Research paperEnhancing cognitive restructuring with concurrent fMRI-guided neurostimulation for emotional dysregulation–A randomized controlled trial
Introduction
Emotional dysregulation is a key problem that cuts across psychiatric disorders and is associated with considerable burden of illness. Conventional approaches to psychiatric treatment emphasize remediating neurobehavioral processes associated with the downregulation of emotional arousal. For instance, emotion regulation skills building, a component of many cognitive behavioral therapies, is effective in decreasing psychopathology across affective disorders (Neacsiu et al., 2014; Neacsiu et al., 2018); nevertheless, selective treatments that target transdiagnostic emotional dysregulation are still lacking. Improvement in emotional functioning happens at a slow pace and is limited in magnitude and scope (Neacsiu et al., 2014; Neacsiu et al., 2010). Therefore, there is a critical need to develop new therapeutic approaches that integrate current knowledge about the neurophysiology of emotion regulation into clinical practice. Specifically, combined treatments that manipulate neurobiological pathways of emotion regulation concurrently with psychotherapy could increase training efficacy by facilitating learning, improving compliance by reducing therapy duration, and expanding functional gains beyond what traditional psychotherapies can achieve alone (Neacsiu et al., 2018).
Emerging neuroimaging findings highlight several disruptions in brain function that are associated with clinical emotion dysregulation. When performing emotion regulation tasks, hypoactivation in prefrontal regions such as the dorsolateral (dlPFC), ventrolateral (vlPFC) (Zilverstand et al., 2017), and dorsomedial prefrontal cortex (dmPFC) (Pico-Perez et al., 2017), and hyperactivation in limbic/paralimbic brain areas, such as the left anterior insula (Pico-Perez et al., 2017) and amygdala (Zilverstand et al., 2017), characterize difficulties in changing emotional arousal in anxiety and mood disorders. Importantly, the tasks used for these neuroimaging studies overlap with skills taught in cognitive behavioral therapy (CBT), especially with cognitive restructuring (CR). Meta-analytic studies of CR have consistently identified activation in this emotion regulation network in healthy subjects (Buhle et al., 2014) and in anxious and depressed adults (Pico-Perez et al., 2017). Although this fronto-limbic network may not encompass all modes of emotion regulation (e.g., meditation practice extends to additional brain regions) (Hölzel et al., 2011), these findings provide a rigorous scientific foundation for hypothesizing a neural signature of transdiagnostic emotion dysregulation in response to negative arousal (Fernandez et al., 2016).
Thus, a transdiagnostic intervention for emotional dysregulation can be constructed to alter this neural dysfunction. CR is a fundamental skill taught in many evidence-based psychotherapies for mood, anxiety, and stress disorders (Hawley et al., 2017; Goldin et al., 2012; Kaczkurkin and Foa, 2015; Clark, 2013; Leahy and Rego, 2012; Watkins et al., 2018; Van Dis et al., 2020; Ciharova et al., 2021) that has also been studied in basic neuroscience (Powers and LaBar, 2019; Ochsner et al., 2012). CR involves thinking differently about a situation in order to change the emotional experience and is currently one of the most studied emotion regulation strategies across both basic and clinical research (Webb et al., 2012). Effective use of reappraisal during an emotion regulation task increases high frequency heart rate variability (HF-HRV) (Denson et al., 2011), a marker of effective emotion regulation (Butler et al., 2006; Di Simplicio et al., 2012). Functional neuroimaging studies examining CR have found activation distributed throughout a fronto-limbic network, including the dlPFC, vlPFC, ACC, superior frontal gyrus (SFG)/frontal pole, amygdala, and insula (Pico-Perez et al., 2017; Powers and LaBar, 2019; Ochsner et al., 2012). Theoretical and empirical findings highlight that CR can be further subdivided into specific tactics, such as reframing and distancing (Pico-Perez et al., 2017; Powers and LaBar, 2019), although these tactics largely overlap in their neural representation.
In this study, we propose to augment CR practice with neurostimulation targeted towards the same regulatory neural network in order to shorten the required time to learn this skill. Emerging evidence suggests that noninvasive neurostimulation, such as repetitive transcranial magnetic stimulation (rTMS) can alter emotional processes (Mai et al., 2019) and enhance performance on affective tasks (Feeser et al., 2014) in healthy samples, especially stimulation is administered during an active task (Luber et al., 2017). In transdiagnostic clinical adults, active versus sham rTMS applied over the left and right dlPFC conducted in conjunction with CR practice led to significant enhancement of physiological (HF-HRV), behavioral (regulation duration), and self-report (subjective distress) indices of emotion regulation, up to a month later in a transdiagnostic clinical sample (Neacsiu et al., 2021). The hypothesized mechanism is that neurostimulation facilitates neural processing in localized cortical regions via inducing Hebbian-like plasticity (Stefan et al., 2000) which may have therapeutic effects and may remediate deficits in affected neural networks (Luber et al., 2008).
