Hearing Research 399 (2021) 107992

Contents lists available at ScienceDirect

Hearing Research
journal homepage: www.elsevier.com/locate/heares

Review Article

Do rat auditory event related potentials exhibit human mismatch

negativity attributes related to predictive coding?
Jaishree Jalewa a, Juanita Todd a, b, c, Patricia T. Michie a, b, c, Deborah M. Hodgson a, b, c,
Lauren Harms b, c, d, *
a
School of Psychology, University of Newcastle, Callaghan, New South Wales, Australia
b
Priority Research Centre for Brain and Mental Health Research, University of Newcastle, Callaghan, New South Wales, Australia
c
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
d
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Rodent models play a significant role in understanding disease mechanisms and the screening of new
Received 12 December 2019 treatments. With regard to psychiatric disorders such as schizophrenia, however, it is difficult to replicate
Received in revised form the human symptoms in rodents because these symptoms are often either ‘uniquely human’ or are only
29 April 2020
conveyed via self-report. There is a growing interest in rodent mismatch responses (MMRs) as a
Accepted 4 May 2020
Available online 28 May 2020
translatable ‘biomarker’ for disorders such as schizophrenia. In this review, we will summarize the at-
tributes of human MMN, and discuss the scope of exploring the attributes of human MMN in rodents.
Here, we examine how reliably MMRs that are measured in rats mimic human attributes, and present
Keywords:
Mismatch negativity
original data examining whether manipulations of stimulus conditions known to modulate human
Schizophrenia MMN, do the same for rat MMRs. Using surgically-implanted epidural electroencephalographic elec-
Mismatch responses trodes and wireless telemetry in freely-moving rats, we observed human-like modulations of MMRs,
Electroencephalogram namely that larger MMRs were elicited to unexpected (deviant) stimuli that a) had a larger change in
Deviance pitch compared to the expected (standard) stimulus, b) were less frequently presented (lower proba-
Probability bility), and c) had no jitter (stable stimulus onset asynchrony) compared to high jitter. Overall, these
Jitter findings contribute to the mounting evidence for rat MMRs as a good analogue of human MMN,
Predictive coding
bolstering the development of a novel approach in future to validate the preclinical models based on a
translatable biomarker, MMN.
© 2020 Elsevier B.V. All rights reserved.

Contents

1. Mismatch negativity (MMN) in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2. MMN and relevance to predictive coding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Why are animal models of MMN important? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. What are the features of human MMN that are important to model in an animal? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Predictive coding (prediction error vs. adaptation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2. Other measures relevant to predictive coding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2.1. Sensitivity to deviance difference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2.2. Sensitivity to deviant probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2.3. Other factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. How well do existing reports of rat MMN show that they model each of these aspects? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.1. Adaptation independence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

* Corresponding author. Priority Research Centre for Brain and Mental Health
Research, University of Newcastle, Callaghan, New South Wales, Australia.
E-mail address: lauren.harms@newcastle.edu.au (L. Harms).

https://doi.org/10.1016/j.heares.2020.107992
0378-5955/© 2020 Elsevier B.V. All rights reserved.
2 J. Jalewa et al. / Hearing Research 399 (2021) 107992

4.2. Sensitivity to deviance difference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4.3. Sensitivity to deviant probability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.4. Sensitivity to SOA manipulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5. Original research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.1. Ethics statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.2. Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.3. Surgery to implant EEG electrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.4. Sound generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.5. Mismatch response (MMR) testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.6. Experiment design and stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.7. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1.8. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.1. Effect of deviance difference on rat MMRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.2. Effect of deviant probability on rat MMRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.3. Effect of SOA variability (jitter) on rat MMRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6. General discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1. Mismatch negativity (MMN) in humans responses to expected sounds in the environment are relatively
small, whereas unpredictable sounds evoke larger responses, pro-
1.1. Introduction portional to how unexpected the sound is. Such neural adjustment
(gain-control) is an important property that enables us to ignore
Previous studies strongly support the presence of auditory predictable sounds, stay focused on the stimuli of interest, while
sensory dysfunction in schizophrenia and altered responses of the still remaining alert to potentially important changes in the sur-
auditory system in individuals with schizophrenia when discrimi- rounding environment. This gain-control is reflected in the ampli-
nating a deviant sound from standard repetitious tones (Javitt and tude of mismatch negativity (MMN), an auditory component of the
Sweet, 2015; Na €a
€t€
anen and Kahkonen, 2009; Catts et al., 1995; event related potential (ERP) or magnetic field, automatically eli-
Salisbury et al., 2002; Javitt et al., 1995, 1996). Since the first pub- cited in response to a rare, unexpected deviant stimulus among
lication of reduced mismatch negativity (MMN) in schizophrenia expected common standard stimuli in an oddball sequence para-
(Shelley et al., 1991), many subsequent papers have replicated the digm (Garrido et al., 2009; Na €a€ta
€nen and Alho, 1995b) (Fig. 1).
reduced amplitude of MMN in schizophrenia patients (Todd et al., To elicit an MMN response, the deviance must be discriminable.
2012), a phenomenon well-established by meta-analyses of more Considering the simplest paradigm, a deviant sound can differ from
than 100 studies (Bodatsch et al., 2015; Erickson et al., 2016; the standards along any acoustic physical dimension including
Umbricht and Krljes, 2005). Moreover, studies have shown that frequency (pitch), intensity, duration or deviation in stimulus onset
MMN amplitude is reduced in schizophrenia in response to deviant asynchrony (SOA, time between the onset of adjacent stimuli) or
sounds (Umbricht et al., 2003; Magno et al., 2008) across a wide omission of stimuli in a regular progression. If the deviant and
range of stimulus conditions including stimulus deviance type, standard sounds are discriminable, subtraction of the responses
probability and interstimulus/interdeviant interval (Javitt et al., evoked by frequent standard sounds from the responses evoked by
1998; Javitt, 2000; Shelley et al., 1999; Michie et al., 2000; Todd infrequent deviant sounds result in a difference response wave-
et al., 2008). Furthermore, significantly reduced MMN amplitude form, from which the MMN amplitude is observed at approximately
has been found in both first-episode as well as ultra-high risk 100e250 ms post-stimulus in humans (Fig. 1C) (Javitt et al., 1994,
populations in comparison to healthy individuals (Nagai et al., 2008; Na €€
ata€nen et al., 1978, 2007; Na €a
€t€
anen and Alho, 1995b;
2017; Perez et al., 2014), suggesting MMN as a biomarker of dis- Na€€ €nen and Michie, 1979).
ata
ease progression (Carbajal and Malmierca, 2018; Tada et al., 2019; MMN is also generated by deviants that violate complex abstract
Avissar and Javitt, 2018). Overall, due to its quantitative nature and rules. For instance, complex auditory stimuli such as speech sounds
the findings of reduced MMN amplitude in neurodevelopmental (De La Salle et al., 2019, Maiste et al., 1995; Na €a
€t€
anen et al., 1997;
and neuropsychiatric disorders, MMN is of interest to cognitive Alho et al., 1998; Wang et al., 2012) or ‘melodies’ (harmonic tones)
neuroscience. The extent of clinical potential possessed by MMN (Quiroga-Martinez et al., 2019; Tervaniemi et al., 2015; Vuust et al.,
necessitates the investigation of human MMN attributes in rodent 2012; Brattico et al., 2006; Fujioka et al., 2004, 2005) elicit MMN in
models, which are important for preclinical research in order to humans (Nikjeh et al., 2009).
develop novel therapeutic interventions. Over the past decade, the The MMN response has been attributed to neural generators
number of studies on rodent models of MMN has increased sub- within the temporal and frontal lobes (auditory cortex, including
stantially, many of them focusing on how well human MMN attri- primary auditory cortex (A1), located along the superior temporal
butes are recapitulated in rodent responses. In this review, we will gyrus) (Fishman, 2014; Giard et al., 1990; Na €a
€ta
€nen and Alho,
discuss the main attributes of human MMN and how well they are 1995a; Alho, 1995; Kasai et al., 1999), and is dependent on the ac-
recapitulated in studies of rodent mismatch responses (MMRs), tivity of NMDA receptors (glutamatergic neurotransmission) (Javitt
followed by original data that also addresses some of the main et al., 1996; Gunduz-Bruce et al., 2012; Kort et al., 2017). Moreover,
questions. MMN occurs as two components - one that is typically earlier
Optimal auditory sensory processing ensures that neural (generated in the superior temporal gyrus) and another that is
 J. Jalewa et al. / Hearing Research 399 (2021) 107992 3

