The coupling of low-level auditory dysfunction and oxidative stress in psychosis patients
Introduction
Low-level sensory deficits are increasingly recognized as core dysfunctions in patients with chronic schizophrenia (Ethridge et al., 2015, Javitt, 2009, Turetsky et al., 2008). However, it is largely uninvestigated whether there is a link between disease-related pathology of schizophrenia and low-level sensory deficits. We investigated low-level auditory processing in a group of psychosis disorder patients in the early phases of the disease, and correlated it with blood measures of oxidant state. This should reveal whether low-level auditory processing is linked to a key pathological hub in schizophrenia and could serve as a biomarker for psychosis and schizophrenia.
Sensory processing deficits have been observed in patients with chronic schizophrenia (Doniger et al., 2002, Foxe et al., 2005, Foxe et al., 2001, Javitt, 2015, Knebel et al., 2011, Oribe et al., 2013, Rosburg et al., 2008) as well as in patients at early stages of the disease (Foxe et al., 2011, Hall et al., 2011, Hong et al., 2009, Oranje et al., 2013, Salisbury et al., 2010). In the auditory modality, the P50 and the N100 components of the auditory evoked potential (AEP) reflect this sensory impairment. Differences in the P50 between patients and controls have been found in isolated auditory stimulus processing (Clementz and Blumenfeld, 2001, Jin et al., 1997) as well as in gating paradigms identifying a less than typically-reduced P50 amplitude in the second of a pair of tones in patients (Onitsuka et al., 2013, Potter et al., 2006). Compared to controls, patients also show reduced amplitude of the N100 components (Ahveninen et al., 2006, Anokhin et al., 2007, Ethridge et al., 2015, Force et al., 2008, Rihs et al., 2013, Turetsky et al., 2008, Wu et al., 2013), on the basis of which schizophrenic patients and controls can be distinguished on the group level (del Re et al., 2015) and on a single-subject level (Neuhaus et al., 2014). Moreover, there is evidence that low-level sensory deficits might be a characteristic trait marker of individuals with a genetic risk for developing schizophrenia (Light and Makeig, 2015, Light and Swerdlow, 2015) as indicated by the P50 in healthy subjects carrying a hereditary risk for the development of schizophrenia (Turetsky et al., 2012) and the N100 in first degree relatives or in subjects carrying a genetic risk (Ahveninen et al., 2006, Anokhin et al., 2007, Foxe et al., 2011, Frangou et al., 1997, Rihs et al., 2013).
A potential pathophysiological mechanism of schizophrenia is an impaired antioxidant defense system involving glutathione (GSH) in conjunction with N-methyl-d-aspartate receptor (NMDAR) hypofunction. This combination has been suggested to lead to effects across both acute and long-term timescales. The former entails impaired sensory processing of the variety discussed above, and the latter is supported by altered excitation-inhibition induced by aberrant function of fast-spiking parvalbumin-positive interneurons (PVI) (Do et al., 2009, Hardingham and Do, 2016). Altered levels of GSH and other antioxidants are found in CSF and post-mortem tissue (Do et al., 2000, Flatow et al., 2013, Gawryluk et al., 2011; see also Kim et al., 2016 for NAD +/NADH alterations) and are consistent with polymorphisms in key genes for GSH synthesis reported for schizophrenia (Gysin et al., 2007, Rodriguez-Santiago et al., 2010, Tosic et al., 2006). The impaired antioxidant defense mechanism is further confirmed by increased lipid and protein oxidation in the blood, the cerebrospinal fluid and post-mortem tissue (for reviews see Do et al., 2009, Yao and Keshavan, 2011) and has been validated in GSH-deficient animal models reproducing schizophrenia phenotypes including NMDAR hypofunction (Steullet et al., 2006) and impaired PVI activity (Cabungcal et al., 2013, Steullet et al., 2010). Causal links between NMDAR hypofunction and sensory processing impairments have been provided by neuropharmacological interventions and more recently by studies of genetic models (e.g. Chen et al., 2015, Javitt, 2009). More specifically, auditory processing impairments have been observed in auditory evoked potentials, including P50, N100, and P300 components, as well as in oscillatory activity across frequency bands following acute administration of NMDAR agonists in patients as well as in some cases in healthy participants. Additionally, administering N-Acetyl-Cysteine (NAC) which is a GSH precursor to chronic schizophrenia patients led to improved MMN generation (Lavoie et al., 2008).
