Digital twin brain reveals state-specific stimulation targets for abnormal brain dynamics in tinnitus

Tinnitus affects 10-15% of adults globally, yet there are still no effective treatments for this major health condition. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation technique, allows modulation of pathologically altered functional activities to promote symptom remission. However, its efficacy critically depends on the selection of stimulation targets, and substantial interindividual variability has been observed in clinical trials. Here, we aimed to identify potential target regions that are causally involved in alleviating distinct functional abnormalities using the digital twin brain (DTB).

A cohort of 89 participants was used to characterize whole-brain neural activity patterns. Multimodal neuroimaging data were used to develop the tinnitus-specific DTB and to generate causal response maps based on more than 1.64 million virtual stimulations. Whole-brain gene expression data were further integrated to examine the neurobiological plausibility of the DTB-derived causal response maps. Finally, we validated the predictive capacity of such response maps using an independent rTMS dataset.

We identified two aberrant brain states that emerged sequentially with disease progression, predominantly overlapping with the somatomotor and default mode networks, respectively. DTB-derived causal response maps revealed that the modulation of sensory and cognitive states requires stimulation of distinct, functionally specialized regions. Specifically, parieto-occipital regions play a crucial role in sensory modulation, while the dorsolateral prefrontal cortex exerts a causal influence on cognitive modulation. Moreover, these causal response maps correlate with the expression of tinnitus risk genes. By incorporating individual connectivity profiles of target regions, DTB-derived causal response maps accurately predicted rTMS effects on both sensory state (r > 0.85, P_permutation < 0.01) and cognitive state (r > 0.78, P_permutation < 0.05). Particularly, the predictive capacity exhibited a state-specific nature.

This work suggests that brain functional alterations in tinnitus evolve with disease progression, and DTB has the potential to predict rTMS effects on distinct brain states, thereby informing more precise and targeted noninvasive brain stimulation interventions for tinnitus.

Trial registered with https://www.chictr.org.cn/indexEN.html , Explore the mechanism of repetitive transcranial magnetic stimulation intervention in tinnitus based on multi-modal functional magnetic resonance imaging (ChiCTR2100047989), Submitted June 2021, First Patient Enrolled July 2021.