Drugs affecting neuromodulation, for example by dopamine or acetylcholine, take centre stage among therapeutic strategies in psychiatry. These neuromodulators can change both neuronal gain and synaptic plasticity and therefore affect electrophysiological measures. An important goal for clinical diagnostics is to exploit this effect in the reverse direction, i.e., to infer the status of specific neuromodulatory systems from electrophysiological measures. In this study, we provide proof-of-concept that the functional status of cholinergic (specifically muscarinic) receptors can be inferred from electrophysiological data using generative (dynamic causal) models. To this end, we used epidural EEG recordings over two auditory cortical regions during a mismatch negativity (MMN) paradigm in rats. All animals were treated, across sessions, with muscarinic receptor agonists and antagonists at different doses. Together with a placebo condition, this resulted in five levels of muscarinic receptor status. Using a dynamic causal model - embodying a small network of coupled cortical microcircuits - we estimated synaptic parameters and their change across pharmacological conditions. The ensuing parameter estimates associated with (the neuromodulation of) synaptic efficacy showed both graded muscarinic effects and predictive validity between agonistic and antagonistic pharmacological conditions. This finding illustrates the potential utility of generative models of electrophysiological data as computational assays of muscarinic function. In application to EEG data of patients from heterogeneous spectrum diseases, e.g. schizophrenia, such models might help identify subgroups of patients that respond differentially to cholinergic treatments.

中文翻译：

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基于模型的听觉失配阴性反应对毒蕈碱受体功能的预测

影响神经调节的药物，例如通过多巴胺或乙酰胆碱，在精神病学治疗策略中处于中心地位。这些神经调节剂可以改变神经元增益和突触可塑性，因此影响电生理指标。临床诊断的重要目标是在相反方向上利用这种作用，即从电生理学指标推断特定神经调节系统的状态。在这项研究中，我们提供了概念证明，可以使用生成（动态因果）模型从电生理数据推断胆碱能（特别是毒蕈碱）受体的功能状态。为此，我们在大鼠不匹配阴性（MMN）范式中使用了两个听觉皮质区域的硬膜外EEG记录。在整个疗程中对所有动物进行了治疗，与毒蕈碱受体激动剂和拮抗剂的剂量不同。连同安慰剂条件，这导致毒蕈碱受体状态达到五个水平。使用动态因果模型-包含耦合的皮层微电路的小型网络-我们估算了突触参数及其在整个药理条件下的变化。与突触功效相关的参数估计（神经调节）显示了毒蕈碱的分级作用以及激动药和拮抗药理条件之间的预测有效性。这一发现说明了电生理数据生成模型作为毒蕈碱功能的计算分析的潜在实用性。在将来自异类频谱疾病（例如精神分裂症）的患者的EEG数据应用时，