Interleaved Perfrontal TMS/fMRI in Schizophrenia

描述(申请人提供)：精神分裂症与相当大的发病率和经济负担有关。关于它的病理生理学知识仍然不完整。一些证据表明，精神分裂症患者的大脑背外侧前额叶皮质(DLPFC)可能存在功能障碍。神经成像研究报告了参与认知任务的精神分裂症患者的DLPFC活动不足和活动过度。这些明显的矛盾可能部分归因于受试者的技能、表现和每项任务的难度。经颅磁刺激(TMS)是一种利用强磁场激活神经元的非侵入性技术，是一种不依赖于受试者依从性或努力程度的直接脑刺激方法。我们南加州大学的团队开创了TMS/fMRI交错扫描技术，通过TMS获得大脑活动的实时图像。在这里，我们计划在精神分裂症受试者中使用交叉TMS/fMRI来研究DLPFC是否真的活动不足，并表征对TMS的血氧水平依赖(BOLD)反应。我们假设，与匹配的健康对照组相比，在患有精神分裂症和明显的负面症状(如运动和平淡的情感)的受试者中，TMS线圈下的rCBF反应将较弱。具体方法：在这项为期3年的资助计划中，我们计划招募15名有明显阴性症状且未服用抗精神病药物(至少2周)的男性精神分裂症患者和15名年龄、利手、父母教育和吸烟习惯相匹配的健康对照组。他们将被评为精神病、情绪、锥体外系症状和认知。他们将接受高分辨率结构扫描，以确定左侧额中回(Brodmann Area 9)的位置，并测量头骨到前额叶皮质、头骨到运动皮质的距离比率。在不同的一天，他们将接受TMS/fMRI的交叉治疗。我们将以1赫兹的频率间歇性地刺激左额中回，并进行即时大胆的fMRI扫描。每一次21秒的TMS前后将有相同长度的无刺激。TMS将在运动阈值的80%、100%和120%(移动拇指所需的强度)下随机提供。如果需要，使用的强度将根据前额叶萎缩的程度进行调整。RCBF的变化将是主要的结果衡量标准。结论：本研究建立在健康受试者和1例精神分裂症患者的交叉前额叶TMS/功能磁共振成像的初步工作基础上，以及阴性的TMS研究基础上。 精神分裂症的症状。它将评估TMS/fMRI在这一人群中是否是一种可行和安全的方法。它将描述对TMS的大胆反应(假设精神分裂症患者的TMS比对照组更弱)。这是更好地了解精神分裂症受试者对非侵入性刺激的神经元反应的必要的第一步。在未来的工作中，这项R2I拨款的结果将有助于研究DLPFC的功能连接，TMS与复杂的认知和药理学探测的关系，并可能增加对如何恢复精神分裂症患者DLPFC功能的理解。

DESCRIPTION (provided by applicant): Schizophrenia is associated with considerable morbidity and economic burdens. Knowledge about its pathophysiology is still incomplete. Some evidence exists that the brain's dorsolateral prefrontal cortex (DLPFC) may be dysfunctional in schizophrenia. Neuroimaging studies have reported both hypoactive and hyperactive DLPFC in subjects with schizophrenia involved in a cognitive task. These apparent contradictions may be due in part to the subjects' skill, performance and the difficulty of each task. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that employs a high magnetic field to activate neuron and a direct method of brain stimulation that does not depend on subject's compliance or effort. Our group at MUSC has pioneered the interleaved TMS/fMRI technology to get real-time images of brain activity with TMS. Here, we plan to use interleaved TMS/fMRI in schizophrenia subjects to investigate if DLPFC is truly hypoactive and characterize the Blood Oxygen Level Dependent (BOLD) response to TMS. We hypothesize that in subjects with schizophrenia and prominent negative symptoms (such amotivation and flat affect) will show a weaker rCBF response underneath the TMS coil as compared to matched healthy controls. Specific Methods: In this 3 year grant proposal, we plan enroll 15 schizophrenia males with prominent negative symptoms and neuroleptic free (for at least 2 weeks) and 15 healthy controls matched for age, handedness, parental education and smoking habits. They will be rated for psychosis, mood, extrapyramidal symptoms and cognition. They will undergo a high resolution structural scan to determine the location of left middle frontal gyrus (Brodmann Area 9) and to measure the distance ratio from skull to prefrontal cortex over skull to motor cortex. On a different day, they will undergo an interleaved TMS/fMRI session. We will stimulate intermittently over the left middle frontal gyrus at 1Hz and acquire 'in-the-moment BOLD fMRI scans. Each 21-second epoch of TMS will be preceded and followed by an equal length of no stimulation. TMS will be randomly delivered at 80%, 100% and 120% of motor threshold (intensity necessary to move the thumb). The intensity used will be adjusted relative to the degree of prefrontal atrophy if needed. Changes in rCBF will be the primary outcome measures. Conclusions: This study builds on the Prs preliminary work with interleaved prefrontal TMS/fMRI in healthy subjects and in one case of schizophrenia, as well as TMS research in negative symptoms of schizophrenia. It will assess whether TMS/fMRI is a feasible and safe method in this population. It will characterize the BOLD response to TMS (which is hypothesized to be weaker in schizophrenia subjects compared to controls). This is a necessary first step to better understand neuronal response to non-invasive stimulation in subjects with schizophrenia. In future work, results from this R2I grant will help investigating the functional connectivity of the DLPFC, the relation of TMS to complex cognitive and pharmacological probes and possibly add to the understanding of how to restore DLPFC function in patients with schizophrenia.