Background 3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. The current study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathological brain function associated with schizophrenia. Methods Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a one-month Phase-2 study of DMXB-A. Functional magnetic resonance imaging (fMRI) was performed on 16 non-smoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the α7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia. Results Compared to placebo, both 150 mg and 75 mg b.i.d. DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex and medial frontal gyrus activity, and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype. Conclusion The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biologic effects of novel therapeutic agents.

Objectives-People with schizophrenia often have difficulty ignoring unimportant noises in the environment. While experimental measures of sensory gating have yielded insight into neurobiological mechanisms related to this deficit, the degree to which these measures reflect the experience of people with schizophrenia is unknown. The goal of this study was to develop a novel, clinically relevant sensory gating paradigm and to assess differences in brain hemodynamic responses during the task in schizophrenia.Methods-Thirty-five subjects, including 18 outpatient subjects with schizophrenia and 17 healthy comparison subjects were scanned on a 3T MR system while passively listening to a mixture of common sounds simulating what a person may experience in a busy urban setting. The stimuli included multiple conversations and events recorded from a neighborhood gathering, music and conversations from the radio. P50 evoked responses from a typical paired-click sensory gating task also were measured.Results-Listening to the "urban white noise" stimulus produced robust activation of the auditory pathway in all subjects. Activation was observed in the bilateral primary and secondary auditory cortices, medial geniculate nuclei, and inferior colliculus. Greater activation was observed in subjects with schizophrenia, relative to comparison subjects, in the hippocampus, thalamus and prefrontal cortex. Higher P50 test/conditioning ratios also were observed in subjects with schizophrenia. These evoked responses correlated with hemodynamic responses in both the hippocampus and prefrontal cortex.Conclusions-The finding of greater activation of the hippocampus, thalamus and prefrontal cortex during a sensory gating task with high face-validity further supports the involvement of these brain regions in gating deficits in schizophrenia. This link is strengthened by the observed correlation between evoked responses in the paired-click paradigm and hemodynamic responses in fMRI sensory gating paradigm.