Given this collective evidence, we hypothesized that early sensory processing deficits will be linked to GSH dysregulation measures in psychosis. A peripheral measure of brain GSH levels is a high oxidative status of blood redox indices, namely the ratio of GPx/GR which correlates negatively with brain GSH levels in early-psychosis patients (Xin et al., 2016). The present study investigated for the first time the link between the sensory deficits and potential pathophysiological characteristics of psychosis. AEPs and peripheral GPX/GR was measured and correlated in psychosis disorder patients and healthy controls and reveal a potential association between sensory deficits and oxidative stress in patients.
Section snippets
Participants
A total of 51 individuals participated in this study. There were 21 psychosis disorder patients (19 men, 17 right-handed) aged 18–35 years (mean ± SD = 24 ± 4 years) at the time of EEG recording. The patients were recruited from the TIPP program (Treatment and Early Intervention in Psychosis Program, University Hospital, Lausanne) (Baumann et al., 2013), which is a 3 year program specialized in the treatment of the early phase of psychosis that included only patients that had not received > 6 months of
Impaired early-latency responses
Patients compared to controls showed a weaker auditory response to frequent stimuli at P50/N100 and at a later time windows as measured by GFP (mean r2 for = 0.08, min/max = 0.14/0.22) (Fig. 1A) as exemplary also shown by Cz (mean r2 = 0.15, min/max = 0.08/0.22) in Fig. 1B. There was no evidence for significant topographic differences between groups as quantified by global dissimilarity (maximum number of consecutive and significant time points: 12; max/min = 1.48/0.22). No violation of normality over
Discussion
This study showed that early auditory ERPs are severely impaired in psychosis disorder patients in the early stages of the disease and moreover are coupled with peripheral measures of redox balance. This coupling was delimited in time to specifically those post-stimulus latencies when responses from patients were significantly weaker than those from controls and was limited in space to the anterior prefrontal cortex; a brain area previously identified as vulnerable to oxidative stress (
Role of the funding sources
Financial support was provided by the Swiss National Science Foundation (grants: PY00P1_148184/1 to E.G., 320030_149982 and 320030_169206 to M.M.M.; 320030_122419 to P.C. and KQ.D, and the National Centre of Competence in Research project “SYNAPSY, The Synaptic Bases of Mental Disease” [project 51AU40-125759]), the Damm-Etienne and Alamaya foundations and the Swiss Brain League (2014 Research Prize to M.M.M.). P.S.B. is supported by the Leenaards foundation. These sources had no further role in
Author contributions
Conceived and designed the study: MMM, SC, PC, KQD
Acquired the data: JFK, CR, CF, RJ, MF, LA, PSB
Analyzed and interpreted the data: EG, JFK, CR, MMM
Drafted the manuscript: EG, JFK, MMM
Critically revised the manuscript: all authors
Supervised the study: MMM, PC, KQD
All authors contributed to and have approved the final manuscript.
Conflict of interest
Authors report no conflict of interest.
Acknowledgements
Cartool was programmed by Denis Brunet (https://sites.google.com/site/fbmlab/cartool/cartooldownload), and the STEN toolbox by Jean-François Knebel (http://www.unil.ch/line/home/menuinst/about-the-line/software--analysis-tools.html). Both are freely available and are supported by the EEG Brain Mapping Core of the Center for Biomedical Imaging (CIBM; www.cibm.ch). Lucas Spierer, Fosco Bernasconi, and Aurelie Manuel assisted with the EEG acquisition.
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These authors made equal contributions to this work.