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

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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.