Fig. 1. Illustration of oddball sequence paradigm and mismatch negativity (MMN). A. Descending deviant oddball sequence where unexpected low frequency deviants (LF DEV)
are interspersed among expected high frequency standards (HF STD). B. Ascending deviant oddball sequence where unexpected high frequency deviants (HF DEV) are interspersed
among expected low frequency standards (LF STD). A & B together forms a flip-flop control sequence, which allows for the comparison of the response to a stimulus when it is a
deviant to the same tone when it is a standard, thus this design controls for the differential responses to the physical characteristics of the stimuli. C. MMN (the shaded area), is an
‘auditory surprise signal’: the more surprising the deviant sound, the larger the MMN size. MMN is measured as a subtraction waveform, obtained by subtracting the standard
response from the deviant response. C. Adapted from (Kujala and Na €€ata
€nen, 2001) with permission.

usually slightly later (generated in the inferior frontal gyrus),
demonstrated by both EEG and hemodynamic measurements
(Doeller et al., 2003; Li et al., 2019). Further, MMN generation in
humans is hypothesised to occur due to activity in large pyramidal
cells in the supragranular layers, based on studies in macaques
(Javitt et al., 1994), as reviewed in (Todd et al., 2012).
1.2. MMN and relevance to predictive coding
There have been two dominant hypotheses proposed to explain
the underlying neuronal mechanism of MMN generation (Na €€ €nen
ata
et al., 2005; May and Tiitinen, 2010). According to the ‘Neural
Adaptation hypothesis’, repeated presentation of the standard
(common) stimuli results in adapted/attenuated activity from the
responsive neurons along the auditory pathway, while these neu-
rons stay responsive to those stimuli (the deviants) that occur less
frequently (Ja €€
askela€inen et al., 2004; Na €€ €nen et al., 2005;
ata
Ulanovsky et al., 2004, Na €a
€ta
€nen et al., 1978). This effect is called
stimulus-specific adaptation (SSA) (Duque et al., 2018), and is
known to occur in the auditory system of cats (Ulanovsky et al.,
2003, 2004), rats (Malmierca et al., 2009; Szymanski et al., 2009;
Von Der Behrens et al., 2009; Antunes et al., 2010; Taaseh et al.,
2011), mice (Duque et al., 2018), and non-human primates
(Fishman and Steinschneider, 2012). For SSA reviews, see
(Malmierca et al., 2015; Pe rez-Gonzalez and Malmierca, 2014; Ayala
et al., 2016). In a purely adaptation-based framework of MMN, rare
deviants activate afferents that are less adapted than those stimu-
lated by the frequent standards and thus, elicit a larger obligatory
N1 response, which yields the MMN. Initial studies on anesthetized
cats showed that the neurons in primary auditory cortex (A1)
exhibit strong SSA (Ulanovsky et al., 2003, 2004). Additionally,
€€
Ja askela€inen et al. proposed that MMN in humans is not different
from the adapted/attenuated N1 response and suggested that there
is no separate MMN mechanism (J€ €skel€
aa ainen et al., 2004). Further,
May and Tittinen comprehensively reviewed the possibility of
MMN generation based on the adaptation hypothesis and proposed
that MMN is part of a latency and amplitude modulated auditory
N1 response (May and Tiitinen, 2010). However, data from studies
investigating the adaptation and memory-based hypotheses of
MMN have supported the notion that MMN is due to other mech-
anisms and cannot be solely attributed to adaptation (Jacobsen and
Schro€ ger, 2001; Maess et al., 2007).
Another explanation of the MMN generation is based on the
‘Sensory memory hypothesis (regularity violation)’, according to
which MMN is a novel (non-obligatory) ERP component that re-
flects a deviation between properties of an incoming sound and
those of a neural ‘memory trace’ established by the preceding
standard sounds (Na €a
€t€
anen et al., 2005). The brain forms a model
(hypothesis), based on previous sensory input, incorporating the
rule underlying the regularity when a sequence of sounds are
presented. Based on this rule, the brain generates a prediction
regarding the next sound in the sequence, and the prediction error
associated with sounds matching the prediction declines. When
properties of the incoming sound fail to agree with the prediction, a
much larger prediction error signal is elicited (Naatanen, 2001;
Naatanen and Winkler, 1999; Paavilainen, 2013). According to the
predictive coding model, MMN is therefore a highly informative
measure of prediction error signalling, which results from a viola-
tion of the hypothesised auditory pattern by the unexpected
auditory stimulus (Damaso et al., 2015; Duque et al., 2015; Fishman,
2014; Garrido et al., 2009; Durschmid et al., 2016), as hierarchical
models allow the brain to construct prior expectations in a dynamic
and context-sensitive manner (Friston, 2005). Prediction errors
drive efficient use of cognitive resources to help direct which
4 J. Jalewa et al. / Hearing Research 399 (2021) 107992
aspects of the environment provide important information about
changes that may need to be incorporated to improve future pre-
dictions. As such, the processes underlying prediction and predic-
tion error generation serve a relevance-filtering function. An
important contextual variable to this process is time, which de-
termines how the relevance of sound is filtered in a given context
(Todd et al., 2018). The amplitude of prediction error indexed by
MMN can therefore serve as a measure of how relevant a deviant
sound is in the context of the regularities (standards), but this
quantification is also impacted by an accumulated estimate of
‘confidence’ in the goodness-of-fit of the active prediction model.
Confidence in this sense can be thought of as reflecting precision in
the model, which is inversely proportional to variance in the sen-
sory input (Lieder et al., 2013). As the relevance of a deviation in
sound is based on the information extracted from the regularities,
the period of stability of a pattern over time is an important factor
that influences the MMN amplitude (Todd et al., 2011, 2018; Lieder
et al., 2013; Cowan, 1984; Bendixen et al., 2007; Cowan et al., 1993;
Winkler et al., 1996; Bader et al., 2017). When the regularities are
stable (low variability), precision is higher, which means precision
is inversely proportional to the environmental variance (Fitzgerald
and Todd, 2018). Moreover, each time the sensory input matches
the top-down expectation, precision estimates increase, and when
deviation occurs from the expectation under a high-confidence
scenario (higher precision), it results in larger MMN. Further, this
accumulated confidence results in stronger predictions for the
likely future events. Overall, an exposure to a very predictable
context for a sufficient amount of time results in confident higher-
level predictions and this is referred to as contextual learning on
which the expression of MMN depends (Todd et al., 2013, 2014a,
2018; Frost et al., 2016; Tavano et al., 2014; Wacongne et al., 2011;
Lieder et al., 2013).
Further, predictive coding, which is a general theory of
perceptual inference, has been considered as a general framework
that attempts to unify both of the above mentioned hypotheses
(Garrido et al., 2009). According to this framework, the brain is
considered as a hierarchically organised system where each level
adjusts between the bottom-up sensory inputs and top-down
predictions (Garrido et al., 2009). In summary, the ‘predictive
coding framework’ has been proposed to explain both the ‘repeti-
tion suppression’ (or, adaptation) caused by stimulus repetition,
and ‘prediction error’ (also called ‘deviance detection’), an
enhanced response to a stimulus that violates an expected regu-
larity (Parras et al., 2017; Garrido et al., 2009; Carbajal and
Malmierca, 2018).
2. Why are animal models of MMN important?
The reduction in MMN in schizophrenia patients have been
associated with poor functional outcome (Rasser et al., 2011; Light
and Braff, 2005; Featherstone et al., 2018), which has led to a strong
interest in MMN as a potential clinically useful biomarker (Erickson
€a
et al., 2016; Light and Na €t€
anen, 2013). The correlation with func-
tional impairment is important and more consistent across studies
than correlations with clinical symptoms (particularly positive
symptoms), suggesting that MMN does appear to be a reflection of
some basic aspect of the integrity of the nervous system that de-
termines how well the individual functions. In fact, Rasser and
colleagues suggest links between MMN and frontotemporal grey
