Identifying mechanisms of response to therapeutic intervention in clinical high risk (CHR) for psychosis: a bridge to treatment

该更新申请建立在我们目前由R 01 NIH Fogarty国际中心支持的研究基础上 赠款，题为“前驱症状向早期精神病转变的心理生物学后续研究” （R01MH111448）。该提案侧重于临床高风险研究中的两个持续需求：1） 与向精神病转变和其他功能和临床相关的新生物标志物的鉴定 结果;和2）识别可用于未来临床研究的特定脑回路目标 审判我们假设，临床相关的生物标志物的个体特异性预后的乳腺癌将是 通过纳入利用神经可塑性的定量评估的措施来加强， 很可能会有所改变在这种观点中，乳腺癌的结果可能由病理生理学和 通过大脑通过神经可塑性机制适应和响应病理生理的能力（即，别稳态）。 因此，我们建议通过给药非侵入性的， 神经调节通过两种新的范式，正如我们已经证明的那样， 精神分裂症的阴性和阳性症状这两种神经调节技术是：1。重复 经颅磁刺激（rTMS）1和2。真实的时间fMRI神经反馈增强正念冥想 （mb-rt-fMRI-NFB）2.我们将收集两种传统的生物标志物（临床、神经心理学、ERP、MRI、DTI和 静息状态MRI）以及新的变稳态生物标志物（即，生物标志物，量化神经变化前， 相对于干预后）。这两种干预措施以前没有用于过受试者， 在200 ℃（每个实验条件50 ℃）和100 HC条件下测试5年。此外，我们将 继续提高上海精神卫生中心（SMHC）的知识能力， 合作者是基础。我们还将研究这些干预措施在非洲的有效性， 未来的治疗方法（目标1和2），我们将测试传统和变应性生物标志物作为预测因子 临床和神经认知结果（目标3）。此外，我们还将通过以下方式大大提高研究能力： 在已有成就和合作的基础上，并将我们的影响力扩大到新的机构 (Aim 4）。这种竞争性的更新利用了单个站点（SMHC）的一系列独特优势， 与上海研究团队的合作，该团队已被证明是目前赠款中最富有成效的 周期我们相信这项高度新颖的研究将有助于未来治疗干预的发展 这将防止这一弱势群体产生不利后果，同时， 将丰富该领域的新见解的病理生理学的这种情况。

This renewal application builds upon our current study supported by the R01 NIH Fogarty International Center grant, entitled “Psychobiological Follow-up Study of Transition from Prodrome to Early Psychosis” (R01MH111448). This proposal focuses on two persistent needs in clinical high risk (CHR) research: 1) the identification of novel biomarkers associated with transition to psychosis and other functional and clinical outcomes; and 2) the identification of symptom-specific brain circuit targets that can be engaged in future clinical trials. We hypothesize that clinically relevant biomarkers for individual-specific prognosis in CHR will be enhanced by the inclusion of measures that capitalize on the quantitative assessment of neural plasticity and are likely amenable to change. In this view, CHR outcomes are likely determined by both pathophysiology and by the brain’s capacity to adapt and respond to pathophysiology via neural plasticity mechanisms (i.e., allostasis). We thus propose to examine brain circuit plasticity biomarkers relevant to CHR by administering non-invasive neuromodulation via two novel paradigms that, as we have demonstrated, engage brain networks involved in negative and positive symptoms in schizophrenia. These two neuromodulation techniques are: 1. repetitive transcranial magnetic stimulation (rTMS)1 and 2. real time fMRI neurofeedback enhanced mindful meditation (mb-rt-fMRI-NFB)2. We will collect both traditional biomarkers (clinical, neuropsychological, ERP, MRI, DTI and resting state MRI) as well as novel allostatic biomarkers (i.e., biomarkers that quantify neural changes pre- relative to post-intervention). These two interventions, which have not been used with CHR subjects before, will be tested in 200 CHR (50 CHR per experimental condition) and 100 HC over 5 years. Furthermore, we will continue to enhance knowledge capacity at the Shanghai Mental Health Center (SMHC), where our Chinese collaborators are based. We will also examine the effectiveness of these interventions in CHR as a bridge to future therapeutic treatments (Aims 1 and 2), and we will test traditional and allostatic biomarkers as predictors of clinical and neurocognitive outcomes (Aim 3). Additionally, we will significantly enhance research capacity by building on already established achievements and collaborations, and by extending our reach to new institutions (Aim 4). This competitive renewal capitalizes on a unique set of strengths at a single site (SMHC) and on a collaboration with the Shanghai research team, which has proven to be most productive in the current grant cycle. We believe that this highly novel study will contribute to the development of future therapeutic interventions in CHR, which will prevent this vulnerable population from developing adverse outcomes and, at the same time, will enrich the CHR field with new insights into the pathophysiology of this condition.