Reimer Adriano E, Dastin-van Rijn Evan M, Kim Jaejoong, Mensinger Megan E, Sachse Elizabeth M, Wald Aaron, Hoskins Eric, Singh Kartikeya, Alpers Abigail, Cooper Dawson, Lo Meng-Chen, de Oliveira Amanda Ribeiro, Simandl Gregory, Stephenson Nathaniel, Widge Alik S
Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minnesota, MN 55454, USA.
Sci Transl Med. 2024 Dec 18;16(778):eadp1723. doi: 10.1126/scitranslmed.adp1723.
Brain disorders, in particular mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. Here, we propose a potential path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result using a set-shifting task in rats. DBS-like stimulation of the midstriatum improved reaction times without affecting accuracy, mirroring our human findings. Impulsivity, motivation, locomotor, and learning effects were ruled out through companion tasks and model-based analyses. To identify the specific cognitive processes affected, we applied reinforcement learning drift-diffusion modeling. This approach revealed that DBS-like stimulation enhanced evidence accumulation rates and lowered decision thresholds, improving domain-general cognitive control. Reanalysis of prior human data showed that the same mechanism applies in humans. This reverse/forward translational model could have near-term implications for clinical DBS practice and future trial design.
脑部疾病，尤其是精神疾病，或许可通过直接的脑部电刺激得到有效治疗，但临床进展需要了解治疗机制。动物模型并未起到帮助作用，因为不存在精神疾病的直接动物模型。在此，我们通过利用大多数精神疾病的一个共同因素：认知控制受损，提出了一条绕过这一障碍的潜在途径。我们之前表明，深部脑刺激（DBS）可改善人类的认知控制。我们现在利用大鼠的一种定势转换任务对该结果进行逆向翻译。对纹状体中部进行类似DBS的刺激可缩短反应时间而不影响准确性，这与我们在人类中的发现一致。通过伴随任务和基于模型的分析排除了冲动性、动机、运动和学习效应。为了确定受影响的具体认知过程，我们应用了强化学习漂移扩散模型。该方法表明，类似DBS的刺激提高了证据积累率并降低了决策阈值，改善了领域通用的认知控制。对先前人类数据的重新分析表明，相同的机制也适用于人类。这种逆向/正向转化模型可能对临床DBS实践和未来试验设计具有近期影响。