matter pathology may mediate the link between MMN and func-
tional status in patients (Rasser et al., 2011). Although MMN
impairment in schizophrenia patients is one of the most highly
replicated neurophysiological features of the disorder (Na €€
ata€nen
et al., 2016), currently available treatments provide only partial
remediation of the MMN reduction (Zhou et al., 2013; Greenwood
et al., 2018; Yuan et al., 2009; Swerdlow et al., 2016). Similar
treatment-resistance is also found for the cognitive impairments of
schizophrenia (Kahn and Keefe, 2013; Kahn et al., 2015; Forray and
Buller, 2017; Altamura and Glick, 2010), which have a substantial
negative impact on patient functioning (Greenwood et al., 2005,
Zaragoza Domingo et al., 2015; Bowie et al., 2018). Unfortunately,
pre-clinical validation of potential novel antipsychotics in animal
models, often fail in human clinical trials, particularly for cognitive
impairments. This is partly attributed to lack of suitable animal
models of disease with associated biomarkers of neural-circuit
function across species (Young and Light, 2018; Young and Geyer,
2015; Light and Na €a€ta
€nen, 2013), but also because of use of
flawed analogues of human cognitive tasks (Young and Geyer,
2015). If rodent MMRs are found to be accurate analogues of hu-
man MMN, and a biomarker of the integrity of neural circuit
function, they could potentially be used as complimentary outcome
measures, alongside behavioural examinations, in preclinical drug
development studies. Further, an effective treatment that amelio-
rates the MMN deficit has the potential to improve remission rates
given recent evidence that remission is predicted by the magnitude
of MMN along with other factors (Kim et al., 2020).
Therefore, it is important to investigate and understand
whether rodents exhibit the attributes of human MMN. If the sci-
entific community is able to demonstrate that the rodent brain is
capable of generating mismatch responses (MMRs) with similar
features to human MMN, the door can be opened to further ex-
amination of the neurocircuitry and pharmacology of these re-
sponses, and their relationship with cognitive impairments,
potentially leading to the discovery of novel treatments that can
serve as new candidate therapies.
Moreover, successful demonstration of the MMRs in rats, anal-
ogous to humans, has the potential to facilitate approaches for
validation of schizophrenia animal models. The great value of MMN
as a translational measure is that it is automatically elicited, par-
ticipants do not need to receive instruction or pay attention to
generate an MMN to auditory stimuli. In this way, MMRs can be
elicited in rodents without the need for lengthy training. Mea-
surement of rodent MMRs can complement other investigations of
schizophrenia-like behaviour in animal model validation studies.
However, to do this, we need to ensure that the rodent MMRs meet
certain criteria of human MMN in order to maximize the trans-
lational potential of MMN. This will allow us to comprehend the
underlying mechanism of MMN and, will become an important tool
to validate rodent models.
3. What are the features of human MMN that are important
to model in an animal?
MMN is a signal of enhanced prediction error that occurs in
response to an unexpected stimulus due to violation of a pattern of
regularity, as opposed to a decrease in response to a repeated
stimulus (adaptation). When seeking to establish a rodent analogue
of human MMN it is important to consider that the responses
measured will be unlikely to show the same morphology in a rat
brain as it is a differently-sized and -shaped brain compared to the
human brain. Confidence in a rodent analogue therefore cannot be
based on ‘face’ validity determined by familiarity but should
instead be sought through establishing ‘construct’ validity. An
important task in determining the validity of a rodent MMN
analogue is therefore to establish whether we are measuring
something that maps on to the same construct (i.e. predictive
coding) which can be facilitated by exploring whether amplitude
modulation seen in human MMN occurs in a rodent.
 J. Jalewa et al. / Hearing Research 399 (2021) 107992
3.1. Predictive coding (prediction error vs. adaptation)
Although a hotly debated topic, there is accumulating evidence
that the kind of “active” prediction implicated in the mismatch
process can indeed be separated from adaptation (Harms et al.,
2016; N€ aa€ta
€nen et al., 2005). The first compelling evidence for
some degree of adaptation-independent MMN responses in
humans was published by Jacobsen and Schro € ger who developed
an experimental protocol to control for the refractoriness effects in
order to demonstrate that MMN occurs even when these are
controlled (Jacobsen and Schro € ger, 2001). The study involved pre-
sentation of 50 ms tones in three blocks (ascending deviant,
descending deviant and control). The control block comprised of 10
equiprobable tones of varying frequency (pitch) presented in a
pseudorandom sequence including the tones presented in the
oddball sequence as deviant and standard (Jacobsen and Schro € ger,
2001), at the same probability (10%) as they are in the oddball se-
quences. This sequence type, known as the ‘many standards’, the
‘Jacobsen’ or the ‘equiprobable’ control condition, can be used to
disentangle the two variables confounded with standard and
deviant stimuli presentation: those of probability and expectation.
That is, the deviant is both improbable and unexpected, whereas
the standard is both probable and expected. If responses to these
stimuli differ, is it due to probability or expectation? If probability
was solely responsible for the MMN, this would be consistent with
the adaptation hypothesis, whereas if expectation were respon-
sible, the prediction error hypothesis would be supported. Thus, a
response to the control stimulus, improbable but not violating an
expected pattern (because no pattern is established), can be
compared to the deviant response to isolate the effect of the
violation of the expected regularity in the sequence. Significant
‘classic MMN’ was observed in the deviant vs. standard comparison
but in addition, significant differences were found in the deviant
compared to the control (Jacobsen and Schro €ger, 2001). This finding
suggested that MMN in humans, at least in part, could be attributed
to a memory-based prediction error process other rather than
adaptation alone (Jacobsen and Schro € ger, 2001). Using a similar
control methodology, an additional study also demonstrated
similar effects for duration deviants (Jacobsen and Schro €ger, 2003).
Whole-head magnetoencephalography studies have demonstrated
that adaptation and memory-based mechanisms can be separated
in time using many standards control (Maess et al., 2007; Hsu et al.,
2010), supporting that MMN is a memory-based response. More-
over, a neuronal model of predictive coding in MMN supports the
idea that MMN results from an active cortical prediction rather than
a passive synaptic habituation (Wacongne et al., 2012).
Memory-based prediction error responses have also been found
in studies using a cascade control, which is a regular cascadic
sequence where tones are presented in either ascending or
descending frequencies (Ruhnau et al., 2012). Unlike the many
standards control, where tone order is random, the cascade
sequence establishes a pattern of regularity. In other words, the
cascade control tone is highly comparable to the deviant tone in the
oddball sequence: it is the same physical tone, presented at the
same rate, and presented within a sequence where a prediction can
be generated. The control tone only differs from the oddball deviant
in one way: it ‘fits’ with the predictive model, whereas the deviant
violates the prediction. This may suggest that the corrected MMN
obtained based on cascade control sequence would give a more
accurate quantification of prediction error when compared to the
MMN calculated based on many standards control sequence. But, a
recent study by Wiens et al. have demonstrated that both the
controls are comparable controls for the auditory frequency MMN
in oddball tasks (Wiens et al., 2019; Parras et al., 2017).
Na€a
€ t€
anen et al. further reviewed the evidence in favour of the
5
memory-based hypothesis. According to some of the in-
terpretations based on the adaptation hypothesis, MMN latency
and duration should be similar to the N1 response, an experimental
manipulation should affect MMN and N1 similarly, and no MMN
should be elicited in the absence of N1. However, N1 responses are
