The impact of nicotinergic modulation on brain excitability, plasticity and cognition in schizophrenia

神经可塑性受损被认为是精神分裂症最重要的病理生理状态之一。特别是，认知缺陷发生在所有疾病阶段，是功能下降和生活质量差的主要原因，与神经可塑性受损有关。申请人提供的生理调查显示，有可能量化精神分裂症患者的运动-皮质可塑性受损，这些损伤也与疾病阶段、遗传因素和吸烟状况有关（吸烟患者表现出可塑性，而不吸烟患者则没有）。后一项发现尤其具有相关性，因为高达75%的精神分裂症患者吸烟。其他人在健康受试者身上进行的生理工作显示，通过靶向尼古丁能刺激来调节运动-皮质可塑性的可能性。系统评估尼古丁对皮质可塑性和兴奋性以及认知的影响，对于提高我们对精神分裂症患者极高吸烟率的理解，以及提高非侵入性脑刺激在这一人群中的疗效至关重要。在第一个项目中，将研究通过alpha4beta2/alpha7烟碱能部分/完全激动剂伐尼克兰进行的烟碱能刺激对皮质可塑性、兴奋性和认知的影响。在第二个项目中，将进行一项随机对照先导研究，以评估联合方法（神经刺激+尼古丁能刺激）治疗精神分裂症的疗效（增强神经刺激）。在这个项目中，不同的生理技术（经颅磁刺激、经颅直流电刺激、配对联想刺激、表面肌电图）、标准化和可操作的临床数据和认知功能评估以及认证的戒烟计划将被应用。该试验将根据德国药品法（AMG）进行，并将遵循ICH/GCP法规。这些紧密相连的项目将首次研究精神分裂症患者的尼古丁能刺激与大脑可塑性之间的相互作用。这将允许解开关于代偿假说的精神分裂症中烟草依赖高比率的生理基础。该试点试验首次尝试通过靶向药物调节来提高非侵入性脑刺激治疗精神分裂症的疗效。

Impaired neural plasticity is discussed as one of the most important pathophysiological states underlying schizophrenia. In particular, cognitive deficits occurring at all disease stages and being the main contributors to reduced functionality and poor quality of life, have been linked to this impaired neural plasticity. Physiological investigations provided by the applicant showed the possibility to quantify this impaired motor-cortical plasticity in patients with schizophrenia and these impairments have also been linked to the disease stage, genetic factors and to the smoking status (smoking patients show plasticity, whereas non-smoking patients do not). The latter finding is from particular relevance as up to 75% of all schizophrenia patients smoke. Physiological work from others conducted on healthy subjects displays the possibility to modulate motor-cortical plasticity via targeted nicotinergic stimulation. A systematic evaluation of nicotinergic effects on cortical plasticity and excitability as well on cognition are from the highest importance to improve our understanding of the tremendous high smoking rates in schizophrenia and, moreover, to improve the efficacy of non-invasive brain stimulation in this population. In the first project, the impact of nicotinergic stimulation via alpha4beta2/alpha7 nicotinergic partial/full agonist varenicline on cortical plasticity, excitability and cognition will be investigated. In the second project, a randomized-controlled pilot study to evaluate the efficacy of a combined approach (neurostimulation + nicotinergic stimulation) for the treatment of schizophrenia will be performed (Enhanced Neurostimulation). During this project different physiological techniques (transcranial magnetic stimulation, transcranial direct current stimulation, paired-associative stimulation, surface-electromyography), standardized and operationalized assessments of clinical data and cognitive functions and a certified smoking-withdrawal program will be applied. The pilot-trial will be performed according to the German Drug Law (AMG) and will follow ICH/GCP regulations. These closely interlinked projects will allow for the first time the investigation of the interaction between nicotinergic stimulation and brain plasticity in schizophrenia. This will allow to disentangle the physiological underpinnings of the high rates of tobacco dependency in schizophrenia with regard to the compensatory hypothesis. The pilot-trial represents the first attempt to improve the efficacy of non-invasive brain stimulation for the treatment of schizophrenia by a targeted pharmacological modulation.