Mapping shared and specific cortical after-effects of repetitive TMS on brain function.

Repetitive transcranial magnetic stimulation (rTMS) is a powerful non‑invasive technique for brain modulation [], yet its observed effects exhibit substantial heterogeneity across studies. This variability is frequently attributed to the wide diversity of rTMS protocols, which include distinct targeting sites (e.g., motor and prefrontal cortex) and stimulation protocols (for instance, high‑frequency rTMS and theta burst stimulation (TBS)) [–]. While different protocols are known to influence overlapping cognitive or clinical domains [–], it remains unclear whether they engage shared or distinct large-scale brain circuits. This is critical as rTMS after-effects propagate through functionally connected networks beyond the stimulation site [–], raising a key unresolved issue: does rTMS modulate a common cortical system across protocols, and if so, what organizational principles, such as cortical hierarchy, govern its architecture? Furthermore, given that rTMS acts through neuromodulatory mechanisms [–], engages multiple cognitive domains [–, , ], and is clinically applied across a range of brain disorders [, , , –], the alignment between the common after‑effects observed across distinct rTMS protocols and their neurochemical substrates, cognitive correlates, and disorder‑related functional alterations remains unclear. To identify both shared and protocol-specific functional effects, we employed the amplitude of low-frequency fluctuations (ALFF), a widely recognized, reliable and regionally specific metric for assessing the amplitude of BOLD fluctuations [, ]. As a direct measure of local activity amplitude, ALFF is sensitive to both widespread changes common across protocols and focal alterations unique to individual ones. Its utility in capturing rTMS-induced plasticity has been demonstrated in prior studies [, ]. More importantly, ALFF is mechanistically informative: its variance has been linked to neurochemical processes, including regional excitatory-inhibitory balance and the function of specific neurotransmitter systems [, ]. This neurochemical link is pivotal, as rTMS after-effects are established to arise through the modulation of these neurotransmitter systems [–]. Furthermore, ALFF correlates with differences in cognitive performance and is altered in several brain disorders [], domains that are direct targets of rTMS interventions [–]. Consequently, ALFF serves as a convergent biomarker, positioned to bridge rTMS protocol-induced changes in brain activity, their underlying neurochemical substrates, and their behavioral and clinical relevance. To this end, we integrated pre- and post-rTMS fMRI data from 283 sessions across nine real single-session protocols and three sham conditions in 211 healthy participants. We quantified cortical changes using ALFF to map after-effects induced by each real protocol compared to its matched sham control. We then systematically examined whether the spatial patterns of these changes (1) are organized along the cortical hierarchy [, ], (2) correlate with the distributions of key neurotransmitter receptors [], (3) relate to meta-analytic maps of task-based cognitive activation [], and (4) associate with functional abnormality observed in brain disorders [, ]. By integrating these multiscale associations, our work provides an integrative framework for understanding how rTMS reshapes the human brain.