closely time-locked to the onset of the stimulus and even a change
in magnitude of the stimulus does not affect the peak latency. But,
MMN latency is affected by magnitude of the stimulus change,
which indicates that the latency and duration of N1 and MMN do
not track together (Na €a€t€
anen et al., 2005). Second, an MMN
response is elicited even in the absence of N1 response, in a stim-
ulus omission paradigm (Yabe et al., 1997, 1998; Na €a
€t€
anen et al.,
2005). Third, the sensitivity of N1 to various pharmacological ma-
nipulations differs from that of MMN. For example, MK-801
(NMDA-receptor antagonist) administration eliminated the MMN
response in monkeys but had no effect on the equivalent of N1
responses (Javitt et al., 1996; Na €€ €nen et al., 2005). Such
ata
adaptation-independence can also be found for auditory ERPs
outside the MMN timescale and in the middle latency response
period, a timescale associated more with late subcortical and early
cortical auditory processing (Grimm et al., 2011; Grimm and Escera,
2012; Escera et al., 2014).
3.2. Other measures relevant to predictive coding
3.2.1. Sensitivity to deviance difference
MMN is generated by an automatic discrimination process
(Lyytinen et al., 1992) and human studies have shown modulation
of MMN amplitude by the degree of stimulus deviance. That is, an
increase in the magnitude of the difference between the deviant
and standard sound results in an increased MMN amplitude and a
decreased peak latency (Pakarinen et al., 2007; Horva th et al., 2008;
€ ger and Winkler, 1995;
Tiitinen et al., 1994; Todd et al., 2012; Schro
Tse and Penney, 2008). As noted earlier, research demonstrates that
MMN is elicited in response to simple changes on a variety of
stimulus dimensions: frequency (Grimm and Schro €ger, 2007;
Na€€
ata€nen et al., 1982; Paavilainen et al., 1993b), duration
(Paavilainen et al., 1993a; Joutsiniemi et al., 1998; Hsu et al., 2010;
Suga et al., 2016; Kompus et al., 2015) or intensity (Winkler et al.,
1990; Althen et al., 2011). For deviants that vary on simple stim-
ulus dimension, MMN size relates to deviance discrimination as
MMN gets smaller with smaller deviance difference and eventually
disappears when the subject is unable to behaviourally distinguish
the stimulus difference (Daikhin and Ahissar, 2012; Na €a
€t€anen et al.,
2007). In regards to predictive coding, this suggests that a predic-
tion error response will adjust in size depending on the size of the
prediction violation, which means that the larger the deviance
difference in a given context, the greater the degree of violation,
which therefore leads to comparatively larger prediction error
response. However, the response cannot keep increasing, but
instead normalises to context (divisive normalisation) (Carandini
and Heeger, 2011).
3.2.2. Sensitivity to deviant probability
The probability of occurrence of a deviant stimulus among the
regular standard stimuli is also a critical determinant of MMN size
(Sabri and Campbell, 2001; Shelley et al., 1999). Human studies
have found that MMN amplitude increases with decreasing prob-
ability of occurrence of a deviant (rare deviant or highly unexpected
change). In other words, larger MMN occurs to more marked
probability violation (Todd et al., 2012; Sabri and Campbell, 2001;
Horva th and Winkler, 2004; Sonnadara et al., 2006; Lopez-
Caballero et al., 2016). The deviant probability is relevant for pre-
dictive coding as the precision associated with a model of regularity
will be influenced by the number and size of failures to account for
6 J. Jalewa et al. / Hearing Research 399 (2021) 107992
sensory input e i.e., the probability of occurrence of the deviant
stimulus. For instance, having a sequence with a 25% deviant
probability relative to a sequence with a 10% deviant probability
will reduce the precision associated with the prediction that the
standard is the next stimulus. Under such a low-confidence sce-
nario, when the prediction is violated, smaller MMN will be
generated.
3.2.3. Other factors
In addition to the magnitude of deviance difference and deviant
probability, manipulation of the stimulus onset asynchrony (SOA,
the time between the onset of one stimulus to the onset of the next)
affects the MMN amplitude, as demonstrated in human studies
€€
(Ja askela€inen et al., 1999; Sabri and Campbell, 2001; Müller et al.,
2005; Sussman et al., 1999; Weise et al., 2014). As SOAs increase
past 1s, the MMN decreases until it disappears at SOAs of 10s,
which is in agreement with the hypothesis that MMN is reliant on
auditory sensory memory (Ja €€ €inen et al., 1999; Sabri and
askela
Campbell, 2001). Further, the timing of stimulus presentation is
an important contextual variable that determines filtering of sound
based on relevance. Moreover, the period of stability or the degree
of regularity i.e., how regularly the sounds occur, influences the
MMN amplitude (Todd et al., 2018; Jones, 2002). We describe
variability in timing as ‘jitter’, which means variability in the SOA.
Research findings have shown that larger MMN is produced in
response to sequences with a regular SOA, as compared to a vari-
able SOA (Winkler et al., 2001; Takegata and Morotomi, 1999; Todd
et al., 2018; Tervaniemi et al., 1997; Takegata et al., 2001a, 2001b).
Recently, another attribute of human MMN has been estab-
lished. Although the brain can quickly begin to alter predictions
based on the introduction of a new ‘standard’ stimulus (as few as
2e3 repetitions of a new regularity are enough for adjustment), it
has been shown that the stimulus composition presented first can
have lasting effects. In other words, what we learn first results in a
bias towards processing of a sound (Todd et al., 2011). The first
report on this primacy bias or ‘first-impression bias’ used a two-
tone sequence where a short and long duration sound switched
roles as standard and deviant multiple times in different sound
sequences creating different periods of “rule” or regularity stability.
One of the main findings of this study was that only the tone that
was encountered first as a deviant was impacted by the period of
local stability e that is, it was larger for longer periods of a stable
rule and smaller for shorter periods of a stable rule (Todd et al.,
2011). The MMN to deviant sounds in the alternate block type did
not show this same modulation by stability. This difference in the
pattern of modulation in longer and shorter period of stability in
these alternating block sequences only occurs when there is a
regularity in the block length (Todd et al., 2018). A series of studies
on this first impressions bias (Todd et al., 2013, 2014b; Mullens
et al., 2014, 2016; Frost et al., 2016) have supported the hypothe-
sis that the different modulation patterns of MMN amplitude in the
two blocks are due to systematically higher precision in models of
the first block type versus the second block type that continue so
long as the longer term block structure is predictable, but drop as
soon as this longer term pattern is broken (Mullens et al., 2016;
Fitzgerald and Todd, 2018). Most recently, through the application
of dynamic causal modelling, the hypothesised differences in pre-
cision for the two blocks were supported by significant differences
in model parameter associated with precision e that is, the degree
of inhibitory gain on the superficial pyramidal cell representing the
“prediction error” units (Fitzgerald et al., 2019).
The detection of violations in regularity form the basis of pre-
dictive coding and a special case of prediction violation is the
processing of omissions or missing stimuli (Bendixen et al., 2012).
Several studies have shown that MMN can be elicited in the human
brain in response to an unexpected omission of an auditory stim-
ulus (Joutsiniemi and Hari, 1989; Hughes et al., 2001; Wacongne
et al., 2012; Yabe et al., 1997; Raij et al., 1997; Horva th et al.,
2007; Nordby et al., 1994). In other words, sound omission elicits
an MMN-like response, time-locked to the expected onset of the
sound (Winkler and Czigler, 2012; Oceak et al., 2006). Based on the
assumption that the physically absent stimulus cannot actually
produce a perceptual response, it has been argued that omission
MMN is evidence of ‘pure’ memory-based, prediction error process
(May and Tiitinen, 2010; Yabe et al., 1997; Na€€ €nen et al., 2005).
ata
4. How well do existing reports of rat MMN show that they
model each of these aspects?
It is not surprising to find that non-primate animals such as
rodents exhibit SSA to auditory stimuli: it is a relatively ‘simple’
