Patient-informed biomechanical modelling reveals mechanical mechanism of brain damage in idiopathic normal pressure hydrocephalus

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a globally growing neurological disorder in older adults, radiologically characterised by enlargement of ventricles. However, it remains unknown whether ventricular enlargement can produce biomechanical loading large enough to drive brain morphological changes and tissue damage. Here, we develop an anatomically detailed biomechanical model of ageing human brain and apply ventricular enlargement using a three-dimensional displacement field derived from MRI of iNPH patients and age-matched controls. The model accurately reproduces radiological markers of iNPH, including Evans index, callosal angle and high-convexity sulcal narrowing. It further predicts large mechanical strains in periventricular white matter, particularly within the corpus callosum and anterior thalamic radiations, tracts consistently implicated in iNPH imaging abnormalities. These findings provide strong evidence that ventricular enlargement induces mechanical strain that contributes to iNPH brain abnormalities, which can potentially be reversed by reducing strain following shunting surgery. The biomechanical brain model forms the foundation of a predictive digital platform and future “digital twin” technology to support diagnosis, patient stratification and treatment planning in iNPH. Key Points We develop an anatomically detailed biomechanical model of the brain, incorporating sulci, septum pellucidum and all four ventricles. A novel data-driven loading approach is introduced which uses 3D displacement fields from finite element-based registration of healthy and iNPH patient MRI, replacing the arbitrary pressure gradients of previous models. The model predictions closely match established radiological markers measured in iNPH patients, including Evans index, callosal angle and high-convexity sulcal narrowing. Ventricular enlargement generates large mechanical strains concentrated in periventricular white matter, providing a biomechanical explanation for the structural abnormalities observed in iNPH. Competing Interest Statement D.J.S. serves on the Alzheimer Society Research Advisory Board and the Rugby Football Union Concussion Advisory Board. D.J.S. serves on the Editorial Board of the journal Brain. D.J.S. has received research contributions from Alamar, although unrelated to this work. C.C. has received honoraria for B-Braun (lectures) and Roche (advisory board). P.A.M. reports funding from the National Institute for Health and Care Research (NIHR), Alzheimer Research UK (ARUK), Federation Internationale de Football Association (FIFA), the Football Association (FA), LifeArc, Dementias Platform UK, the Medical Research Council (MRC), and the UK Dementia Research Institute (UK DRI). He also participates in and independent Data Safety Monitoring Board for Johnson & Johnson, is a Trustee of the Alzheimer Society, and is the NIHR Research Delivery Network (RDN) National Specialty Lead for Dementia and Neurodegeneration. All other authors have nothing to declare.