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

奖励在驾驶行为中起着核心作用。奖励系统功能障碍越来越被概念化 作为跨诊断现象1，2，与许多精神病理学有关。有机会直接调整 通过有针对性的干预进行奖励处理在精神病学中可能具有广泛的机制和临床价值， 两者都适用于奖赏反应回路过度活跃或不活跃的障碍。的首要目标是 这份R21提案关注的是抑郁症患者的一个这样的机会：我们将评估 奖赏完成度的电生理测量，奖赏正性(RewP)，它一致地 在抑郁症中迟钝，可以通过前额叶-纹状体奖赏回路的有针对性的神经刺激而移动。这个 拟议工作的前提是一份完善的实证文献，它证实了REWP作为一种衡量标准 主观奖赏价值，抑郁相关的REWP的钝化可能反映减弱 奖励完成者。无创脑刺激技术，如重复经颅磁 刺激(RTMS)，调节皮质活动，并提供新的途径来探索奖励回路。上一首 研究证实，具有rTMS的额扣带回奖励回路的兴奋增加了RewP幅度 尼古丁成瘾，但通过rTMS可以在多大程度上挽救抑郁症中迟钝的RewP。 因此，我们建议先导性研究开始通过重复测量研究来解决这一文献差距 使用多指标方法来探索被动和绩效依赖下的奖励系统运行情况 奖励条件。我们将检验单次间歇性theta爆发的假控制效应 刺激(ITBS)个体背内侧前额叶/前扣带回(dmPFC/dACC)靶区 患有严重抑郁症(MDD)。我们将检验ITBS对预期和以后消费的影响 除了我们主要关注REWP之外的奖励措施，从而利用时间精度 脑电通过将奖励过程分解为子成分过程并检查它们的差异来提供 对神经刺激的敏感性。特定目的1检查刺激前病例对照RewP的差异， MDD的REWP震级随ITBS的变化。具体目标2审查病例对照和 组内MDD ITBS对后期消费奖励措施--后期正向潜力的影响 (LPP)。具体目标3考察了病例对照和组内MDD ITBS对奖励预期的影响。 我们的方法是创新的，因为i)几乎没有使用经过充分验证的REWP或类似的先例 测量作为rTMS调制的指标，尽管推测MDD和II)WE的奖赏回路功能低下 靶向一个与抑郁症病理生理密切相关但与食品和药物不同的区域 经政府批准的治疗抑郁症的背外侧前额叶rTMS靶点和ii)。在这里，我们评估 挖掘奖励预期和完善的措施分析正价位系统的作用 对ITBS的反应，为未来的生物标记物验证和全程rTMS临床试验奠定了基础。

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.