process that can presumably occur at the single synapse level. A
memory-based prediction error mechanism, however, necessitates
far more complexity, such as sensory memory, prediction genera-
tion, stimulus comparison and prediction error processes, and it is
not as readily assumed that the rodent brain is capable of engaging
in all of these processes to generate a ‘true’ human-like MMN with
some degree of prediction error. That said, the shifting and ori-
enting of behavioural responses to unexpected stimuli is certainly
observed in many other animal species, even those of less ‘intelli-
gence’ than rodents, so it would not be surprising if the rodent
brain is capable of generating prediction error responses. Studying
MMRs in rodents is a relatively new and growing field of research
(Featherstone et al., 2018; Tikhonravov et al., 2008). Some initial
studies conducted as early as the 1990s report the presence of ERPs
and MMN-like activity in rodents (Yamaguchi et al., 1993; Ehlers
et al., 1994). In the rodent brain, MMN-like ERPs have been
observed to commence less than 100 ms from stimulus onset.
MMN-like activity elicited in response to the deviant tones have
been found in anesthetized rats (Ruusuvirta et al., 1998;
Tikhonravov et al., 2010; Astikainen et al., 2006), awake rats
(Eriksson and Villa, 2005) and awake mice (Umbricht et al., 2005;
Ehrlichman et al., 2008). Moreover, anesthetized rats have
demonstrated a comparable ability of change detection in the
speech sounds (Ahmed et al., 2011; Astikainen et al., 2014; Kurkela
et al., 2016) and complex sounds (Yang et al., 2019).
However, as reviewed above, the MMN in humans has specific
characteristics, and demonstrates unique attributes in response to
changing stimuli parameters. Apart from adaptation-independence
and other criteria to determine whether MMRs exist in rodents, (as
reviewed in (Harms et al., 2016)), there are additional important
attributes associated with human MMN that remains unexplored in
rodents and thus, need to be investigated. These attributes include
sensitivity to the amount of ‘mismatch’ (i.e., difference in the
physical properties of the standard vs the deviant or-deviance
difference), to differences in deviant probability, to sequence
jitter, to the primacy bias, and to omission deviants. To utilize MMN
as a biomarker and to bridge the pre-clinical and clinical gap, we
need to overcome the argument that MMN-like responses can be
explained by adaptation. Additionally, we need a battery of
neurophysiological outcome measures in rodents, exhibiting fea-
tures equivalent to that of human MMN. While the properties of
human MMN in terms of primacy bias and omission are important
and to our knowledge, no studies have investigated these yet, it is
not our intention to cover them here, and they remain to be
determined.
4.1. Adaptation independence
The generation of a human-like MMN has been demonstrated in
 J. Jalewa et al. / Hearing Research 399 (2021) 107992
rodents by including carefully-designed control sequences. To
determine whether the rat brain is capable of generating deviance
detection (a criteria of human MMN) (Harms et al., 2016), Harms
and colleagues used three different control sequences - 1. the flip-
flop control (Fig. 1A &B) (to control for differential responses to the
physical characteristics of standards and deviants as in (Jacobsen
and Schro € ger, 2003)); 2. the many standards control (to control
for differential adaptation as in (Jacobsen and Schro € ger, 2003;
Jacobsen and Schro €ger, 2001)) and, 3. the cascade control (to con-
trol for differential adaptation) (Harms et al., 2014; Ruhnau et al.,
2012). In the flip-flop oddball sequences, two oddball sequences
are presented, such that the identity of the standard and deviant
reverses, which means that the same tone appears as a standard in
one sequence, and a deviant in the other. In a many standards
control sequence, the deviant tone is present among other equi-
probable tones and the tones are presented pseudo-randomly so no
pattern of regularity is established. Similarly, the cascade control
sequence presents the same stimuli presented as deviants, at the
same rate when they are deviants, but they are within an estab-
lished pattern of regularity and therefore, can serve as a control that
represents both a rare and expected stimulus. While the majority of
rodent studies have used many standards control sequence, some
have used cascade control sequence. Harms et al. observed
adaptation-independent prediction error responses using the many
standards control, but not with the cascade control (Harms et al.,
2014). However, subsequent studies using both anesthetized rats
and awake mice, improved upon the design of the cascade
sequence and were able to observe prediction error responses us-
ing unitary recordings in localised auditory areas (Parras et al.,
2017) as well as by recording local field potentials from the dura
above the auditory cortex (Yang et al., 2019).
Using a many standards control, memory-based change detec-
tion, analogous to humans has been observed in anesthetized rats
(Astikainen et al., 2011; Ahmed et al., 2011; Ruusuvirta et al., 2015;
Shiramatsu et al., 2013; Parras et al., 2017; Yang et al., 2019), awake
rats (Harms et al., 2014; Polterovich et al., 2018) and anesthetized
mice (KURKELA et al., 2018). Furthermore, Nakamura et al. con-
ducted studies in awake as well as anesthetized rats to investigate
whether rat can produce a deviant response to high/low frequency
and long/short duration deviant sounds. The authors used a many
standards control and found that awake rats exhibited MMN-like
activity in response to high frequency and long duration tones
(Nakamura et al., 2011).
Along similar lines, other studies have employed cascade control
sequences to dissociate SSA from the prediction error response in
anesthetised rats (Parras et al., 2017; Yang et al., 2019). Control
measures such as many standards and the cascade control are
useful for understanding and exploring the MMN mechanism.
However, this requires a careful placement of the deviant and
standard sounds in the control sequence as studies have found
differential ERPs in response to when the sounds are assigned in
the middle (may result in an overestimation of the MMN) vs edge
(extreme substandard effect, which may result in an underesti-
mation of deviance detection) in the control sequence (Harms et al.,
2014, Jacobsen and Schro €ger, 2001; Jacobsen and Schro € ger, 2003).
Additionally, different levels of Df (frequency difference between
two consecutive sounds in control sequence) may result in differ-
ential across-frequency adaptation, resulting in confounded find-
ings. Furthermore, stimulus type also plays an important role as
Yang et al. found genuine MMN in anesthetized rats in response to
4000 Hz sound only and not 4600 Hz while using both many
standard as well as cascade controls (Yang et al., 2019). On the
contrary, Nakamura et al. demonstrated genuine MMN in response
to high frequency sound but not low frequency sound (Nakamura
et al., 2011). Overall, we (Harms et al., 2014; Nakamura et al.,
7
2011) and others (Chen et al., 2015; Hamm and Yuste, 2016; Jung
et al., 2013; Shiramatsu et al., 2013; Sivarao et al., 2014), have
demonstrated that MMR in rodents cannot be explained by adap-
tation only and there exists a mechanism of prediction error
response, similar to human MMN.
4.2. Sensitivity to deviance difference
Although MMN-like responses have been studied and demon-
strated in animal models, few studies have demonstrated that ro-
dent MMRs show the same sensitivity to deviance magnitude as
the human MMN. An initial study in the awake, freely moving rats
found MMN-like response to the duration deviant magnitude
(Roger et al., 2009). Further, Shiramatsu et al. investigated the
sensitivity of putative MMN in the auditory cortex of anesthetized
rats to the deviance magnitude and found that mean amplitude to a
small change in frequency was smaller in comparison to the large
change in frequency (Shiramatsu et al., 2013). Another study in
anesthetized rats found that auditory cortical responses to the
deviant and the MMR amplitude were larger for increased differ-
ences between the deviant and the standard (Ruusuvirta et al.,
2015). These findings demonstrate that the rat brain certainly has
the capability to generate MMRs that scale with deviance differ-
ence. However, additional replication using different recording
systems and methods, and in addition, in awake rats, would greatly
consolidate this conclusion. To examine if the manipulations in
