Using electrophysiology to index non-invasive brain stimulation effects on reward system neurobiology in depression

奖励在驱动行为中起着核心作用。奖励系统功能障碍越来越被概念化 transdiagnosis现象1，2，与许多精神病理学相关。有机会直接调节 通过有针对性的干预进行奖励处理可能在精神病学中具有广泛的机制和临床价值， 这两种疾病都是奖励反应回路过度活跃或不活跃的疾病。的首要目标 这个R21建议关注抑郁症患者的一个这样的机会：我们将评估是否有一个 奖励完善的电生理测量，奖励积极性（RewP），这是一致的 在抑郁症中变得迟钝，可以通过有针对性的神经刺激前额叶-纹状体奖励回路来移动。的 所提出的工作的前提是一个完善的实证文献，充实的RewP作为一种措施 主观奖励评估，与抑郁相关的RewP钝化可能反映了衰减 奖励圆满。非侵入性脑刺激技术，如重复经颅磁刺激， 经颅磁刺激（rTMS），调节皮层活动，并提供新的途径来探测奖励电路。先前 研究表明，用rTMS刺激额扣带回奖赏回路会增加RewP幅度 在尼古丁成瘾，但在何种程度上钝化RewP抑郁症可以通过rTMS拯救是未知的。 因此，我们建议进行试点研究，开始通过重复测量研究来解决这一文献空白， 采用多尺度方法探讨被动和绩效依赖下的奖励系统功能 奖励条件。我们将研究单次间歇性θ爆发的假控制效应 刺激（iTBS）到个体的背内侧前额叶/前扣带皮层（dmPFC/dACC）目标 患有重度抑郁症（MDD）。我们将研究iTBS对预期和后来的消费的影响， 奖励措施，除了我们的主要重点是RewP，从而利用时间精度 脑电通过将奖赏加工分解为子成分加工并检查它们的差异来提供 对神经刺激的敏感性具体目标1检查刺激前的病例对照RewP差异， 以及在MDD中作为iTBS的函数的RewP幅度的变化。具体目标2检查病例对照， 组内MDD iTBS对后期完善性奖励测量的影响，即后期正电位 （LPP）。具体目标3研究了病例对照和组内MDD iTBS对奖励预期的影响。 我们的方法是创新的，因为i）使用经过充分验证的RewP或类似方法的先例很少 作为rTMS调制的指标，尽管MDD中的奖励回路功能减退，ii）我们 靶向与抑郁症病理生理学密切相关的区域3，但与食品和药物管理局不同。 管理部门批准的抑郁症背外侧前额叶rTMS目标和ii）。在这里，我们评估 利用奖励预期和完善的措施来检验正效价系统在 对iTBS的反应，为未来的生物标志物验证和全程rTMS临床试验奠定基础。

Rewards play a central role in driving behavior. Reward system dysfunctions are increasingly conceptualized as transdiagnostic phenomena 1,2, relevant to many psychopathologies. The opportunity to directly modulate reward processing through targeted intervention could have broad mechanistic and clinical value in psychiatry, both for disorders in which reward-responsive circuits are overactive or underactive. The overarching goal of this R21 proposal focuses on one such opportunity in individuals with depression: we will evaluate whether an electrophysiological measure of reward consummation, the Reward Positivity (RewP), which is consistently blunted in depression, can be moved by targeted neurostimulation of a prefrontal-striatal reward circuit. The premise of the proposed work is a well-developed empirical literature that substantiates the RewP as a measure of subjective reward valuation, with depression-associated blunting of the RewP likely reflecting attenuated reward consummation. Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), modulate cortical activity and offer novel avenues to probe reward circuitry. Previous research establishes that excitation of a fronto-cingulate reward circuit with rTMS increases RewP magnitude in nicotine addiction, but the extent to which blunted RewP in depression can be rescued via rTMS is unknown. We therefore propose pilot research to begin to address this literature gap via a repeated-measures study that uses a multi-measure approach to probe reward system functioning under passive and performance-dependent reward conditions. We will examine sham-controlled effects of single session intermittent theta burst stimulation (iTBS) to a dorsomedial prefrontal/anterior cingulate cortex (dmPFC/dACC) target in individuals with major depressive disorder (MDD). We will examine iTBS effects on anticipatory and later consummatory reward measures in addition to our primary focus on the RewP, thus capitalizing on the temporal precision EEG affords by decomposing reward processing into subcomponent processes and examining their differential sensitivity to neurostimulation. Specific Aim 1 examines case-control RewP differences before stimulation, and changes in RewP magnitude as a function of iTBS in MDD. Specific Aim 2 examines case-control and within-group MDD iTBS effects on a later-stage consummatory reward measure, the late positive potential (LPP). Specific Aim 3 examines case-control and within-group MDD iTBS effects on reward anticipation. Our approach is innovative because i) there is little precedent for using the well-validated RewP or similar measures as indices of rTMS modulation, despite putative hypofunction of reward circuitry in MDD and ii) we target a region strongly implicated in depressive pathophysiology3 but distinct from the Food and Drug Administration-approved dorsolateral prefrontal rTMS target for depression and ii). Here, we evaluate measures tapping reward anticipation and consummation to assay positive valence system functioning in response to iTBS, setting the stage for future biomarker validation and full-course rTMS clinical trials.