Mazandaran Association of Emergency Medicine Humanistic Studies and Social Researches 3092-6467 2 1 2025 12 20 The Neurobiological Basis of Borderline Personality Disorder: An Integrative Review 236651 10.22034/hssr.2025.236651 EN Mehrsa Eftekhari Master of Science in Chemical Engineering, Biotechnology, Islamic Azad University, North Tehran Branch, Tehran, Iran 0009-0009-7749-0371 Journal Article <span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;">Background:<span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;"> Borderline Personality Disorder (BPD) is a severe and complex psychiatric illness characterized by pervasive instability in affect regulation, impulse control, interpersonal relationships, and self-image. While historically understood through psychosocial lenses, contemporary research has established a robust neurobiological foundation. This review synthesizes current evidence to provide an integrative model linking genetic predisposition, early environmental adversity, and alterations in brain structure, function, and neurochemistry. <span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;">Objectives:<span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;"> To systematically review and integrate evidence on the structural, functional, neurochemical, and genetic correlates of BPD, and to propose a coherent neurodevelopmental etiological model that explains core clinical symptoms. <span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;">Methods:<span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;"> A narrative review was conducted using PubMed, Scopus, and PsycINFO for literature published between 2005-2025. Search terms included "borderline personality disorder neurobiology," "BPD neuroimaging," "BPD genetics," and "fronto-limbic." Priority was given to meta-analyses, systematic reviews, and original research with robust methodology. Findings were synthesized thematically to construct an integrated model. <span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;">Results:<span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;"> Converging evidence confirms a primary dysfunction in fronto-limbic and salience networks, characterized by amygdala and insula hyperreactivity to emotional stimuli coupled with diminished prefrontal (especially orbitofrontal and anterior cingulate cortices) regulation. Structural alterations in these regions are prevalent. Neurochemically, dysfunction in serotonergic and oxytocinergic systems, alongside hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, are central. Significant gene-environment interactions (e.g., involving SLC6A4, FKBP5) mediate risk, with epigenetics providing a mechanism for the biological embedding of early trauma. Effective psychotherapies induce measurable neuroplastic changes, normalizing these dysfunctions. <span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;">Conclusions:<span style="font-size: 14.0pt; font-family: 'Times New Roman',serif; mso-ascii-theme-font: major-bidi; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-bidi; mso-bidi-theme-font: major-bidi; color: #0f1115; mso-font-kerning: 0pt; mso-ligatures: none;"> BPD is best conceptualized as a neurodevelopmental disorder of emotion regulation and social cognition. A triple-network dysfunction model—involving hyperactive salience, underactive executive control, and altered default mode networks—effectively explains the core phenotype. This model unifies biological and psychosocial perspectives, reduces stigma, and directs future research toward circuit-based therapeutics and preventative interventions for at-risk individuals.

https://www.hssres.com/article_236651_e464da766ee6b687e0e9fe9e6f7c2276.pdf