Neural Information Processing Group, Institute of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany.
School of Physics, Engineering and Computer Science, University of Hertfordshire, Hatfield, UK.
Sci Rep. 2021 Oct 14;11(1):20387. doi: 10.1038/s41598-021-99793-w.
The mechanisms underlying circuit dysfunctions in schizophrenia (SCZ) remain poorly understood. Auditory steady-state responses (ASSRs), especially in the gamma and beta band, have been suggested as a potential biomarker for SCZ. While the reduction of 40 Hz power for 40 Hz drive has been well established and replicated in SCZ patients, studies are inconclusive when it comes to an increase in 20 Hz power during 40 Hz drive. There might be several factors explaining the inconsistencies, including differences in the sensitivity of the recording modality (EEG vs MEG), differences in stimuli (click-trains vs amplitude-modulated tones) and large differences in the amplitude of the stimuli. Here, we used a computational model of ASSR deficits in SCZ and explored the effect of three SCZ-associated microcircuit alterations: reduced GABA activity, increased GABA decay times and NMDA receptor hypofunction. We investigated the effect of input strength on gamma (40 Hz) and beta (20 Hz) band power during gamma ASSR stimulation and saw that the pronounced increase in beta power during gamma stimulation seen experimentally could only be reproduced in the model when GABA decay times were increased and only for a specific range of input strengths. More specifically, when the input was in this specific range, the rhythmic drive at 40 Hz produced a strong 40 Hz rhythm in the control network; however, in the 'SCZ-like' network, the prolonged inhibition led to a so-called 'beat-skipping', where the network would only strongly respond to every other input. This mechanism was responsible for the emergence of the pronounced 20 Hz beta peak in the power spectrum. The other two microcircuit alterations were not able to produce a substantial 20 Hz component but they further narrowed the input strength range for which the network produced a beta component when combined with increased GABAergic decay times. Our finding that the beta component only existed for a specific range of input strengths might explain the seemingly inconsistent reporting in experimental studies and suggests that future ASSR studies should systematically explore different amplitudes of their stimuli. Furthermore, we provide a mechanistic link between a microcircuit alteration and an electrophysiological marker in schizophrenia and argue that more complex ASSR stimuli are needed to disentangle the nonlinear interactions of microcircuit alterations. The computational modelling approach put forward here is ideally suited to facilitate the development of such stimuli in a theory-based fashion.
精神分裂症（SCZ）的电路功能障碍的潜在机制仍知之甚少。听觉稳态反应（ASSR），特别是在伽马和β频段，已被认为是 SCZ 的潜在生物标志物。虽然 40 Hz 驱动的 40 Hz 功率降低在 SCZ 患者中得到了很好的证实和复制，但在 40 Hz 驱动期间 20 Hz 功率增加的研究尚无定论。可能有几个因素可以解释这种不一致，包括记录方式（EEG 与 MEG）的敏感性差异、刺激（点击序列与调幅音）的差异以及刺激幅度的差异。在这里，我们使用了 SCZ 中 ASSR 缺陷的计算模型，并探索了三种与 SCZ 相关的微电路改变的影响：GABA 活性降低、GABA 衰减时间增加和 NMDA 受体功能低下。我们研究了输入强度对伽马（40 Hz）和β（20 Hz）频段功率的影响，发现在实验中观察到的伽马刺激期间β功率的显著增加，只有在 GABA 衰减时间增加且仅在特定输入强度范围内的模型中才能重现。更具体地说，当输入处于此特定范围内时，40 Hz 的节律驱动会在对照网络中产生强烈的 40 Hz 节律；然而，在“类似 SCZ”的网络中，延长的抑制会导致所谓的“节拍跳过”，其中网络只会强烈响应每个其他输入。这种机制是在功率谱中出现明显的 20 Hz β峰的原因。另外两种微电路改变不能产生实质性的 20 Hz 分量，但当与增加的 GABA 能衰减时间结合使用时，它们进一步缩小了网络产生β分量的输入强度范围。我们的发现表明，β分量仅存在于特定的输入强度范围内，这可能解释了实验研究中看似不一致的报告，并表明未来的 ASSR 研究应系统地探索其刺激的不同幅度。此外，我们为精神分裂症中的微电路改变和电生理标记之间提供了一种机制联系，并认为需要更复杂的 ASSR 刺激来理清微电路改变的非线性相互作用。这里提出的计算建模方法非常适合以基于理论的方式促进此类刺激的开发。