degree of deviance have an effect on rodents as in humans, we
tested the MMR against low, mid and high deviance difference,
discussed later in this review.
4.3. Sensitivity to deviant probability
Larger MMR amplitudes have been observed in awake rats using
epidural recordings, in response to frequency deviants with 0.1
probability of occurrence as compared to 0.2, thus providing initial
support for the hypotheses that the rat brain can generate a MMR
with probability sensitivity (Jung et al., 2013). On similar lines,
Sivarao et al. found sensitivity of MMR in freely behaving rats to
deviant probability and the authors suggest that low deviant
probability is important to establish a context of regularity (Sivarao
et al., 2014). To confirm this attribute in rats, we conducted a sys-
tematic study and investigated the effect of low, mid and high
probability manipulation.
4.4. Sensitivity to SOA manipulation
As observed in humans, some rodent studies have demonstrated
a dependence of MMR amplitude on the sensory memory trace by
manipulating the inter stimulus interval (ISI) (KURKELA et al., 2018;
Astikainen et al., 2011). The ISI is roughly equivalent to the SOA, but
measures the offset-to-onset time, rather than presenting an onset-
to-onset time, as the SOA does. Larger MMR amplitude have been
observed in response to deviant sounds with shorter 375 ms ISIs
compared to longer 600 ms ISI in anesthetized mice (KURKELA
et al., 2018). Earlier, similar effects of ISI manipulation have been
shown by Astikainen and colleagues in anesthetized rats
(Astikainen et al., 2011). These findings indicate that the rat brain
does indeed show sensitivity to SOA manipulations, similar to hu-
man MMN, which indicate that rat MMRs may also reflect memory
processes. A thus far unanswered, but relevant question, is to
determine the limit of the rat brain’s auditory sensory memory in
this context, i.e. what is the largest SOA at which rat MMRs can still
be observed?
In the current study, we will focus on some of the key attributes
of human MMN that either have not yet been addressed in rodents
8 J. Jalewa et al. / Hearing Research 399 (2021) 107992
at all, or not been addressed in our specific experimental setup:
sensitivity to deviance difference, sensitivity to probability
manipulation and sensitivity to environmental uncertainty (or SOA
‘jitter’).
5. Original research
5.1. Methods
5.1.1. Ethics statement
All experiments followed the stringent guidelines of the Na-
tional Health and Medical Research Council’s Australian code of
practice for the care and use of animals for scientific purposes. The
Animal Care and Ethics Committee, University of Newcastle, NSW,
Australia approved the experimental protocols (Ethics approval
number: A-2016-610). The surgical procedures were executed un-
der maintained anaesthesia and all efforts were made to reduce the
number of animals, and minimize the pain and suffering following
surgery through use of analgesics.
5.1.2. Animals
Male and female Wistar rats (age: 3e4 months, n ¼ 10e12 per
sex) underwent surgeries for the study. All the rats were housed in
pairs in the standard cages, in the temperature and humidity
controlled Behavioural Sciences animal facility at the University of
Newcastle, under normal light 12hr day-night cycle, and had ad
libitum access to the food and water.
5.1.3. Surgery to implant EEG electrodes
Surgery was performed to implant stainless steel screw elec-
trodes, similar to the previous studies from the laboratory (Harms
et al., 2014). Rats were anesthetised with isoflurane and fixed
upon a stereotaxic frame (Stoelting, IL, USA), using ear bars. Car-
profen (5 mg/kg s.c.) and buprenorphine (0.05 mg/kg s.c.) were
administered as analgesics prior to the start of the surgery. Six
0.9 mm burr holes were drilled at locations corresponding to the
four recording sites [dorsal to the left and right frontal cortices (LFC
and RFC, 2.00 mm anterior to Bregma and 2.00 mm lateral to the
midline), the left and right auditory cortices (LAC and RAC, 5.00 mm
posterior to Bregma and 4.00 mm lateral to the midline)], the
ground electrode (left posterior cortex, 2.00 mm anterior to
Lambda and 2.50 mm left of the midline), and the reference elec-
trode dorsal to the cerebellum (1.00 mm posterior to Lambda and
1.00 mm to the right of the midline). The complete assembly of the
connector along with six screws and their respective wires were
fixed to the head using self-adhesive cement (SmartCem2, Dents-
ply, Australia) followed by temporary crown and bridge material
dental cement (Integrity, Dentsply, Australia). The skin was then
glued back onto the dental cement with Vetbond, followed by
subcutaneous administration of sterile 0.9% saline (10 ml/kg body
weight, s.c.) to balance for any fluid loss during the surgery. Testing
was performed after a week of post-surgery recovery.
5.1.4. Sound generation
A custom program was written in Presentation software (Neu-
robehavioral Systems, Inc.) to generate the auditory stimuli (fre-
quency-modulated broadband tones, oscillating around a central
frequency ± 3%), which were amplified, and delivered through a
speaker mounted on the roof of the experimental chamber (Harms
et al., 2014). A sound meter (Bruel & Kjaer Model 2260) was used to
calibrate the intensity of the free-field sounds to approximately
70 dB sounds in the range of 6636Hz and 12233Hz. Stimuli used
were always broadband frequency-modulated tones of 100 ms in
duration, each centred on a particular frequency (e.g. 12233Hz) ±
3%, with 10 ms rise/fall times.
5.1.5. Mismatch response (MMR) testing
MMRs were investigated in awake, freely moving rats. Using a
reusable adhesive, a B-100mAh battery was connected to a wire-
less-10-channel telemetric headstage (Multi Channel Systems,
Reutlingen, Germany). The wireless headstage was then inserted
into the socket on the rat’s head (implanted earlier, as described in
section 5.1.3), and the rat was placed in a 32 cm diameter circular
plastic bucket (containing bedding) below the speaker through
which acoustic stimuli were presented, in a sound-attenuating
chamber (Med Associates, St. Albans, USA). Multi Channel Sys-
tems MCRack software was used to record the EEG data. Digitiza-
tion of each channel of EEG data was performed at 2000 Hz (high
pass filter 0.1 Hz, low pass filter 5000 Hz, voltage range ± 12.4 mV)
(Harms et al., 2014).
5.1.6. Experiment design and stimuli
5.1.6.1. Deviance difference experiment. Rats were tested on three
conditions of increasing frequency difference between the deviant
and standard stimuli: 1. low deviance difference (standard 6636 Hz,
deviant 8137 Hz), 2. mid deviance difference (standard 6636 Hz,
deviant 9977 Hz) and, 3. high deviance difference (standard
6636 Hz, deviant 12233 Hz) in a flip-flop design (so that standard
and deviant ERPs were elicited by the tones with identical physical
characteristics). The roles of standard (87.5%) and deviant (12.5%) in
each condition were reversed resulting in an ascending (low fre-
quency standard and high frequency deviant) or a descending (high
frequency standard and low frequency deviant) deviant sequence.
The three deviance difference conditions across two flip-flop se-
quences resulted in a total of six sequences presented to the rats.
EEG was recorded for each rat on each of these six sequences in a
randomised order for a single session (lasting 1 h 33 min that
included a minimum 1 min silence between each sequences). For
each sequence type, a total of 200 deviants and 1400 standards
were presented in a pseudorandom order with a SOA of 500 ms,
and no fewer than three standards between each deviant.
5.1.6.2. Probability difference experiment. Rats were exposed to
ascending and descending oddball sequences comprising two tones
(a low frequency tone of 6636 Hz and a high frequency tone of
12233 Hz), in a flip-flop design. Three different deviant probability
conditions were used: 1/4 (25%, high), 1/8 (12.5%, mid), 1/16
(6.125%, low). As above, there were six types of sequences, pre-
sented to each rat, in a randomised order within a single session.
The sessions lasted longer than the deviance difference experiment,
as a sufficient number of deviant stimuli needed to be presented for
the low probability condition. Each session lasted 2 h 13 min, and
out of a total of 2400 stimuli presented for each sequence type at an
SOA of 500 ms, there were 150, 300 and 600 deviants presented in
the low, mid and high probability conditions, respectively.
5.1.6.3. Jitter experiment. Rats were exposed to ascending and
descending oddball sequences comprising two tones (a low fre-
