Abnormal temporal difference reward-learning signals in major depression
Abnormal temporal difference reward-learning signals in major depression
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DOI：
10.1093/brain/awn136
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发表时间：
2008-08-01
期刊：
影响因子：
14.5
通讯作者：
Steele, J. D.
中科院分区：
文献类型：
--
作者：
Kumar, P.;Waiter, G.;Steele, J. D.
快感缺失是重性抑郁症（MDD）的核心症状，长期以来被认为与多巴胺能功能降低有关。然而，大多数抗抑郁药不直接作用于多巴胺系统，所有抗抑郁药都有延迟的完全治疗效果。最近，有人提出抗抑郁药不能改变抗抑郁药无反应MDD中的多巴胺功能。有令人信服的证据表明，多巴胺神经元编码一个特定的阶段（短时间）奖励学习信号，由时间差异（TD）理论描述。目前还没有其他神经元编码TD奖励学习信号的证据，尽管这样的证据可能会及时发现。在本研究中没有探索TD信号的神经元底物。相信号被认为具有与强直（长持续时间）信号完全不同的性质。没有研究调查MDD中的阶段性奖励学习信号。因此，在奖励学习任务中，使用fMRI扫描长期接受抗抑郁药物治疗的MDD成人，以及未用药和急性服用抗抑郁药物西酞普兰的对照组。检验了三个假设：第一，MDD患者的TD奖励学习信号减弱;第二，对照组急性给予抗抑郁药后TD奖励学习信号减弱;第三，重度抑郁症患者TD信号改变的程度与疾病严重程度相关。实验结果支持上述假设。MDD患者在许多非脑干区域（腹侧纹状体（VS），扣带前扣带喙侧和背侧，压后皮质（RC），中脑和海马）的奖励学习信号显著减少。然而，TD信号在患者的脑干中增加。正如预测的那样，对照组急性抗抑郁药给药与TD信号减弱相关，而急性西酞普兰给药并未增加脑干TD信号。在许多地区，MDD异常信号的幅度与疾病严重程度评级相关。这些发现强调了阶段性奖励学习信号的重要性，并且与抗抑郁药不能使抗抑郁药无反应MDD的奖励学习功能正常化的假设一致。虽然有证据表明，一些抗抑郁药急性抑制多巴胺功能，几乎所有抗抑郁药的长期作用是增强多巴胺受体激动剂的反应性。这种区别可能有助于阐明抗抑郁药的延迟作用。最后，与精神分裂症的近期研究类似，MDD中异常阶段性奖励学习信号的发现意味着对症状和治疗机制的综合理解是可能的，跨越生理学，现象学和药理学。
Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.