Understanding the Borderline Brain: A Review of Neurobiological Findings in Borderline Personality Disorder (BPD)

Abstract

Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence from 112 studies published up to 2025 is synthesized, encompassing structural MRI, resting-state and task-based functional MRI, EEG, PET, and emerging machine learning applications. Consistent disruptions are observed across the prefrontal-amygdala circuitry, the default mode network (DMN), and mentalization-related regions. BPD shows a dominant and stable pattern of hyperconnectivity in the precuneus. Transdiagnostic comparisons with PTSD and cocaine use disorder (CUD) suggest partial overlap in DMN dysregulation, though BPD-specific traits emerge in network topology. Machine learning models achieve a classification accuracy of 70-88% and may support the tracking of early treatment responses. Longitudinal fMRI studies indicate that psychodynamic therapy facilitates the progressive normalization of dorsal anterior cingulate cortex (dACC) activity and reductions in alexithymia. We discuss the role of phenotypic heterogeneity (internalizing versus externalizing profiles), the potential of neuromodulation guided by biomarkers, and the need for standardized imaging protocols. Limitations include small sample sizes, a lack of effective connectivity analyses, and minimal multicenter cohort representation. Future research should focus on constructing multimodal biomarker panels that integrate functional connectivity, epigenetics, and computational phenotyping. This review supports the use of a precision psychiatry approach for BPD by aligning neuroscience with scalable clinical tools.

Keywords: biomarkers; borderline personality disorder; default mode network; fMRI; functional connectivity; machine learning; psychodynamic therapy; transdiagnostic.

Figure 1

PRISMA flow diagram of the study selection process [10]. A total of 1284 records were identified through database searches. After removing 276 duplicates, 1008 records were screened by title and abstract. Of these, 781 were excluded, and 227 full-text articles were assessed for eligibility. Following the exclusion of 115 full-text articles, 112 studies were included in the final synthesis.

Figure 2

Structural and functional brain alterations in borderline personality disorder. Schematic representation of key neuroanatomical abnormalities in BPD and their associated functional deficits.

Figure 3

Neurochemical systems implicated in BPD. Schematic representation of disrupted neural network connectivity associated with core symptoms of BPD. Highlights include impaired top-down regulation from the prefrontal cortex to the amygdala, dysregulated default mode network activity, and deficits in social cognition networks. These disruptions contribute to affective instability, identity disturbance, and interpersonal dysfunction.

Figure 4

Functional connectivity disruptions in borderline personality disorder (BPD). Summary diagram of key neurotransmitter systems involved in BPD pathophysiology. Includes serotonergic dysregulation (linked to impulsivity), dopaminergic alterations (related to reward processing and affect), oxytocinergic deficits (associated with attachment and empathy), and emerging evidence on glutamatergic imbalance.

Figure 5

Longitudinal change in dorsal anterior cingulate cortex (dACC) activation and alexithymia (TAS-20 scores) over 12 months of psychodynamic psychotherapy in individuals with borderline personality disorder (BPD). dACC activation (blue line) shows progressive normalization (increasing Z-scores), while TAS-20 scores (red line) decrease over time, indicating improved emotional awareness. Measurements were taken at baseline, 4 months, 8 months, and 12 months. Lower TAS-20 scores reflect therapeutic progress. Data adapted from [69].