quency tone of 6636 Hz and a high frequency tone of 8137 Hz), in a
flip-flop design. This difference is equivalent to the low deviance
difference of the previously described paradigm (section 5.1.6.A).
Three different SOA conditions were used: 500 ms SOA (No Jitter),
450e550 ms variable SOA (Low Jitter), and 250e750 ms highly
variable SOA (High Jitter). The SOA in variable SOA conditions var-
ied pseudorandomly in 10 and 50 ms steps for the Low and High
Jitter conditions, respectively. As above, there were six types of
sequences, presented to each rat, in a randomised order within a
single session. For each sequence type, a total of 200 deviants and
1400 standards were presented in a pseudorandom order, with no
fewer than three standards between each deviant.
 J. Jalewa et al. / Hearing Research 399 (2021) 107992
5.1.7. Data extraction
Data were processed off-line using EEGDisplay (version 6.4.1) as
described in Harms et al. (2014). An initial step involved exclusion
of gross artefact intervals in the continuous EEG record using an
automated algorithm that rejected signals exceeding ±1400 mV.
Thereafter, epochs were extracted from the continuous EEG con-
sisting of 100 ms pre-stimulus baseline and a 300 ms post-stimulus
interval. At epoch extraction, ERPs were baseline corrected over a
100 ms pre-stimulus interval. Epochs were averaged for each rat
and separately for each stimulus type. After the pre-processing
steps of bad channel rejection and artefact rejection prior to seg-
menting into epochs and averaging, the latency ranges of individual
ERP components were determined based on the morphologies of
the ERPs, taken from grand averages and thereafter, their mean
amplitude extracted for each rat. The ERPs showed distinct com-
ponents characterised by negative and positive peaks (extracted
over latency windows). For the deviance difference experiment,
mean amplitude measures were extracted from four peaks at the
following time windows: N18: 14e22.5 ms (AC), 11.5e21 ms (FC);
P32: 24.5e39.5 ms (AC), 22e42 ms (FC); N54: 40e67.5 ms (AC),
42.5e67.5 (FC); N86: 67.5e105 ms (both sites) (Supplementary
Figs. 4A and B). Likewise, mean amplitudes were extracted for the
probability dataset using the following time windows: N18:
14e22.5 ms (AC), 12e20.5 ms (FC); P32: 23.5e40 ms (AC),
21.5e44 ms (FC); N54: 42e67 ms (AC), 46e67 (FC); N86:
67e105 ms (both sites) (Supplementary Figs. 4C and D). Similarly,
mean amplitudes were extracted for the jitter experiment dataset
using the following time windows: N18: 13e22 ms (AC), 13e22 ms
(FC); P32: 22.5e42.5 ms (AC), 20.5e42.5 ms (FC); N54: 43e70 ms
(AC), 46e67 (FC); N86: 70e105 ms (both sites) (Supplementary
Figs. 4E and F). While EEG was recorded at left and right AC as
well as left and right FC, MMRs were averaged across left and right
sites.
5.1.8. Statistical analysis
The sample size for the experiments was n ¼ 10e12 per sex. All
the analyses were performed using SPSS 25 and analysis of variance
(ANOVA) with repeated measures was used to analyse the mean
amplitudes of the ERP components and the effect of Deviance dif-
ference, Probability or Jitter. For each of the three experiments, an
initial repeated measures ANOVA was performed on mean ampli-
tude responses with within-subjects factors of Stimulus (DEV, STD),
Frequency (High, Low), Site (AC, FC), and the experimental
manipulation of either Deviant difference (High, Medium, Low),
Probability (Low, Mid, High) or Jitter (No Jitter, Low Jitter, High
Jitter). The primary purpose of this initial analysis was to determine
which frequency produced significant MMRs, given that for each
experiment there was both a high frequency deviant and a low
frequency deviant. In these analyses, we examined the effect of
Stimulus (DEV vs. STD) on the mean amplitude response for each
component of the ERP, and whether the effect of Stimulus was
present for both frequencies or one only (for example, high fre-
quency, as demonstrated previously (Harms et al., 2014)). Such an
effect would be demonstrated by a significant
Stimulus  Frequency interaction followed by relevant Stimulus
contrasts at each frequency. If there was evidence that only high-
frequency stimuli produced an MMR (i.e. DEV > STD), we limited
further analyses to just the high frequency stimuli.
For subsequent analyses, the MMR was computed for each
condition: DEV e STD. In this computation, and in analyses
comparing deviant and standard stimuli, the flip-flop control was
employed and only stimuli of the same frequency were compared,
e.g., 8137Hz deviant vs. 8137Hz standard. The second major anal-
ysis used a repeated measures ANOVA with the MMR as the
dependent variable, and within-subjects factors of Deviance
9
Difference/Probability/Jitter (depending on the experiment), Site
(AC and FC) and Frequency (low and high if both were included). If
interactions with site were observed, appropriate post-hoc com-
parisons at each site were conducted.
In the final analysis of each experiment, significant effects of
independent variables on MMRs were followed up to determine
whether DEV responses, STD responses, or both, underpinned
changes in the MMR. Repeated measures ANOVA were used with
either the deviant or standard mean amplitude response as the
dependent variable, and with Deviance Difference/Probability/Jitter
(depending on the experiment), Site (AC and FC) and Frequency
(low and high if both were included) as within-subjects factors.
5.2. Results
5.2.1. Effect of deviance difference on rat MMRs
For all components, significant MMRs (Deviant > Standard)
were only found for high frequency stimuli as demonstrated by
significant Frequency  Stimulus interactions (N18: F(1,20) ¼ 30.836,
p < 0.001; P32: F(1,20) ¼ 41.679, p < 0.001; N54: F(1,20) ¼ 19.582,
p < 0.001; N86: F(1,20) ¼ 6.622, p ¼ 0.018), followed by significant
(p < 0.05) posthoc pairwise effects demonstrating DEV > STD for
responses to high, but not low frequency stimuli. Therefore, further
analyses to study the deviance difference effect was performed on
mean amplitudes in response to high frequency stimuli only.
The degree of difference between the deviant and standard
affected the difference MMR measure for each component, as
demonstrated by main effects of Deviance (N18: F(2,40) ¼ 5.346,
p ¼ 0.009; P32: F(2,40) ¼ 6.049, p ¼ 0.005; N54: F(2,40) ¼ 10.713,
p < 0.001; N86: F(2,40) ¼ 5.848, p ¼ 0.006). The evoked potentials to
the three levels of ascending frequency are presented in Fig. 2 for
the MMR difference waves (Fig. 2A), deviant ERP (Fig. 2C) and
regular standard ERP (Fig. 2E). The post hoc comparisons indicated a
significant effect of the deviance difference on the mean ampli-
tudes (±standard error, SE) of all the MMR components [N18: ((high
vs. mid, p ¼ 0.017) (high vs. low, p ¼ 0.018),); P32: ((high vs. low,
p ¼ 0.008), (mid vs. low, p ¼ 0.007); N54: ((high vs. mid, p ¼ 0.002)
(high vs. low, p ¼ 0.001),); N86: ((high vs. low, p ¼ 0.007))] (Fig. 2B).
There were no Site  Deviance interaction effects on the mean
amplitudes of N18, P32 and N54 MMR components, however, N86
(F(2,40) ¼ 3.427, p ¼ 0.042) component exhibited significant
Site  Deviance interaction effect. Further post hoc comparisons
revealed a significant Deviance effect on the N86 mean amplitudes
in auditory cortex only [(low vs. mid, p ¼ 0.003) (low vs. high,
p ¼ 0.001),] and not in the frontal cortex [(low vs. mid, p ¼ 0.803),
(low vs. high, p ¼ 0.133) (mid vs. high, p ¼ 0.101),].
The MMR is a difference measure, and therefore is influenced by
two factors: the response to the deviant and that to the standard.
Therefore, we performed additional analyses to examine what
underlies the sensitivity to the MMR to changes in deviance dif-
ference: does the response to the deviant, the standard, or both,
change? Significant Deviance difference effects were found for
deviant response for all components (N18: F(2,40) ¼ 9.709, p < 0.001;
P32: F(2,40) ¼ 3.697, p ¼ 0.034; N54: F(2,40) ¼ 19.591, p < 0.001; N86:
F(2,40) ¼ 7.656, p ¼ 0.002), and similar to the MMR, all pairwise post
hoc comparisons revealed that the deviant response in the high
deviance difference condition was consistently higher than that in
the low deviance difference condition (Fig. 2D). For the Standard
stimulus (Fig. 2F), there were no significant main effects of
Deviance.
5.2.2. Effect of deviant probability on rat MMRs
Frequency  Stimulus interactions were observed on mean
amplitude responses (N18: F(1,23) ¼ 9.376, p ¼ 0.006; P32:
F(1,23) ¼ 19.833, p < 0.001; N54: F(1,23) ¼ 41.000, p < 0.001; N86:
10 J. Jalewa et al. / Hearing Research 399 (2021) 107992

