Pathophysiology of Auditory Hallucinations

描述（由申请人提供）：本次R01拨款更新的总体目标是确定精神分裂症和分裂情感性障碍患者的听觉/言语幻觉（AVHs）的病理生理基础。拟议的研究计划源自最初拨款期间完成的两项功能磁共振成像研究。第一种方法检测到在AVHs发生之前，左侧额下回和右侧颞叶区域的活动增强，而在此之前，这些区域之间的功能耦合升高。我们的第二项研究考察了静息功能连通性（FC），沿着韦尼克区、韦尼克区右侧同源物、左侧IFG和壳核的功能环连接位点进行总结。与诊断相似的无AVHs患者和健康对照相比，精神分裂症幻觉者在皮质纹状体回路中表现出更强的FC。这些发现提出了一个具体的假设，将进一步验证，即加强皮质纹状体耦合连接左IFG，后颞区和壳核导致偶发性共激活状态，是致幻的。具体目标#1是利用两个语音感知任务，在幻觉患者中，与非幻觉患者和健康对照者相比，在包含皮质纹状体环路的相同大脑区域中，引起过度的区域激活，这些区域在该患者亚组中被发现在基线时超连接。一个任务是检测通过语音语调表达的负面情绪，而第二个任务是区分有意义的短语和部分由非单词音节串组成的短语。具体目标#2是在内部语音生成任务中使用功能磁共振成像来验证我们完成的研究中检测到的皮质纹状体超连接是通路效率低下引起的补偿的假设。我们的预测是，在产生幻觉的患者中不会发现通路效率低下的证据，这与我们的替代超连接->共激活模型是一致的。具体目标#3是证明异常的白质通路区分幻觉患者与非幻觉患者和健康对照。这将通过进行弥散张量成像研究来测量前弓状束的分数各向异性和下纵束的平均弥散性来完成。具体目标#4是证明静息时连接壳核和韦尼克区的FC预测了双颞期1赫兹重复经颅磁刺激（rTMS）后AVHs的后续改善，并且这种干预引起的FC减少水平也与AVHs的改善水平正相关。25例精神分裂症谱系障碍伴活动性房颤患者，25例诊断相似但近期无房颤病史的患者，以及25例健康对照。这些研究将为AVHs的机制基础提供重要的新见解。

DESCRIPTION (provided by applicant): The overall objective of this R01 grant renewal is to ascertain the pathophysiological basis of auditory/verbal hallucinations (AVHs) in patients with schizophrenia and schizoaffective disorder. The proposed research plan derives from two fMRI studies completed during the initial grant period. The first detected heightened activity prior to AVHs in the left inferior frontal gyrus (IFG) and right temporal regions that in turn was preceded by elevated functional coupling between these regions. Our second study examined resting functional connectivity (FC) summed along a functional loop linking sites in Wernicke's area, a right homologue of Wernicke's area, left IFG, and the putamen. Hallucinators with schizophrenia demonstrated robustly greater FC summed across this corticostriatal loop compared to similarly diagnosed patients without AVHs and healthy controls. These findings suggest a specific hypothesis that will be further tested, namely that heightened corticostriatal coupling linking left IFG, posterior temporal regions and the putamen leads to episodic coactivation states that are hallucinogenic. Specific Aim #1 is to utilize two speech perception tasks to elicit excessive regional activation in hallucinators compared to nonhallucinating patients and healthy controls in the same brain regions comprising the corticostriatal loop found to be hyperconnected at baseline in this patient subgroup. One task is detection of negative emotionality expressed via speech intonation, while the second task is to distinguish meaningful phrases from phrases comprised partially of non-word syllable strings. Specific Aim #2 is to use fMRI during an inner speech generation task to test the hypothesis that corticostriatal hyperconnectivity detected in our completed study is a compensation arising from pathway inefficiency. Our prediction is that evidence of pathway inefficiency in hallucinating patients will not be detected, which is consistent with our alternative hyperconnectivity->coactivation model. Specific Aim #3 is to demonstrate aberrant white matter pathways that distinguish hallucinating patients from nonhallucinating patients and healthy controls. This will be accomplished by conducting a diffusion tensor imaging study to measure fractional anisotropy in the anterior arcuate fasciculus and mean diffusivity in the inferior longitudinal fasciculus. Specific Aim #4 is to demonstrate that at rest FC linking the putamen and Wernicke's area predicts subsequent improvement in AVHs following a course of bitemporal 1-Hz repetitive transcranial magnetic stimulation (rTMS), and that level of reduction in FC induced by this intervention also correlates positively with level of improvement in AVHs obtained. Twenty-five patients with schizophrenia spectrum disorder and active AVHs, 25 patients with similar diagnoses but without a recent history of AVHs, and 25 healthy controls will be studied. These studies will provide critical new insights into the mechanistic basis of AVHs.