Intermittent theta-burst stimulation in ischemic stroke: a mitochondria-centered framework connecting microglial...

Ischemic stroke triggers a mitochondrial metabolic crisis that propagates secondary injury through neuroimmune and neuron-intrinsic mechanisms. Within minutes, collapse of oxidative phosphorylation (OXPHOS) drives succinate accumulation; upon reperfusion, rapid succinate re-oxidation generates a burst of mitochondrial reactive oxygen species (ROS) via reverse electron transport, triggering neuroinflammation, blood-brain barrier disruption, and regulated neuronal death. Intermittent theta burst stimulation (iTBS), a time-efficient repetitive transcranial magnetic stimulation protocol, targets this crisis at a systems level. Preclinical evidence indicates that iTBS restores neurovascular integrity, reprograms microglial activation by suppressing the succinate/hypoxia-inducible factor-1α (HIF-1α)-driven Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)/ NLR family pyrin domain-containing 3 (NLRP3) inflammasome cascade, and promotes a reparative immune microenvironment. We further propose that restoration of microglial OXPHOS may couple inflammatory resolution to enhanced synthesis of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), forming a metabolic bridge between immune resolution and neuronal survival-a connection assembled from independently supported components but not yet tested as an integrated pathway in the iTBS context. At the neuron-intrinsic level, iTBS suppresses apoptosis via miR-34c-5p/p53/Bax signaling, attenuates ferroptosis by restoring iron homeostasis and antioxidant capacity, and reinforces mitochondrial quality control through transcription factor EB (TFEB)-mediated autophagy. We propose a mitochondria-centered framework wherein mitochondrial homeostasis serves as the central integrative hub linking microglial immunometabolic reprogramming to neuron-intrinsic survival programs. This framework is intended as a hypothesis-generating synthesis rather than a summary of established causal pathways; several of its central links, including the microglial succinate-itaconate axis and the OXPHOS-trophic bridge, remain to be tested directly in iTBS-treated tissue. Preliminary clinical studies report functional improvements across motor, cognitive, language, and swallowing domains, although sample sizes are limited and protocols heterogeneous. We discuss translational challenges including parameter heterogeneity, and note that peripheral markers such as plasma succinate and cell-free mitochondrial DNA warrant exploration as candidate pharmacodynamic indices rather than as a validated response-guided panel.