Pathophysiology of Auditory Hallucinations

描述(申请人提供)：此次R01资助续期的总体目标是确定精神分裂症和分裂情感障碍患者产生幻听/言语幻觉(AVH)的病理生理学基础。拟议的研究计划源于在最初赠款期间完成的两项功能磁共振研究。首先检测到动静脉搏先在左侧额下回(IFG)和右侧颞叶区域活动增强，继而在这些区域之间的功能耦合增强。我们的第二项研究检查了静息功能连接性(FC)，该功能环连接Wernicke区、左侧IFG和壳核的右同源部位。患有精神分裂症的扁平苔藓患者在这个皮质纹状体环路上表现出明显更大的Fc总和，与类似诊断的没有AVH的患者和健康对照组相比。这些发现提出了一个将被进一步检验的特定假设，即连接左侧IFG、后颞区和壳核的皮质-纹状体耦合增强导致导致幻觉的间歇性共同激活状态。具体目标1是利用两个语音感知任务，在幻觉者中诱导过度的区域激活，与非幻觉患者和健康对照组相比，在这个患者亚组中，相同的大脑区域包括皮质纹状体环路，发现在基线时是超连接的。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测试假设，即在我们完成的研究中检测到的皮质纹状体高连接性是由于通路低效引起的补偿。我们的预测是，不会检测到幻觉患者路径效率低下的证据，这与我们的替代过度连接-&gt；共激活模型是一致的。具体目标#3是为了证明有幻觉的患者与无幻觉的患者和健康对照的脑白质通路的不同。这将通过进行扩散张量成像研究来实现，以测量前弓状束的分数各向异性和下纵束的平均扩散率。具体目的#4是证明在静息状态下，连接壳核和Wernicke区的Fc可以预测双时相1赫兹重复经颅磁刺激(RTMS)后动静脉动静脉高压的后续改善，并且这种干预导致的动静脉动静脉高压的降低程度也与获得的动静脉动静脉高压的改善水平呈正相关。25名精神分裂症谱系障碍和活动期AVH患者、25名诊断相似但近期无AVH病史的患者和25名健康对照将被研究。这些研究将为AVH的机制基础提供关键的新见解。

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.