Network Mediation of Experiential and Expressive Deficits in Psychotic Disorders

项目总结/摘要 精神障碍很容易通过幻觉的所谓“阳性症状”来识别， 妄想和思维障碍然而，“阴性症状”的严重程度（例如，失动，快感缺乏， 和面部表情缺陷）是功能结果的最佳预测因子， 独立住房。抗精神病药物在改善这些症状方面是适度有效的。我们 缺乏对这些症状如何在神经回路水平上介导的共识。没有 生物“目标”，如电路病理生理学，我们开发新干预措施的能力至关重要 阻碍。 我们实验室和其他人以前的工作使用了无任务或“休息状态”功能性磁 共振成像（rsfMRI）检查阴性症状严重程度的神经相关性。我们的初步 数据表明，阴性症状的严重程度与小脑和小脑之间的连接障碍有关。 背外侧前额叶皮质（DLPFC）。我们使用以下方法对这种网络-症状关系进行了实证检验： 重复经颅磁刺激（rTMS）来操纵网络连接。我们观察到rTMS 诱导的功能连接性增加与阴性症状的改善密切相关 严重性，与网络连接介导负面神经病学的假设一致。 我们建议测试小脑-DLPFC网络连接障碍导致负性 精神分裂症的症状使用受试者内纵向实验设计，我们将测量网络 rTMS操作小脑-DLPFC连接之前和之后的连接和症状严重程度。我们 将通过基于报告者的方法以及独立于评估者的客观指标量化症状严重程度 测试动机缺乏快感缺乏和面部表情我们的假设是网络的逆转 连接障碍将导致负面症状严重程度和网络参与程度降低 将解释症状改善的个体差异。 如果成功的话，这个项目将建立一个生物目标， 改善精神障碍的这些致残性、耐药性症状的方法。

Project Summary / Abstract Psychotic disorders are readily identified by the so-called `positive symptoms' of hallucinations, delusions, and thought disorder. However, the severity of `negative symptoms' (e.g. amotivation, anhedonia, and facial expression deficits) are the best predictors of functional outcomes such as employment and independent housing. Antipsychotic medications are modestly effective in ameliorating these symptoms. We lack a consensus understanding of how these symptoms are mediated at the level of neural circuits. Without a biological `target' such as circuit pathophysiology, our ability to develop new interventions is critically hampered. Previous work from our laboratory and others have used task-free or `resting state' functional Magnetic Resonance Imaging (rsfMRI) to examine the neural correlates of negative symptom severity. Our preliminary data determined that negative symptom severity is correlated with dysconnectivity between the cerebellum and Dorso-Lateral Pre-Frontal Cortex (DLPFC). We empirically tested this network-symptom relationship using repetitive transcranial magnetic stimulation (rTMS) to manipulate network connectivity. We observed that rTMS induced increases in functional connectivity were strongly associated with improvement in negative symptom severity, consistent with the hypothesis that network connectivity mediates negative symptomology. We propose to test the hypothesis that cerebellar-DLPFC network dysconnectivity causes negative symptoms in schizophrenia. Using a within-subject, longitudinal experimental design, we will measure network connectivity and symptom severity before and after rTMS manipulation of cerebellar-DLPFC connectivity. We will quantify symptom severity via reporter based methods as well as rater-independent; objective measures that test amotivation, anhedonia, and facial expression. Our hypothesis is that reversal of network dysconnectivity will give rise to reduced negative symptom severity and the magnitude of network engagement will explain individual variance in symptomatic improvement. If successful, this project will establish a biological target for engagement by a variety of experimental methods towards the amelioration of these disabling, medication-resistant symptoms of psychotic disorders.