Spectral Features of Raphe fMRI Time Series Data in Depression

描述（由申请人提供）：抑郁症仍然是毁灭性的，致命的，经济负担。抗抑郁药靶向5-羟色胺（5-HT）神经元在海马核，但5-HT通路的原因和参与抑郁症的病理生理学仍不清楚。有证据表明，在抑郁症中，5-羟色胺代谢物在代谢上非常活跃，但矛盾的是，5-羟色胺代谢物在脊髓液中的水平很低。抗抑郁药改善血清素功能，但导致血清素代谢物水平进一步下降。其原因尚不完全清楚。区域活动可以被看作是一个时间序列，揭示了与区域间通信相关的代谢活动的动态特征。区域活动和信号似乎在频谱的多个狭窄范围内波动。每个单元可以同时是几个信号的源。时间序列数据的频谱分析将信号按频率（类似于音乐中的音高）分组。为了研究这一点，一个试验组的抗抑郁药治疗的患者（n=11）进行了两次功能性MRI扫描，间隔一周。在每次扫描之前，给予饮食（或假）以快速消耗5 HT的前体，称为急性色氨酸消耗（ATD）。比较了两种测试方法下raphi BOLD信号的时间序列特征。谱功率描述了信号内特定频率随时间的波动强度。在ATD患者中，Raphi的快速波动（0.25至0.12 Hz）变得更加强烈（p= 0.004）。功能连接性被测量为来自前丘脑信号的缓慢波动（0.03至0.06 Hz）之间的相关性。它与ATD明显下降。这两个发现符合一个模型的功能障碍。ATD期间5 HT可用性低可能与局部中间神经元和轴突侧支自身受体的5 HT抑制活性丧失有关。中间神经元在没有5 HT抑制作用的情况下更活跃，在血氧水平依赖性（BOLD）信号中会出现激活。神经元活动也会增加代谢努力，以响应失去的自身感受器反馈。这种增加的活动出现在较高的频率，这不会改善在低频率存在的功能连接。在低频率下的功能连接在没有5 HT前体的情况下减少。需要复制和推广这些研究结果。该扩展的目标包括在未经治疗的抑郁症中检查这些指标，将未经治疗的抑郁症与缓解的抑郁症进行比较，以及预处理指标与抗抑郁药反应的关联。反应预测测试可能成为一个长期目标。检测将具体反映可用治疗机制的反应概率。20名单相抑郁症患者将在治疗前完成两次扫描测试，并在舍曲林治疗12周后完成两次扫描。将以双盲、随机顺序给予ATD和假饲料。本研究有助于加深对抑郁症患者Raphi功能障碍的动力学特征的认识。 公共卫生相关性：脑成像将用于测量受抗抑郁药影响的区域的活动波动。当我们降低血清素的可用性时，一种新的分析方法显示，该地区的快速波动增加，但与其他地区的缓慢波动减少。这些方法可以帮助我们了解血清素对大脑网络功能的贡献。

DESCRIPTION (provided by applicant): Depression remains devastating, lethal, and financially burdensome. Antidepressants target serotonin (5HT) neurons in raph¿ nuclei, but 5HT pathway causation and involvment in the pathophysiology of depression remains unclear. Evidence suggests that the raph¿ is metabolically hyper-active in depression, but, paradoxically, levels of the 5HT metabolite are low in spinal fluid. Antidepressants improve serotonin function, but cause further decrease levels of the serotonin metabolite. Reasons for this are not fully understood. Regional activity may be viewed as a time series, revealing dynamic features of metabolic activity relevant to inter-regional communication. Regional activities and signaling appear to fluctuate within multiple narrow ranges of the frequency spectrum. Each unit may be a source of several signals at once. Spectral analysis of time series data separates signals into groups by their frequencies (similar to pitch, in music). To study this, a pilot group of antidepressant-treated patients (n=11) was scanned with functional MRI twice, one week apart. Prior to each scan, a diet (or sham) was given to rapidly deplete the precursor of 5HT, called acute tryptophan depletion (ATD). Time series features of raphi BOLD signals were compared between the two tests. Spectral power describes the intensity of fluctuations at specific frequencies within a signal over time. Rapid fluctuations (.25 to .12 Hz) in the raphi became more intense with ATD (p=.004). Functional connectivity was measured as the correlation between slow fluctuations (.03 to .06 Hz) from raph¿ and anterior thalamus signals. It declined markedly with ATD. These two findings fit together in a model of raph¿ dysfunction. Low 5HT availability during ATD may be associated with a loss of 5HT inhibitory activity at local interneurons and axonal collateral autoreceptors. Interneurons, more active without 5HT inhibitory effects, would appear activated in blood oxygenation level dependent (BOLD) signals. Neuronal activity would also increase in metabolic efforts to respond to lost autoreceptor feedback. This increased activity appeared at the higher frequencies, which would not improve the functional connectivity that was present at low frequencies. Functional connectivity at low frequencies was diminished in the absence of the 5HT precursor. Replication and extension of these findings is needed. Goals for this extension include examinations of these metrics in untreated depression, comparisons of untreated with remitted depression, and associations of pretreatment metrics with antidepressant response. A response-predictive test may become a long-range goal. raph¿ testing would specifically reflect response probability for available treatment mechanisms. Twenty unipolar depressed patients will complete two scan tests before treatment and two scans after 12 weeks of sertraline treatment. ATD and sham diets will be given in a double-blind, random sequence. The study will improve our understanding of dynamical features of raphi dysfunction in depression. PUBLIC HEALTH RELEVANCE: Brain imaging will be used to measure fluctuations in activity in a region affected by antidepressants. When we decreased serotonin availability, a new analysis method showed increased rapid fluctuations in the region but decreased sharing of slow fluctuations with other regions. These methods may help us understand serotonin contributions to brain network function.