Neurobiological correlates of auditory processing in health and disease: an RDoC study

 描述(由申请人提供)：本提案侧重于听觉感知，这是研究领域标准(RDoC)认知系统领域内的一个子结构，在健康和传统(DSM-IV和DSM-V)疾病类别中听觉知觉障碍的病理生理学中的作用。总体目标是表征听觉感觉学习的神经生物学和神经计算基础，以确定导致听觉知觉障碍的病理生理机制，特别是听觉言语幻觉(AVH)。我们的目标是招募以下组：精神分裂症和分裂情感障碍伴轻度和高度AVH(n=15)，妄想性障碍(无AVH的妄想性精神病；n=15)，耳鸣(无AVH的听觉知觉障碍；n=15)，以及匹配的健康对照组(不同程度的亚临床知觉障碍；n=30)。我们将获得所有受试者的广泛的临床、神经认知和遗传特征，以及多模式成像：(1)使用[11C]PHNO和苯丙胺范式，对丘脑、纹状体和中脑内的D2/3受体和DA的储存/释放能力进行PET测量；(2)基于模型的功能磁共振测量(FMRI)测量在概率的听觉辨别任务期间听觉区域的感觉预测错误信号；(3)磁共振波谱测量听觉皮质中的谷氨酸浓度；(4)基于任务和休息状态的功能磁共振测量感觉丘脑皮质的连通性；(5)基于血DNA样本的全基因组测序。我们将在所有诊断组的总体样本中测试听觉PE缺陷是否预测AVH(SA1)，并与纹状体和丘脑DA改变(SA2)和听觉皮质谷氨酸增加(SA3)相关。我们还将探索同一受试者中DA和谷氨酸(EA1)之间的关系，以及听觉PE与听觉丘脑和听觉皮质(EA2)之间连接的关系，并确定一组与听觉PE缺陷(EA3)相关的候选基因。RDoC的这一建议将导致对感觉学习的机制及其在与听觉知觉变化相关的条件下的扰动的进一步理解。

 DESCRIPTION (provided by applicant): This proposal focuses on the role of auditory perception, a subconstruct within the cognitive systems domain of the Research Domain Criteria (RDoC), in the pathophysiology of auditory perceptual disturbances in health and across traditional (DSM-IV and DSM-V) disease categories. The overall aim is to characterize the neurobiological and neurocomputational basis of auditory sensory learning to identify pathophysiological mechanisms leading to auditory perceptual disturbances and, specifically, auditory verbal hallucinations (AVH). We aim to recruit the following groups: schizophrenia and schizoaffective disorder with low- and high-severity AVH (n=15 and n=15, respectively), delusional disorder (delusional psychosis without AVH; n=15), tinnitus (auditory perceptual disturbances without AVH; n=15), and matched healthy controls (varying degrees of subclinical perceptual disturbances; n=30). We will obtain extensive clinical, neurocognitive, and genetic characterization, and multimodal imaging in all subjects: (1) PET measures of D2/3 receptors and DA storage/release capacity within the thalamus, striatum, and the midbrain, using [11C]PHNO and the amphetamine paradigm; (2) Model-based fMRI measures of sensory prediction-error signals in auditory regions during a probabilistic, auditory discrimination task; 3) MR spectroscopy measures of glutamate concentration in the auditory cortex; (4) Task-based and resting- state fMRI connectivity measures in sensory thalamo-cortical projections; (5) Whole genome sequencing based on blood DNA samples. We will test in the overall sample across diagnostic groups if auditory PE deficits predict AVH (SA1) and correlate with altered DA in striatum and thalamus (SA2) and with increased glutamate in the auditory cortex (SA3). We will also explore the relationship within the same subjects between DA and glutamate (EA1) and the relationships of auditory PE to connectivity between auditory thalamus and auditory cortex (EA2) and identify a set of candidate genes associated with auditory PE deficits (EA3). This RDoC proposal will lead to further understanding of the mechanisms of sensory learning and their perturbations in conditions associated with auditory perceptual alterations.