Functional MRI Study of Brain Mechanisms Mediating Anhedonia in Major Depression

自《精神疾病诊断和统计手册》第三版出版以来，快感缺失一直是严重抑郁障碍(MDD)的两个关键诊断标准之一，但人们对其神经基础知之甚少。神经成像研究已经确定了许多被认为与MDD有关的大脑区域。大多数研究都将MDD作为一个综合征实体来处理，并不令人惊讶的是，在确定的大脑区域、功能变化的性质(即活动减少或增加)、偏侧化以及与临床症状的相关性方面，得出了非常不同的结果。临床的异质性和缺乏针对症状的靶点可能是导致这种差异的因素之一。已经提出的假设是，功能受损的中脑边缘多巴胺能通路可能包括部分神经基质，这些神经基质是导致快感缺乏和动力丧失的核心MDD症状的基础。然而，大脑奖赏机制在调节MDD快感缺失中的作用仍不清楚。可用于经验性测量快感缺乏症的适当实验范例的可用性是检验这一假设的先决条件。最近使用货币激励范式与神经成像技术相结合的研究发现，在健康人类处理奖励的过程中，作为中脑边缘多巴胺能通路一部分的结构中存在血流动力学反应。 我们假设MDD患者快感缺乏症与大脑奖励机制受损有关，如眼眶和腹内侧额叶皮质功能障碍与享乐归因能力受损有关，而包含伏隔核的腹侧纹状体区域功能障碍与MDD患者对奖赏环境刺激的反应性降低或缺乏有关。我们的假设是，特定的神经底物与快感缺失的两个精神成分有关，即MDD诊断标准中定义的兴趣丧失和缺乏反应性。我们计划通过使用NIH最近开发的货币激励事件相关功能磁共振成像任务，对患有和不患有明显快感缺乏的MDD患者的奖励反应进行经验测量，以检验我们的假设。我们期望发现，与没有快感缺乏的MDD患者和健康对照组相比，有明显快感缺乏的MDD患者的腹侧纹状体、眼眶和腹内侧额叶皮质的激活减少。这项拟议工作的结果可能为MDD的诊断、分类和治疗提供线索，也可能为识别其他致残性精神疾病(如精神分裂症和成瘾)快感缺失的基本神经机制提供线索。 在过去的一年里，来自抑郁症和健康对照受试者的正电子发射计算机断层扫描和功能磁共振成像数据被获取、分析并在几个国际科学会议上报告。来自这些分析的行为数据表明，抑郁组和对照组在激励大小对绩效的调节上存在显著差异。通过对fMRI数据的分析，证实了这些差异的神经基础，并显示MDD的纹状体(尾状核、伏隔核)和眶额核的多个区域异常激活。正在准备两份手稿来描述这些发现。 此外，增加了两个新的实验任务，并在16名健康对照受试者中获得了新的引导数据，以证明这些任务是令人满意的。一种是奖赏条件作用任务，另一种是工作记忆任务，通过间歇性地使金钱奖励取决于行为表现，对动机和注意力进行不同的调节。对功能磁共振成像和神经认知数据的初步分析表明，这些任务有效地利用了感兴趣的神经和系统，并影响了动机行为，因此对抑郁症患者的研究已经启动。这些研究即将完成和分析，描述结果的论文正在准备出版。 最后，使用PET和C-11拉克洛必利启动了PET研究，以研究自然奖励任务期间内源性多巴胺的释放。我们首次开发了一种测量纹状体区域(如伏隔区)与奖赏相关的多巴胺释放的方法，该方法不受局部血流激活相关变化的干扰，也受运动方面的控制。一份描述这些结果和方法的手稿正在准备中。这项研究现在正扩展到抑郁症患者身上，以检验抑郁症患者中与奖赏相关的多巴胺释放减弱的假设，到目前为止，已经有6名抑郁症受试者被成像。

Anhedonia has been one of the two key diagnostic criteria for major depressive disorder (MDD) since the publication of The Diagnostic and Statistical Manual of Mental Disorders, Third Edition, yet little is known about its neural substrates. Neuroimaging studies have identified numerous brain regions that are thought to be involved with MDD. Most studies dealt with MDD as a syndromal entity, and not surprisingly, yielded quite variable results with respect to the areas of the brain identified, the nature of the functional changes (i.e., decrease or increase in activities), lateralization, and correlation with clinical symptoms. Clinical heterogeneity and lack of symptom-specific targets are presumably among the factors contributing to the variability. The hypothesis that a functionally impaired mesolimbic dopaminergic pathway may comprise a part of neural substrate underlying core MDD symptoms of anhedonia and loss of motivation has been proposed. Nevertheless, the roles of brain reward mechanisms in mediating anhedonia in MDD remain unclear. Availability of appropriate experimental paradigms that can be used empirically to measure anhedonia is a prerequisite to test such a hypothesis. Recent studies using monetary incentive paradigms coupled with neuroimaging techniques have identified hemodynamic responses in structures that serve as part of the mesolimbic dopaminergic pathway during processing rewards in healthy humans. We hypothesize that anhedonia in MDD is associated with impairment of brain reward mechanisms such that dysfunction of the orbital and ventromedial frontal cortices involved in the impaired hedonic attribution capacity, while dysfunction of the ventral striatum area that contains the nucleus accumbens is involved with the reduced or lack of reactivity to rewarding environmental stimuli in patients with MDD. Our hypothesis is that specific neural substrates are linked to the two psychiatric components of anhedonia, i.e., loss of interest and lack of reactivity, as defined in the diagnostic criteria for MDD. We plan to test our hypothesis by using empirical measurement of reward responses in MDD patients with and without significant anhedonia using a monetary incentive event-related functional magnetic resonance imaging task recently developed at NIH. We expect to find reduced activation of the ventral striatum, orbital and ventromedial frontal cortices in response to monetary incentive stimuli in MDD patients with significant anhedonia relative to MDD patients without anhedonia and healthy control. The outcome of the proposed work may provide clues for diagnosis, classification, and treatment of MDD, and may also yield leads for identifying the fundamental neural mechanisms underlying anhedonia in other disabling psychiatric conditions such as schizophrenia and addiction. During the past year, PET and fMRI data from depressed and healthy control subjects have been acquired, analyzed, and reported at several international scientific meetings. The behavioral data from these analyses show significant differences in the modulation of performance by incentive magnitude between the depressives and controls. The neural basis for these differences were demonstrated by analysis of the fMRI data, and showed abnormal activation of several regions of the striatum (caudate, nucleus accumbens) and orbitofrontal corex in MDD. Two manuscripts are in preparation to describe these findings. In addition, two new experimental tasks were added, and new pilot data was obtained in 16 healthy control subjects to demonstrate that these tasks were satisfactory. One involves a reward conditioning task and the other is a working memory task in which motivation and attention are differentially modulated by intermittently making monetary reward contingent on the behavioral performance. The initial analyses of the fMRI and neurocognitive data suggested these tasks were effectively tapping into the neural and systems of interest and influencing motivated behavior, so the studies in depressed patients have been initiated. These studies are nearly completed and analyzed, and papers describing the results are in preparation for publication. Finally, PET studies have been initiated using PET and C-11raclopride to investigate endogenous dopamine release during naturally rewarding tasks. We have developed for the first time a method for measuring reward-related dopamine release in striatal regions such as the accumbens area in a manner that is not confounded by activation-associated changes in local blood flow and also is controlled for the motor aspects. A manuscript is in preparation describing these results and methods. This is now being extended into depressed patients to test the hypothesis that reward-related dopamine release is blunted in depressed patients, and 6 depressed subjects have been imaged thus far.