A predictive coding account of MMN reduction in schizophrenia

Highlights

• The effect of NMDA-R dysfunction is investigated in a neuronal model of MMN.

• NMDA-R dysfunction produces a reduction of the simulated MMN.

• This result is consistent with the reduction of MMN observed in schizophrenic patients.

• Modeling synaptic adaptation does not affect the reduction of MMN when NMDA-R function is affected.

Abstract

The mismatch negativity (MMN) is thought to be an index of the automatic activation of a specialized network for active prediction and deviance detection in the auditory cortex. It is consistently reduced in schizophrenic patients and has received a lot of interest as a clinical and translational tool. The main neuronal hypothesis regarding the mechanisms leading to a reduced MMN in schizophrenic patients is a dysfunction of NMDA receptors (NMDA-R). However, this hypothesis has never been implemented in a neuronal model. In this paper, we examine the consequences of NMDA-R dysfunction in a neuronal model of MMN based on predictive coding principle. I also investigate how predictive processes may interact with synaptic adaptation in MMN generations and examine the consequences of this interaction for the use of MMN paradigms in schizophrenia research.

Introduction

Schizophrenia is a complex neuropsychiatric disorder affecting about 1% if the population worldwide. It is characterized by a large range of positive and negative symptoms. In order to develop new drugs and to better understand this complex disease, it is necessary to use neurophysiological markers of the pathology (Javitt, 2009, Javitt, 2015). In the last 25 years, the mismatch negativity (MMN) has become one of the most popular markers of schizophrenia (Todd, Michie, Schall, Ward, & Catts, 2012).

The MMN is thought to index deviance detection in the auditory domain (Näätänen et al., 2005Näätänen, Jacobsen, & Winkler, 2005) but could reflect a more general cortical computation as counterparts have been observed in other modalities (Krauel, Schott, Sojka, Pause, & Ferstl, 1999; Pazo-alvarez, Cadaveira, & Amenedo, 2003; Shinozaki, Yabe, Sutoh, Hiruma, & Kaneko, 1998; Tales, Newton, Troscianko, & Butler, 1999). It is most commonly elicited by the oddball paradigm: a stream of repetitive (standard) sounds is rarely interrupted by the occurrence of a different oddball sound. When the response evoked by a given tone presented as a standard is subtracted from the response evoked by the same sound presented as a deviant, a negative component can be observed between 100 ms and 200 ms after the onset of the tone over the frontocentral electrodes in EEG. The MMN can also be detected over the temporal sensors in magneto-encephalography (MEG). These topographies correspond to sources in the Heschl’s gyrus or the auditory cortex. Crucially, the MMN is elicited even when subjects do not pay attention to the sounds and engage in other tasks like reading or watching a silent movie. The fact that MMN can be elicited independently of the attentional state of the subject makes it a reliable tool for both clinical use and translational investigation in animal models.

The reduction of MMN amplitude in schizophrenia is a robust finding (Umbricht & Krljes, 2005) in both medicated and unmedicated patients that has been reported in over 120 papers since the first publication by (Shelley et al., 1991). In some cases, the reduction of MMN amplitude in patients correlates with the intensity of the cognitive symptoms (Baldeweg, Klugman, Gruzelier, & Hirsch, 2004). Interestingly, the MMN amplitude is reduced by NMDA receptor (NMDA-R) antagonists like PCP and ketamine in normal subjects and in animals (Javitt, Steinschneider, Schroeder, & Arezzo, 1996; Umbricht et al., 2000). These drugs are also known to elicit psychotic symptoms similar to schizophrenia in normal subjects and to increase psychotic symptoms is schizophrenic patients. For this reason, the NMDA-R deficiency hypothesis is one of the leading theories to explain schizophrenic symptoms.

The predictive coding framework (Rao & Ballard, 1999; Friston, 2005) is attracting more and more attention to explain both MMN generation (Bendixen, Schröger, & Winkler, 2009; Friston, 2005; Lieder, Stephan, Daunizeau, Garrido, & Friston, 2013) and schizophrenic symptoms (Adams, Stephan, Brown, Frith, & Friston, 2013; Fletcher & Frith, 2009). In a previous paper (Wacongne, Changeux, & Dehaene, 2012), we proposed a neuronal model implementing predictive coding principles in the cortical microcircuit and showing that it could reproduce many properties of the MMN as observed in normal subjects. In this paper, we investigate whether the attenuation of MMN amplitude observed in schizophrenic patients can be reproduced by modifying NMDA-R dependent currents in this model.

The MMN was originally reported to be the earliest potential sensitive to deviance. More recent data showed that earlier potentials can also show sensitivity to deviance (Escera & Malmierca, 2014; Grimm, Escera, Slabu, & Costa-Faidella, 2011). Although some argue that MMN could reflect of simple synaptic adaptation (May & Tiitinen, 2009), recent data and models strongly support the contribution of an independent active predictive process in the generation of the MMN that can be dissociated from repetition suppression or synaptic adaptation (Parmentier, Elsley, Andrés, & Barceló, 2011; Strauss et al., 2015; Todorovic & de Lange, 2012; Wacongne et al., 2012). The interaction between passive synaptic adaptation and active prediction is investigated in “normal” and “NMDA-R impaired” models and the implications for the clinical research are discussed.