Post-traumatic stress disorder (PTSD) can lead to debilitating symptoms and negative self-beliefs, often treated through cognitive therapies. However, research shows that about one-third of patients do not respond to these therapies, prompting investigations into the underlying reasons. A recent study scanned the brains of 70 individuals with PTSD and 66 trauma-exposed individuals without PTSD while they engaged in cognitive restructuring. Results indicated that those with PTSD exhibited weaker connectivity between the prefrontal cortex and thalamus, which may hinder their ability to update negative self-beliefs. This structural difference could explain why some patients struggle to benefit from traditional talk therapies. Furthermore, factors such as severe symptoms, ongoing trauma, and cultural influences can affect treatment outcomes. Alternative approaches, including therapies that enhance emotional regulation and emerging treatments like MDMA or ketamine, are being explored to assist those who do not respond to conventional methods. Understanding these neurobiological mechanisms may lead to more effective, tailored interventions for PTSD.