Shared Neural Circuitry in Comorbid Schizophrenia and Nicotine Addiction

描述(申请人提供)：严重精神疾病患者与吸烟有关的健康风险远高于普通人群。其中，精神分裂症患者可能是尼古丁添加风险最高的人群。目前对严重精神分裂症-吸烟共病的可能病因的概念化包括针对神经认知缺陷的自我用药，克服抗精神病药物的副作用，以及共享尼古丁分子通路。然而，共病的潜在大脑回路尚不清楚。识别大脑共病回路对于为临床治疗发展、个体化治疗选择和结果预测开发有效的生物标志物至关重要。最近的数据表明，扣带回-腹侧纹状体回路似乎是与尼古丁成瘾有关的关键途径之一。这些相同的区域也是精神分裂症最常见的区域之一，更多的初步研究表明，精神分裂症中同样的回路也受到了损害。因此，我们推测扣带回-腹侧纹状体环路异常是精神分裂症/尼古丁成瘾共病的关键途径。我们建议检验以下假设，即尼古丁成瘾和精神分裂症患者的扣带-腹侧纹状体环路异常，精神分裂症的病理破坏了这一环路，使患者容易患上更严重的尼古丁成瘾，导致严重的尼古丁成瘾/精神分裂症共病。我们还将检验该回路在预测长期吸烟行为变化方面的临床有效性，在遗传学上，以及它与假定的成瘾机制的关系上。在这一高危人群中识别与吸烟相关的关键大脑回路将为新的治疗开发提供具体的生物标志物，并最终减轻精神分裂症患者与吸烟相关的健康负担。此外，随着公共卫生努力减少吸烟，人口中仍吸烟的人可能会更加依赖，对治疗更具抵抗力。针对吸烟成瘾最严重的人群的努力也可能产生治疗普通人群尼古丁成瘾的新视角。

DESCRIPTION (provided by applicant): The health risk associated with tobacco use in people with severe mental illness is much higher than the general population. Among them, patients with schizophrenia are the population with perhaps the highest risk for nicotine addition. Current conceptualizations of the possible etiologies of the severe schizophrenia-smoking comorbidity include self-medication for neurocognition deficits, overcoming antipsychotic medication side effects, and shared nicotinic molecular pathways. However, the underlying brain circuitry for the comorbidity is unknown. Identifying brain comorbidity circuitry is critical for developing valid biomarkers for clinical therapeutic development, individualizing treatment selection and outcome prediction. Recent data suggest that the cingulate-ventral striatum circuit appears to be one of the key pathways associated with nicotine addiction. These same areas are also among the regions most commonly implicated in schizophrenia, and additional preliminary studies suggest that the same circuit is impaired in schizophrenia. Therefore, we hypothesize that abnormal cingulate-ventral striatum circuit is a key path for schizophrenia/nicotine addiction comorbidity. We propose to test the hypotheses that the cingulate-ventral striatum circuit is abnormal in nicotine addiction and in schizophrenia, and that schizophrenia pathology disrupts this circuit and predisposes patients to more severe nicotine addiction, leading to the severe nicotine addiction/schizophrenia comorbidity. We will also examine the clinical validities of the circuit in prediction of long-term smoking behavioral change, in genetics, and in its relationships to putative addiction mechanisms. Identifying the key brain circuits associated with smoking in this high risk population will provide concrete biomarkers for new therapeutic development, and ultimately reducing the smoking related health burden in schizophrenia patients. In addition, as public health efforts have reduced smoking, those who still smoke in the population may be more dependent and more treatment-resistant. An effort targeting the population most addicted to smoking may also yield novel perspectives to treat nicotine addiction in the general population.