Welcome 2026! The first episode of the new year goes back to absolute fundamentals, discussing the foundations of diagnostic reasoning and how to generate a differential diagnosis in both medicine as a whole and in neurology, falling within our clinical methods series. We begin by discussing systems 1 vs. systems 2 thinking, along with examples provided for each and when each system is appropriate, before moving onto the details of systems 2 thinking, focusing on the aetiological/pathophysiological categories of disease, functional anatomy, and how to marry these together to generate comprehensive differential diagnoses. The episode includes very my coveted, patented (not really!), never-shared-publicly-before mnemonic for a very special surgical sieve. We then discuss how these are applied to medicine and specifically to neurology, focussing on each part of the neuraxis/central nervous system (CNS) and peripheral nervous system (PNS), along with focussing on anatomical patterns (e.g. unilateral vs. bilateral, symmetry, upper vs. lower limbs, motor vs. sensory vs. sensorimotor, whether any ocular, bulbar or pulmonary involvement) and consideration of single vs. multiple lesion patterns to answer the age-old “where is the lesion?” question, as well as considering the tempo of symptom onset (hyperacute, acute, subacute or chronic) to strongly hint answers at the “what is the lesion?” question, to arrive at a provisional diagnosis and sensible investigation and initial management plan. This episode is perfect for medical students and junior doctors, and more senior audience members should also derive value.#medicaleducation #meded #medicine #neurology #doctor #rneurologyeducation