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，经济负担沉重。抗抑郁药物的靶点是中缝核内的5-羟色胺(5-HT)神经元，但5-羟色胺(5-HT)通路的作用机制和参与抑郁症的病理生理机制尚不清楚。有证据表明，在抑郁症中，RAPH代谢过度活跃，但矛盾的是，脊髓液中5-羟色胺的代谢物水平很低。抗抑郁药可以改善5-羟色胺功能，但会进一步降低5-羟色胺代谢物的水平。造成这种情况的原因尚不完全清楚。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源。时间序列数据的频谱分析根据信号的频率(类似于音乐中的音高)将信号分成几组。为了研究这一点，对11名接受抗抑郁药物治疗的先导组患者进行了两次功能磁共振扫描，每隔一周扫描一次。在每次扫描之前，饮食(或假手术)被用来迅速消耗5-羟色胺的前体，称为急性色氨酸耗竭(ATD)。在两次测试中比较了Raphi粗体信号的时间序列特征。频谱功率描述了信号内特定频率随时间的波动强度。随着ATD的发生，Raphi的快速波动(0.25至0.12赫兹)变得更加剧烈(p=0.004)。功能连通性通过RAPH的缓慢波动(0.03至0.06赫兹)和丘脑前部信号之间的相关性来测量。随着ATD的发展，这一指标明显下降。这两个发现在一个中缝功能障碍的模型中是一致的。ATD期间5-羟色胺的低利用率可能与局部中间神经元和轴突侧支自身受体的5-羟色胺抑制活性丧失有关。中间神经元在没有5-羟色胺抑制作用的情况下更加活跃，在血液氧合水平依赖(BOLD)信号中表现为激活。神经元的活动也会在代谢努力中增加，以响应丢失的自身受体反馈。这种增加的活动出现在更高的频率上，这不会改善低频下的功能连接。在缺乏5-羟色胺前体的情况下，低频下的功能连接减弱。需要对这些发现进行复制和推广。这一扩展的目标包括检查未经治疗的抑郁症的这些指标，比较未治疗的抑郁症与缓解的抑郁症，以及治疗前指标与抗抑郁药反应的相关性。反应预测测试可能会成为一个长期目标。RAPH测试将具体反映可用治疗机制的应答概率。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。ATD和假饮食将以双盲、随机顺序给予。这项研究将加深我们对抑郁症RAPHI功能障碍的动力学特征的理解。 与公共健康相关：大脑成像将被用来测量受抗抑郁药物影响的区域活动的波动。当我们降低5-羟色胺的可获得性时，一种新的分析方法显示该区域的快速波动增加，但与其他区域的缓慢波动的份额减少。这些方法可能有助于我们了解5-羟色胺对大脑网络功能的作用。

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.