Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Computational Neuroscience, Hamburg Center of Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg University, Hamburg, Germany.
J Neural Eng. 2024 Oct 16;21(5). doi: 10.1088/1741-2552/ad7f8a.
. Tremor is a cardinal symptom of Parkinson's disease (PD) that manifests itself through complex oscillatory activity across multiple neuronal populations. According to the finger-dimmer-switch (FDS) theory, tremor is triggered by transient pathological activity in the basal ganglia-thalamo-cortical (BTC) network (the finger) and transitions into an oscillatory form within the inner circuitry of the thalamus (the switch). The cerebello-thalamo-cortical (CTC) network (the dimmer) is then involved in sustaining and amplifying tremor amplitude. In this study, we aimed to investigate the generation and progression dynamics of PD tremor oscillations by developing a comprehensive and interacting FDS model that transitions sequentially from healthy to PD to tremor and then to tremor-off state.We constructed a computational model consisting of 700 neurons in 11 regions of BTC, CTC, and thalamic networks. Transition from healthy to PD state was simulated through modulating dopaminergic synaptic connections; and further from PD to tremor and tremor-off by modulating projections between the thalamic reticular nucleus (TRN), anterior ventrolateral nucleus (VLa), and posterior ventrolateral nucleus (VLp).Sustained oscillations in the frequency range of PD tremor emerged in thalamic VLp (5 Hz) and cerebellar dentate nucleus (3 Hz). Increasing self-inhibition in the thalamus through dopaminergic modulation significantly decreased tremor amplitude.Our results confirm the mechanistic power of the FDS theory in describing the PD tremor phenomenon and emphasize the role of dopaminergic modulation on thalamic self-inhibition. These insights pave the way for novel therapeutic strategies aimed at reducing the tremor by strengthening thalamic self-inhibition, particularly in dopamine-resistant patients.
震颤是帕金森病 (PD) 的主要症状，表现为多个神经元群体的复杂振荡活动。根据指掩蔽开关 (FDS) 理论，震颤是由基底节-丘脑-皮质 (BTC) 网络 (手指) 中的短暂病理性活动触发的，并在丘脑内部电路 (开关) 中转变为振荡形式。小脑-丘脑-皮质 (CTC) 网络 (调光器) 随后参与维持和放大震颤幅度。在这项研究中，我们旨在通过开发一个全面且相互作用的 FDS 模型来研究 PD 震颤振荡的产生和进展动态，该模型依次从健康状态过渡到 PD 状态，再过渡到震颤状态，然后过渡到震颤停止状态。我们构建了一个由 BTC、CTC 和丘脑网络的 11 个区域中的 700 个神经元组成的计算模型。通过调节多巴胺能突触连接模拟从健康到 PD 状态的转变；进一步通过调节丘脑网状核 (TRN)、腹外侧核前 (VLa) 和腹外侧核后 (VLp) 之间的投射从 PD 到震颤和震颤停止状态。在丘脑 VLp (5 Hz) 和小脑齿状核 (3 Hz) 中出现了 PD 震颤频率范围内的持续振荡。通过多巴胺能调制增加丘脑的自抑制显著降低了震颤幅度。我们的结果证实了 FDS 理论在描述 PD 震颤现象方面的机制力量，并强调了多巴胺能调制对丘脑自抑制的作用。这些见解为旨在通过加强丘脑自抑制来减少震颤的新治疗策略铺平了道路，特别是在对多巴胺治疗抵抗的患者中。