Increases in HF-HRV during emotional arousal are correlated with and may be a sensitive index of enhanced emotion regulation (Appelhans and Luecken, 2006; Camm et al., 1996; Geisler and Kubiak, 2009). Participants who engage in effective emotion regulation have higher changes in HRV from baseline than those who do not engage in regulation (Butler et al., 2006; Ingjaldsson et al., 2003). Also, successful increase in emotion (via exaggeration) during positive and negatively arousing film clips was strongly connected with change in HRV from baseline (Demaree et al., 2004). A meta-analysis also found a strong connection between HF-HRV and use of cognitive strategies to manage emotions (Thayer et al., 2012). Furthermore, increases in HRV are correlated with the amount of constructive coping adults report they use when distressed (Appelhans and Luecken, 2006; Fabes and Eisenberg, 1997) as well as with successful pursuit of goal under emotional arousal (Fenton-O'Creevy et al., 2012; Elliot et al., 2011). Taken together, these findings strongly suggest that HF-HRV can be a reliable (Geisler and Kubiak, 2009) marker of effective emotional regulation in the context of emotional arousal.
The current double-blinded, placebo-controlled trial extends the prior literature by using individualized fMRI-guided rTMS to optimize the effect of the rTMS-CR intervention on emotion regulation in transdiagnostic adults. This approach ensures that inter-individual differences in brain anatomy and physiology that are crucial for fine-grained targeting are fully accounted for, optimizing our ability to harness the full potential of neurostimulation technology (Neacsiu et al., 2018). Prior findings suggest that using an individualized fMRI stimulation target could yield better rTMS outcomes (Beynel et al., 2019; Sack et al., 2009). We hypothesized that when compared to sham rTMS, active rTMS administered in conjunction with CR will enhance emotion regulation in the moment and up to a week after the intervention. In addition to our primary outcome measures, we planned to explore effects of this intervention a month later and differences in response based on level of proficiency with CR at the beginning of treatment.
Section snippets
Participants and procedures
This study was an adjunctive supplement to a previously reported examination of rTMS enhanced CR (Neacsiu et al., 2021). Both studies were pre-registered under the same Clinical Trials ID (NCT02573246) and ran concurrently between April 2016 and February 2020. The results included here are from the adjunctive supplement only. Both studies were powered using a one-time comparison between sham and active neurostimulation in potentiating emotion regulation in healthy adults (Cohen's d effect
Missing data
Out of 31 ITT participants, one felt faint during the MT procedure and stopped all study procedures at that point. Three participants found rTMS too painful and withdrew during the habituation portion of the intervention (one in sham and 2 in active conditions). Therefore, 27 participants completed the intervention session and follow up assessments (see supplementary Table 2 for demographic data). All ITT available data were included in the outcome analyses. Across the psychophysiological and
Discussion
We examined using a multi-method approach a brief, neuroscience-driven intervention for transdiagnostic emotional dysregulation. Specifically, we combined teaching and practice of a psychological skill, cognitive restructuring, with rTMS targeted towards the emotion regulation network using functional neuroimaging and neuronavigation. In addition, we examined the importance of skill proficiency at the beginning of the intervention on the emerging outcomes. As in our prior study (Neacsiu et al.,
Data availability statement
All data is available upon request.
Funding sources
This research and the completion of the manuscript were supported by a Duke internal award, and KL2 award by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number 5KL2TR001115 (the first author was a fellow on the award).
Author contributions
All authors contributed significantly to the present manuscript. Dr. Neacsiu conceptualized and conducted the study. Drs. LaBar, Appelbaum, and Smoski provided design input, helped problem solve study related issues throughout the study, and contributed to the manuscript preparation. Dr. Beynel conducted the neurostimulation procedures. Dr. Graner completed our fMRI preprocessing pipeline. Dr. Szabo served as the study doctor throughout the study.
Data availability statement
All data is available upon request.
Disclosures
The authors reported no biomedical financial interests or potential conflicts of interest.
Acknowledgments
Data from the present paper were also presented as part of several conference talks. This research and the completion of the manuscript were supported by a KL2 award granted to the first author by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number 5KL2TR001115. The authors would like to thank the participants who took part in this study and to acknowledge Lisalynn Kelley, John Powers, PhD, M. Zachary Rosenthal, PhD, Kevin Haworth,
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