promote extinction of conditioned responses. The UP has demonstrated efficacy in improving ER skills in a range of transdiagnostic samples including BPD. We previously tested the UP plus pharmacotherapy treatment-as-usual (TAU) with TAU alone in the treatment of BD and comorbid anxiety and demonstrated significantly greater effects in the UP+TAU group on ER skills, and this further predicted improvements in anxiety and mood symptoms. A recent study in patients with unipolar depression and comorbid generalized anxiety disorder combined transcranial direct current stimulation (tDCS) with the UP. Results from this study found significantly greater improvement in ER skills, greater endorsement of cognitive reappraisal, greater response inhibition, and greater working memory accuracy and response relative to the UP alone or waitlist control (all p's<.001). The effects held at 3-month follow-up. These results suggest combining UP ER skills training with neuromodulation may confer an advantage over skills training alone.

In this pilot trial, we aim to test the feasibility and acceptability of ER skills training delivered adjunctive to aiTBS in individuals with BPD with regard to recruitment, retention, UP module completion, patient satisfaction with treatment and endorsement of side effects or discomfort (e.g. fatigue). In addition, we aim to collect pilot data on the preliminary efficacy of combined ER skills training (UP) and accelerated TMS (aiTBS). Results from this trial will provide pilot data towards a future randomized controlled clinical trial of this approach.