In this issue of our research digest, we focus on a very recent article from Eric Fertuck, Ph.D. and colleagues entitled:

Rejection Distress Suppresses Medial Prefrontal Cortex in Borderline Personality Disorder.

Dr. Fertuck is an Associate Professor of Psychology at CUNY, NY, a certified TFP supervisor and therapist, a psychoanalyst, as well as a member of ISTFP. The article investigates the neurobiological underpinning of distress related to social exclusion, often a core symptom of borderline personality disorder (BPD). We chose to feature this article not simply because its result shed light on the biological underpinning of BPD, which is of course of interest for our community, but also because its methods are driven by the profound understanding of emotional processes that TFP, and psychoanalytic approaches, allow. By applying a deeper conceptual understanding of social rejection, Fertuck et al. help elucidate a biological mechanism that in the past has been investigated as a categorical, insular, function, leading to mixed results that have been difficult to replicate. We see this contribution as one of the first compelling papers utilizing awareness gained from the psychotherapy setting and psychoanalytic theory to deepen biological knowledge. This type of studies and approaches breaks the stigma of the absence of foundations in psychotherapy and psychoanalytic theory, likewise contributing to the scientific knowledge of clinical effectiveness through its different neurobiological mechanisms.

First, we will quickly review the results of Fertuck et al., to then focus on the creativity of their methodological strategy.

Prior studies have investigated rejection sensitivity by employing a paradigm called the Cyberball game, which is a computer-driven algorithm in which a human subject and two additional virtual players toss a ball to each other in a virtual environment. In one phase of the game, a ball is tossed with equal probability to the subject and to the additional players. In a second phase, the human subject is consistently excluded from receiving the ball. Prior studies have used fMRI to measure brain activity in human subjects while they play Cyberball during inclusion and exclusion phases.

Fertuck et al. studied rejection sensitivity in two groups of subjects, patients with BPD and a control group. Subjects played a modified version of the Cyberball game, and were asked to report their degree of rejection distress after each run. The authors found an inverse correlation between stress related to rejection and the rostro-medial prefrontal cortex (rmPFC) response to exclusion events. Both groups showed similar levels of rmPFC activity in relation to exclusion events, but not surprisingly BPD patients reported higher rejection distress. Strikingly, as more rejection distress was reported, rmPFC responses to rejection events decreased in BPD patients but not in controls. Stronger modulation of the rmPFC response by rejection distress was associated with higher trait rejection expectation.

The authors conclude that rmPFC may normally play an important role in mentalization processes that regulate emotional responses to social rejection. BPD patients may therefore fail to maintain or upregulate rmPFC activity to regulate emotional responses to social rejection, with concomitant inverse coupling between rmPFC activity and social rejection distress contributing to heightened rejection expectation in patients with BPD. This result is of particular interest for the TFP community. More and more studies, several of which are contributions from members of the ISTFP community, have been pointing at an improvement in mentalization as a key therapeutic mechanism for the treatment of personality disorders, as well as a key mediator of TFP efficacy (for example see Keefe et al., 2022; Kivity et al., 2021; Fisher-Kern et al., 2015 and many others).

Fertuck et al., uses their knowledge of psychological functions not only to lead the goals of their study, but also their methodology. Prior studies exploring mechanisms of social rejection in clinical and non-clinical population have led to mixed results, a testament to both the power of fMRI studies to investigate cognitive and emotional processes, as well as the limitation of interpreting those findings given the complexity of human psychology and behavior. The paper by Fertuck et al. strives to overcome this limitation by using a more in depth understanding of interpersonal sensitivity – understanding built both on psychoanalytic theory and on experience gained in the psychotherapy setting – to inform experimental design and data analyses. In making important modifications to the approach taken in prior work, Fertuck et al. obtain data that is likely more applicable to social rejection in real life.

One key example of the modifications made by Fertuck et al. was built on the insight that social inclusion and social exclusion may not simply be two different states of the same underlying affective process, but instead they may be two completely separate processes. When examining the activity of brain areas, prior studies had typically simply subtracted the activity in each brain area in the social exclusion condition from activity observed during the social inclusion condition. If social inclusion and social exclusion are best viewed as distinct processes, then simply subtracting activity across the two conditions may not elucidate how the brain mediates each distinct process. The best approach may therefore be to understand brain activity that underlies each process separately and in each of their own contexts, a key insight taken to heart in the Fertuck et al. paper.

A second key modification made by Fertuck et al. recognized the critical importance of considering the context of rejection events during social exclusion. For example, a social rejection in the context of several recently experienced social inclusions may be perceived differently than if a social rejection is experienced in the context of repeated social exclusion. And indeed this may be the key difference between BPD patients and the rest of the population.

This insight may be critically important for understanding psychopathology and treatment. In everyday life, everyone experiences social exclusion from time to time. However, the development of issues with interpersonal sensitivity for an individual may arise in part from the fact that there was a pattern of social exclusion during her or his psychological development.

Clearly, these results must be replicated and the study extended. But the thoughtfulness of the methodological approach in this paper is striking. Over the last 20 years, a plethora of fMRI studies have been published investigating both clinical and non-clinical human populations, often reporting conflicting results, arguably because of difficulties interpreting the complexity of human behavior. Another limitation has been the number of participants, which has often been insufficient, and the follow-up time to ensure accurate conclusions regarding neural functioning and social cognition.

One way of overcoming the ambiguity of this large body of research is to resort to reductionist behaviors, that is less equivocal in terms of underlying cognitive processes. This is typically obtained in animal studies such as non- human primates experiments. Another way is to approach complex behavior thoughtfully, without preconceived assumptions about cognitive processes underlying it, and this is what Fertuck et al, are doing. This approach is likely to be critical if significant headway is to be made in understanding the neurobiology underlying complex disorders like BPD that are difficult if not impossible to study in animal models.

Silvia Bernardi