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，经济上的负担。抗抑郁药物靶向图核中的5 -羟色胺（5HT）神经元，但5HT通路在抑郁症病理生理中的病因和参与尚不清楚。有证据表明，抑郁症患者的代谢异常活跃，但矛盾的是，脊髓液中5HT代谢物的水平很低。抗抑郁药可以改善血清素的功能，但会进一步降低血清素代谢物的水平。其原因尚不完全清楚。区域活动可以看作是一个时间序列，揭示了与区域间交流有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来源。时间序列数据的频谱分析根据频率（类似于音乐中的音高）将信号分成几组。为了研究这一点，一组接受抗抑郁治疗的患者（n=11）接受了两次功能性MRI扫描，间隔一周。在每次扫描之前，给予饮食（或假药）以迅速消耗5HT前体，称为急性色氨酸消耗（ATD）。比较了两种试验中raphi BOLD信号的时间序列特征。谱功率描述了信号中特定频率随时间的波动强度。快速波动；25到。12 Hz)，随着ATD的增加，图的强度增加（p= 0.004）。功能连通性是用慢波动之间的相关性来衡量的。03到。06赫兹)，来自丘脑前叶信号。随ATD而明显下降。这两项发现在图表功能障碍模型中相吻合。ATD期间低5HT可用性可能与局部中间神经元和轴突侧枝自受体5HT抑制活性的丧失有关。没有5HT抑制作用的中间神经元更活跃，在血氧水平依赖（BOLD）信号中表现为激活。神经元活动也会增加代谢努力，以对失去的自身受体反馈做出反应。这种增加的活动出现在较高的频率，这不会改善存在于低频率的功能连接。在缺乏5HT前体的情况下，低频的功能连接减弱。需要复制和扩展这些发现。该扩展的目标包括在未治疗的抑郁症中检查这些指标，比较未治疗与缓解的抑郁症，以及预处理指标与抗抑郁反应的关联。反应预测测试可能成为一个长期目标。图表测试将具体反映对现有治疗机制的反应概率。20名单极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。ATD和假饮食将按双盲随机顺序进行。本研究将提高我们对抑郁症rapi功能障碍的动力学特征的认识。

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.