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

此续约申请建立在我们目前由R01 NIH Fogarty国际中心支持的研究基础上 格兰特，题为“从先兆症到早期精神病的心理生物学随访研究” (R01MH111448)。本建议侧重于临床高风险(CHR)研究中的两个持久需求：1) 与向精神病及其他功能和临床转变相关的新生物标志物的鉴定 结果；以及2)确定可用于未来临床的症状特定的脑回路靶点 审判。我们假设临床上与慢性阻塞性肺疾病个体预后相关的生物标志物将是 通过纳入利用神经可塑性的定量评估和 可能会顺从于改变。在这种观点下，慢性阻塞性肺疾病的结局可能由病理生理学和 大脑通过神经可塑性机制适应和响应病理生理学的能力(即，异体平衡)。 因此，我们建议通过非侵入性给药来检测与CHR相关的脑回路可塑性生物标记物。 通过两个新的范例进行神经调节，正如我们已经证明的，参与大脑网络参与 精神分裂症的阴性症状和阳性症状。这两种神经调节技术是：1.重复性 经颅磁刺激(Rtms)1和2.实时fmri神经反馈增强正念冥想 (MB-RT-fMRI-NFB)2.我们将收集传统的生物标志物(临床、神经心理学、事件相关电位、磁共振、DTI和 静息状态MRI)以及新的生物标记物(即，量化神经变化的生物标记物)。 相对于干预后)。这两种以前从未用于慢性阻塞性肺疾病受试者的干预措施将 在200cr(每个实验条件下50cr)和100hc下进行测试，为期5年。此外，我们还将 在上海精神卫生中心(SMHC)继续提高知识能力，在那里我们的中国人 合作者是基于。我们还将研究这些干预措施的有效性，将其作为 未来的治疗(目标1和目标2)，我们将测试传统生物标记物和变态生物标志物作为预测指标 临床和神经认知结果(目标3)。此外，我们将通过以下方式显著增强研究能力 在已经建立的成就和合作的基础上，通过将我们的触角伸向新的机构 (目标4)。此竞争性续订利用了单一站点(SMHC)的一组独特优势 与上海研究团队的合作，事实证明，这在目前的赠款中是最有成效的 周而复始。我们相信，这项非常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出现不良后果，同时， 将丰富CHR领域对这种情况的病理生理学的新见解。

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.