Intermittent Theta Burst Stimulation Over Cerebellum Facilitates Neurological Recovery in Poststroke Depression via the cAMP/PKA/CREB Pathway

Stroke. 2025 Mar 18. doi: 10.1161/STROKEAHA.124.048697. Online ahead of print.

ABSTRACT

BACKGROUND: Stroke causes somatic dysfunction and psychological disorders, leading to poststroke depression (PSD). This study investigates mood alterations in PSD models via cerebellar intermittent theta burst stimulation (iTBS).

METHODS: PSD animal models were developed using middle cerebral artery occlusion and chronic unpredictable mild stress procedures. PSD models underwent cerebellar iTBS with different pulse numbers. Neurological recovery was evaluated using open-field test, sucrose preference test, forced swimming test, and balance beam test. Golgi and hematoxylin-eosin staining assessed neuronal repair, while quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and Western blotting evaluated effects on BDNF (brain-derived neurotrophic factor), hypothalamic-pituitary-adrenal axis factors, and the cAMP/PKA (protein kinase A)/CREB (cAMP-response element-binding protein) pathway. The study first determined the effects of different intensities of iTBS stimulation on neurological recovery in PSD rats. Second, the effects of iTBS stimulation on the cAMP/PKA/CREB pathway were verified using adenoviral blockade of PKA and CREB at iTBS-1800.

RESULTS: PSD models showed decreased vertical movement, locomotor distance, and sucrose preference and increased immobility time and balance beam test score, which were reversed by iTBS. iTBS increased dendritic length and spine density in Purkinje cells, alleviated neuronal damage in multiple brain regions, and enhanced BDNF synthesis. It also regulated adrenocorticotropic hormone, cortisol, and GR (glucocorticoid receptor) expression, and activated the cAMP/PKA/CREB pathway.

CONCLUSIONS: Cerebellar iTBS improves PSD by activating the cAMP-PKA/CREB pathway, increasing BDNF, and reducing hypothalamic-pituitary-adrenal axis hyperactivity, suggesting potential for human PSD treatment.

PMID:40099372 | DOI:10.1161/STROKEAHA.124.048697