The Second Hit Hypothesis in Animal and Human Dystonia: The Role of Peripheral Nerve Trauma and Spinal Cord Injury.

Dystonia is a complex movement disorder characterized by involuntary muscle contractions and abnormal postures. Although genetic factors have been implicated in dystonia pathogenesis, recent evidence suggests that additional environmental triggers, referred to as the second hit, may play a significant role in the development and progression of the disease. A remarkably low penetrance in some of the monogenic forms of dystonia supports the need for additional triggers to unmask the phenotype. Given that dystonia has been reported to develop after traumatic events, this review explores the second hit hypothesis in animal models of dystonia and its potential relevance to human dystonia, with particular emphasis on the role of nerve and spinal cord injuries. These injuries trigger significant peripheral changes and profound brain and spinal cord circuit alterations, which require a healthy immune system and functional and structural plasticity responses. We discuss how nerve and spinal cord injuries initiate these key pathomechanistic processes, including neuroinflammation and the reorganization of the central sensorimotor network, which entails adaptive modifications in neural pathways to compensate for the injury. We further highlight future challenges and potential therapeutic implications of nerve and spinal cord injury-induced dystonia. Understanding the interplay between nerve injury, spinal cord injury, neuroinflammation, and dystonia may pave the way for novel therapeutic strategies targeting these factors. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.