頻率調控視丘下核深層腦刺激對運動皮質動態的差異性調節

Abstract

腦深層電刺激（DBS）通過電極在大腦深部的視丘下核（STN）施加高頻電刺激緩解帕金森氏症引起的運動症狀。儘管 STN-DBS 的療效仰賴對運動皮質（MO）投射至 STN 的調節，但 MO 在 DBS 過程中的實際角色仍未完全釐清。 本研究探討不同 DBS 頻率對 MO 神經動態的影響，以深入了解其治療機制。我們利用光遺傳技術選擇性地活化皮質投射至 STN 的路徑，並在半側帕金森氏症小鼠中進行活體雙光子鈣成像。雖然在多種頻率下小鼠的移動表現皆有所改善，但 MO 神經群體的反應則呈現頻率依賴性。值得注意的是，僅有高頻刺激能較好的維持與動作相關的皮質活動模式。另外，我們也發現第五層（L5）神經元與第二/三層（L2/3）神經元對刺激頻率的反應不同，暗示不同皮質層在電刺激下有各自的功能貢獻。 本研究結果強調調整 DBS 參數以保留內源性運動訊號之重要性，並為發展更精準的帕金森氏症神經調控療法提供了新的見解。

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides effective relief of motor symptoms in Parkinson’s disease (PD). Although the therapeutic benefits of STN-DBS depend in part on modulating the motor cortical (MO) inputs to the STN, the precise role of MO during STN-DBS is not fully understood. Here, we examined how MO neuronal dynamics are influenced by different DBS frequencies to gain insights into therapeutic mechanisms and optimize neuromodulatory strategies. We used optogenetic stimulation to selectively activate cortical projections to the STN while performing in vivo two-photon calcium imaging of motor cortex neurons in hemi-parkinsonian mice. Locomotor performance improved over a broad range of stimulation frequencies, yet the underlying MO population responses varied depending on the frequency. Layer-specific analyses revealed that layer 5 (L5) neurons, whose activity is attenuated in the Parkinsonian state, were robustly and consistently modulated across the tested frequencies. In contrast, layer 2/3 (L2/3) neurons were more sensitive to stimulation frequency, suggesting distinct circuit-level contributions. These findings highlight the importance of tailoring DBS parameters to preserve endogenous motor signals in the cortex while maximizing therapeutic effects. Our results provide insight into how frequency-dependent cortical dynamics under STN-DBS contribute to motor recovery, with implications for developing more precise neuromodulatory interventions for Parkinson’s disease.