Neurobiological Mechanisms Underlying Psychological Dysfunction After Brain Injuries

Despite the presentation of similar psychological symptoms, psychological dysfunction secondary to brain injury exhibits markedly lower treatment efficacy compared to injury-independent psychological dysfunction. This gap remains evident, despite extensive research efforts. This review integrates clinical and preclinical evidence to provide a comprehensive overview of the neurobiological mechanisms underlying neuropsychological disorders, focusing on the role of key brain regions in emotional regulation across various forms of brain injuries. It examines therapeutic interventions and mechanistic targets, with the primary goal of identifying pathways for targeted treatments. The review highlights promising therapeutic avenues for addressing injury-associated psychological dysfunction, emphasizing Nrf2, neuropeptides, and nonpharmacological therapies as multi-mechanistic interventions capable of modulating upstream mediators to address the complex interplay of factors underlying psychological dysfunction in brain injury. Additionally, it identifies sexually dimorphic factors as potential areas for further exploration and advocates for detailed investigations into sex-specific patterns to uncover additional contributors to these disorders. Furthermore, it underscores significant gaps, particularly the inadequate consideration of interactions among causal factors, environmental influences, and individual susceptibilities. By addressing these gaps, this review provides new insights and calls for a paradigm shift toward a more context-specific and integrative approach to developing targeted therapies for psychological dysfunction following brain injuries.