Traumatic brain injury, neurobiology of aggression and antisocial behavior: from large-scale brain networks to anatomical and molecular substrates

Traumatic brain injury (TBI) triggers a dynamic pathological cascade that often culminates in chronic neuropsychiatric sequelae, such as reactive aggression and antisocial behavior. While these debilitating manifestations severely impair social reintegration and quality of life, their heterogeneous nature complicates clinical and forensic characterization. This review addresses this challenge through an integrated, multiscale framework that bridges macro-scale network desynchronization with micro-circuit pathology. We illustrate how the mechanical disruption of major white matter tracts decouples large-scale neurocognitive networks, leaving subcortical emotional anchors in a state of unmodulated hyper-reactivity stripped of prefrontal inhibitory control. The macroscopic untethering operates in synergy with localized cellular failures within specific amygdalar subnuclei, where chronic neuroinflammation, oxidative stress, and ascending neuromodulatory alterations durably shift the affective circuitry toward a hyperexcitable state. By mapping these dimensional neurobiological substrates directly onto the DSM-5-TR taxonomic framework, we spark a new neuroforensic debate regarding criminal responsibility, considering the boundaries of volitional control and the contemporary debate on free will in organically compromised patients. This translational perspective guides the evaluation of novel therapeutic strategies, shifting the paradigm away from non-specific pharmacological sedation toward personalized, state-dependent neuromodulation capable of exogenously restoring circuit synchrony and patient clinical outcomes.