Modulation of neurophysiological auditory processing measures by bilateral transcranial direct current stimulation in schizophrenia
Introduction
Schizophrenia is characterized by a wide range of cognitive deficits (Green et al., 2000). Deficits are evident at the earliest stages of sensory processing and negatively impact down-stream processing and daily functioning (Javitt, 2009). These perceptual deficits are targets for novel interventions as correcting low-level defects may cascade into higher-level cognitive improvements (Adcock et al., 2009, Jahshan et al., 2013, Merzenich et al., 2014).
tDCS uses electrical current to modulate cortical excitability (Nitsche and Paulus, 2000, Priori et al., 2009). Early studies targeting motor cortex showed anodal stimulation as enhancing and cathodal stimulation as decreasing neural excitability. However, when used in non-motor processes such as cognition, the effects of anodal and cathodal stimulation are less predictable (Berryhill et al., 2014, Brunelin et al., 2012, Nitsche et al., 2008). By modulating cortical activity, tDCS may modify low level perceptual processes and impact higher-order cognition. As such, tDCS has been gaining interest as a potential treatment in psychiatric illness.
Schizophrenia patients have auditory processing deficits as assessed with event-related potential (ERP) measures, such as mismatch negativity (MMN) and P300, which are both decreased in amplitude compared to healthy controls (Javitt and Freedman, 2015, Light and Braff, 2005, Light et al., 2015, Turetsky et al., 2015). MMN reflects early stage pre-attentional automatic detection of a deviant signal presented in a series of standard signals and indicates the ability to detect novel stimuli (Umbricht and Krljes, 2005). P300 is related to effortful allocation of cognitive resources for context updating when target stimuli are presented among a series of non-targets (Ford, 1999, Jeon and Polich, 2003).
Several studies have examined the effects of tDCS on auditory processing ERPs in healthy individuals (Chen et al., 2014, Heimrath et al., 2015, Impey and Knott, 2015). However, no studies to date have described the effects of tDCS on ERPs in schizophrenia; thus, we do not know if tDCS can engage the neural systems underlying impaired auditory processing assessed with EEG-based measures. The purpose of the current study was to determine if bilateral prefrontal tDCS targeting regions associated with MMN and P300 in schizophrenia patients would result in changes indicating tDCS engagement and modulation of impaired auditory processing systems. As bilateral frontal neural generators of the MMN and P300 have been located (Tsolaki et al., 2015), a montage over bilateral prefrontal areas could potentially engage generators in both hemispheres and result in modulation of MMN and P300 responses. Because this is the first study to evaluate the effects of tDCS on MMN and P300 in schizophrenia, there was no directional hypothesis for ERP response to stimulation.
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Participants
Thirty-six stable, medicated outpatients meeting DSM-IV criteria for schizophrenia were recruited from outpatient clinics at the University of California, Los Angeles (UCLA) and VA Greater Los Angeles Healthcare System (GLA), as well as community board and care facilities (for selection criteria see (Rassovsky et al., 2015)). All participants gave written informed consent after receiving a full explanation of the research according to procedures approved by the Institutional Review Boards of
Results
There were no significant differences in demographic variables, symptom ratings, or illness chronicity among the three stimulation groups (see Table 1).
For MMN, data were analyzed with a 3 (condition: anodal, cathodal, sham) × 2 (time: baseline, follow-up) repeated measures ANOVA. There was a significant main effect for condition, F2, 32 = 3.70, p < 0.04, where sham had the largest amplitude, followed by cathodal, and then the anodal group. The main effect of time, F1, 32 = 3.79, p < 0.07, and the group
Discussion
With the increasing interest in tDCS as a potential treatment for schizophrenia, this preliminary study demonstrated that tDCS was able to modulate MMN amplitude in a schizophrenia sample. MMN has been proposed to be a biomarker of disease severity and amplitudes are reduced in patients compared to controls (Light et al., 2015, Wynn et al., 2010) reflecting impaired early auditory processing. Accordingly, interventions capable of modulating MMN response may help to correct the impaired neural
Role of funding source
This study was supported by the Veterans Administration (VA) Desert Pacific Veterans Integrated Service Network 22 (VISN 22) Mental Illness Research, Education and Clinical Center (MIRECC) infrastructure and by a NARSAD Independent Investigator Grant (PI: Yuri Rassovsky) from the Brain & Behavior Research Foundation (22017).
Contributors
Walter Dunn conducted the study and wrote the first draft of the manuscript. Yuri Rassovsky Jonathan Wynn, Allan Wu, Marco Iacoboni, and Michael Green assisted with study conceptualization, data interpretation, and manuscript preparation. Gerhard Hellemann assisted with statistical analysis and data interpretation.
Conflict of interest
All authors declare that they have no conflicts of interest arising from this manuscript.
Acknowledgments
We thank Albert Chung for the assistance with tDCS equipment and method development.
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