Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Small changes in temporal deviance modulate mismatch negativity amplitude in humans.

The relative sensitivity of mismatch negativity (MMN) amplitude to small changes in temporal (i.e. timing) deviance of an ongoing stimulus train was investigated. MMN was measured at Fz in response to 3.75-15% decrements of inter-stimulus interval from a 400 ms standard with a deviant probability of 1/15. This parameter space represents the smallest degree of deviance and the narrowest range of variation that has been tested in the context of MMN sensitivity to temporal variables. Waveform amplitude was found to significantly increase with degree of temporal deviance even within this relatively narrow parameter space. This finding is consistent with the view that the MMN corresponds to pre-attentive neural activity that subsequently allows the conscious perception of time during temporal discrimination tasks.

Increased hippocampal, thalamic, and prefrontal hemodynamic response to an urban noise stimulus in schizophrenia.

OBJECTIVE: 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 real-world experience of people with schizophrenia is unknown. The goal of this study was to develop a clinically relevant sensory gating paradigm and to assess differences in brain hemodynamic responses during the task in schizophrenia. METHOD: Thirty-five participants, including 18 outpatients with schizophrenia and 17 healthy comparison subjects, underwent scanning on a 3-T MR system while passively listening to an "urban white noise" stimulus, a mixture of common sounds simulating a busy urban setting, including multiple conversations and events recorded from a neighborhood gathering, music, and talk 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 participants. Activation was observed in the bilateral primary and secondary auditory cortices, medial geniculate nuclei, and inferior colliculus. Greater activation was observed in the schizophrenia patients relative to the comparison subjects in the hippocampus, thalamus, and prefrontal cortex. Higher P50 test/conditioning ratios also were observed in the schizophrenia patients. These evoked responses correlated with hemodynamic responses in the hippocampus and the 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 a functional MRI sensory gating paradigm.