Influence of a Nicotinic Treatment on Auditory Sensory Processing in Schizophrenia

Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder with prominent and intrusive experiences of positive (e.g., hallucinations) and negative symptoms (e.g., social withdrawal) in addition to widespread psychosocial, cognitive and sensory processing dysfunctions, which are generally experienced before the onset of the first psychotic episode. At the sensory level, early auditory information processing deficits, characterized at the neural level with event-related potentials (ERPs), are considered possible candidate biomarkers (endophenotypes) for SCZ and potential valid targets for understanding the neurobiology of SCZ and for developing novel therapeutic interventions. Traditional dopamine-targeting pharmacological treatments ameliorate mainly positive symptoms but show little impact on negative symptoms or cognitive/sensory impairments, which persist following medication stabilization. Nicotine, a non-selective nicotinic acetylcholinergic receptor (nAChR) agonist and the main psychoactive compound in tobacco smoking, is consumed by 60-80% of individuals with SCZ and shown with acute dosing to improve cognitive performance and early auditory information processing. The α7 nAChR is explicitly associated with neural and sensory/cognitive processing anomalies in SCZ, but novel α7 nAChR targeting treatments have shown mixed effects, which have been attributed in part to the substantial clinical/cognitive/neurophysiologic heterogeneity in SCZ. One alternative strategy for identifying efficacious novel nicotinic agents in future clinical trials is to use biomarkers to target more homogeneous sub-groups of SCZ patients. The primary objective of this thesis was to conduct separate investigations in stratified sub-groups of healthy volunteers and patients with SCZ, assessing ERP measures of auditory sensory processing in response to the acute effects of a cholinergic treatment combining a dietary supplement, CDP-choline, with selective α7 nAChR agonist properties and galantamine, a nAChR positive allosteric modulator (PAM), which was posited to augment α7 nAChR signalling. Auditory sensory processing was examined with ERP paradigms assessing two functions commonly impaired in SCZ; (a) the ability to inhibit intrinsic neural responses to redundant stimuli, as measured by suppression of the P50 auditory ERP and (b) the ability to facilitate responses to infrequent but salient (deviant) stimuli, as measured by the mismatch negativity (MMN) ERP. Acknowledging the baseline-dependent effects of nicotine, each of the four investigations assessed the role of inter-individual differences in response to the cholinergic treatment by adopting a baseline median-split approach to stratify participants into low, medium, and high P50 baseline suppressors and low and high baseline deviance detectors. A novel ERP design element of this research was to replace the conventional tone/click stimuli typically used to elicit P50/MMN with speech stimuli, thus allowing for more meaningful interpretations of findings in relation to hallucinations and speech processing deficits in SCZ. In investigations with both healthy volunteers and patients with SCZ, the combination treatment exerted similar group-dependent modulatory actions on sensory processing. In contrast to individuals exhibiting high P50 suppression ability and who evidenced reduced sensory gating with active (vs. placebo) treatment, individuals with low P50 suppression showed improved gating following CDP-choline/galantamine administration. Similarly, the combined treatment diminished auditory deviance detection in individuals with high MMN amplitudes but also enhanced deviance detection in individuals with low MMN amplitudes. Findings from these acute drug challenge studies suggest that a PAM-enhanced nicotinic treatment strategy may have pro-sensory properties in SCZ, and they support further investigation with a longer treatment course of this combined CDP-choline/galantamine intervention using dosage challenges to find optimal combinations. Adopting a baseline stratification approach in these trials and utilizing a range of assessment tools would help to individualize treatment and determine if improvements in early auditory information processing with this combination of nicotinic cholinergic treatment impact cognitive and psychosocial functioning.