Fig. 2. Effect of deviance difference on event related potentials averaged over auditory and frontal cortex of the control male and female rats, in the ascending oddball
paradigm. A & B. MMR (Deviant e Standard). A. MMR waveform. Difference wave obtained by subtracting the responses to standard stimulus from the responses to the deviant
stimulus for low (blue), mid (grey), high (red) deviance differences. B. MMR mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components of rat
MMRs. There is a significantly larger MMR amplitude in response to the high deviance difference (in red) as compared to the low deviance difference (in blue) or mid deviance
difference (in grey). C & D. ERP responses to Deviant stimuli. C. Grand averaged ERP response (waveform) to deviant stimuli. D. Deviant mean amplitude. Mean amplitudes (±standard
 J. Jalewa et al. / Hearing Research 399 (2021) 107992 11

F(1,23) ¼ 17.622, p < 0.001). We found that Deviant Auditory Cortex [(low vs. high, p ¼ 0.002), (mid vs. high, p ¼ 0.003),
response > Standard response for all the components (Stimulus Supplementary Fig. 2C], but were also present at the Frontal Cortex
effect: p < 0.05 for all). Further, pairwise comparisons between (low vs. high, p ¼ 0.032; Supplementary Fig. 2D). There were no
Deviant and Standard responses, split for Frequency, revealed that significant Probability effects on the mean amplitudes of any of the
deviant responses were significantly larger than those for stan- components in response to Standard stimuli (Fig. 3E and F).
dards for all the components at high frequencies (p < 0.001 for all
components). In addition, such effects held for two components
5.2.3. Effect of SOA variability (jitter) on rat MMRs
(P32 and N86) for the low frequency stimuli (p < 0.001), but not for
For all components, significant MMRs (Deviant > Standard)
N18 (p ¼ 0.071) or N54 (p ¼ 0.126). Therefore, in the further ana-
were found for high frequency stimuli as demonstrated by signifi-
lyses to examine the probability effect on mean amplitudes, both
cant Frequency  Stimulus interactions (N18: F(1,22) ¼ 10.415,
high and low frequency stimuli responses were included.
p ¼ 0.004; P32: F(1,22) ¼ 21.526, p < 0.001; N54: F(1,22) ¼ 10.482,
Next, we examined the effect of Probability on MMRs. There was
p ¼ 0,004; N86: F(1,22) ¼ 18.080, p < 0.001), but were also found for
a main effect of Probability on MMR mean amplitude for P32
low frequency stimuli at P32 (p ¼ 0.012). Therefore, further ana-
(F(2,46) ¼ 5.614, p ¼ 0.007) and N54 (F(2,46) ¼ 5.244, p ¼ 0.009)
lyses to study the jitter effect was performed on mean amplitudes
components. The post hoc comparisons indicated a significant
in response to both high and low frequency stimuli.
probability effect on the mean amplitudes of P32 (low vs. high,
No significant effects of Jitter were observed for any of the
p ¼ 0.001) and N54 [(low vs. high, p ¼ 0.003) (mid vs. high,
components examined (N18: F(2,44) ¼ 0.388, p ¼ 0.680; P32:
p ¼ 0.027),] MMR components (Fig. 3B). There were significant
F(2,44) ¼ 0.452, p ¼ 0.639; N54: F(2,44) ¼ 2.067, p ¼ 0.139; N86:
main effects of Frequency on MMR mean amplitude for all the
F(2,44) ¼ 0.258, p ¼ 0.774). However, there were significant main
components (N18: F(1,23) ¼ 9.376, p ¼ 0.006; P32: F(1,23) ¼ 19.833,
effects of Frequency on MMR mean amplitude for all the compo-
p < 0.001; N54: F(1,23) ¼ 41.000, p < 0.001; N86: F(1,23) ¼ 17.622,
nents (N18: F(1,22) ¼ 10.415, p ¼ 0.004; P32: F(1,22) ¼ 21.526,
p < 0.001). The post hoc pairwise comparisons revealed a signifi-
p < 0.001; N54: F(1,22) ¼ 10.482, p ¼ 0.004; N86: F(1,22) ¼ 18.080,
cant frequency effect on the mean amplitudes of all the compo-
p < 0.001). The post hoc pairwise comparisons revealed a signifi-
nents (N18 (low frequency vs. high frequency, p ¼ 0.006); P32 (low
cant frequency effect on the mean amplitudes of all the compo-
frequency vs. high frequency, p < 0.001); N54 (low frequency vs.
nents (N18 (low frequency vs. high frequency, p ¼ 0.004); P32 (low
high frequency, p < 0.001); N86 (low frequency vs. high frequency,
frequency vs. high frequency, p < 0.001); N54 (low frequency vs.
p < 0.001) (Supplementary Fig. 1A). In every case, the mean
high frequency, p ¼ 0.004); N86 (low frequency vs. high frequency,
amplitude of a component was larger in response to a high fre-
p < 0.001). Further, there were no significant Frequency  Jitter
quency stimulus. However, there were no significant
interaction effects on the mean amplitudes of any of the compo-
Frequency  Probability interaction effects on the mean amplitudes
nents (N18: F(2,44) ¼ 0.905, p ¼ 0.412; P32: F(2,44) ¼ 1.309, p ¼ 0.280;
of any of the components (N18: F(2,46) ¼ 0.152, p ¼ 0.860; P32:
N54: F(2,44) ¼ 0.176, p ¼ 0.839; N86: F(2,44) ¼ 0.296, p ¼ 0.746)
F(2,46) ¼ 0.854, p ¼ 0.433; N54: F(2,46) ¼ 1.651, p ¼ 0.203; N86:
(Supplementary Fig. 3).
F(2,46) ¼ 0.769, p ¼ 0.469) (Supplementary Fig. 1B).
Although Jitter effects were not significant in the ANOVA, we
Additionally, there were Site  Probability interaction effects on
examined the post-hoc pairwise tests for P32 and N54, given re-
the mean amplitudes of three components (N18: F(2,46) ¼ 4.195,
sults from the Probability experiments suggest these two compo-
p ¼ 0.021; P32: F(2,46) ¼ 4.830, p ¼ 0.012; N54: F(2,46) ¼ 3.944,
nents have MMN-like attributes. There were no pairwise effects of
p ¼ 0.026). Further post hoc comparisons revealed a significant
Jitter on P32, but the MMR response at N54 in the No Jitter con-
Probability effect on the N54 mean amplitudes in auditory cortex
dition was significantly larger than that in the High Jitter condition
only [(low vs. high, p ¼ 0.001) (mid vs. high, p ¼ 0.004),] and not in
(p ¼ 0.042) (Fig. 4B). Further, we investigated whether the deviant
the frontal cortex [(low vs. mid, p ¼ 0.540), (low vs. high, p ¼ 0.080)
response, the standard response, or both was responsible for the
(mid vs. high, p ¼ 0.303),] (Supplementary Fig. 2A), while, a Prob-
jitter effects. Pairwise comparisons indicated a marginal effect of
ability effect was observed on the P32 mean amplitudes in frontal
Jitter for the deviant stimulus for N54 component with larger MMR
cortex only [(low vs. high, p < 0.001) (mid vs. high, p ¼ 0.046),] and
amplitude for ‘no jitter’ as compared to ‘high jitter’ (p ¼ 0.066)
not in auditory cortex [(low vs. mid, p ¼ 0.229), (low vs. high,
(Fig. 4D). There were no significant Jitter effects on the mean am-
p ¼ 0.155) (mid vs. high, p ¼ 0.973),] (Supplementary Fig. 2B).
plitudes of any of the components in response to Standard stimuli
Significant pairwise Site x Probability effects were not observed in
(Fig. 4E and F).
posthoc comparisons for N18.
Further, we investigated whether the deviant response, the
standard response, or both was responsible for the probability ef- 6. General discussion
fects. Probability effects for the deviant stimulus were found for
N54 (F(2,46) ¼ 5.706, p ¼ 0.006), with post-hoc comparisons indi- Using a wireless telemetry system, we examined the effects of
cating that low vs high (p ¼ 0.004) and mid vs high probability three manipulations in freely moving, unrestrained rats: the
(p ¼ 0.008) effects were significant (Fig. 3D). The effect of Proba- physical difference between the expected and unexpected stimuli,
bility on P32 Deviant response was not significant (F(2,46) ¼ 2.496, the probability of the unexpected stimulus and the variability in
p ¼ 0.094). Similar to the MMR, Site x Probability effects were SOAs (jitter). We hypothesised that larger MMRs would be elicited
observed for the Deviant response at P32 (F(2,46) ¼ 3.832, p ¼ 0.029) to unexpected (deviant) stimuli that a) have a larger change in pitch
and N54 (F(2,46) ¼ 3.312, p ¼ 0.045), with Probability effects limited compared to the expected (standard) stimulus, b) are less
to the Frontal Cortex site for P32 (low vs. high, p ¼ 0.002, frequently presented (lower probability), and c) are presented in a
Supplementary Fig. 2D) and were not significant for Auditory Cor- fixed SOA (no jitter) environment. MMRs were elicited and the
tex sites. Probability effects for N54 were significant for the morphology of the components resembled those previously
observed in our laboratory (Harms et al., 2014; Nakamura et al.,

error, SE) of N18, P32, N54 and N86 components in response to the deviant stimulus. E & F. ERP responses to Standard stimuli. E. Grand averaged ERP response (waveform) to
standard stimuli. F. Standard mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components in response to the standard stimulus. (For interpretation
of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
12 J. Jalewa et al. / Hearing Research 399 (2021) 107992

Fig. 3. Effect of deviant probability on event related potentials averaged over auditory and frontal cortex of the control male and female rats, averaged for the frequency. A & B. MMR
(Deviant e Standard). A. MMR waveform. Difference wave obtained by subtracting the responses to standard stimulus from the responses to the deviant stimulus for low (red), mid
(grey), high (blue) probability. B. MMR mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components of rat mismatch responses (MMRs). N54
component has a significantly larger MMR amplitude in response to the low deviant probability (in red) as compared to the high deviant probability (in blue) or mid deviant
probability (in grey). P32 component has a significantly larger MMR amplitude in response to the low deviant probability (in red) as compared to the high deviant probability (in
blue). C & D. ERP responses to Deviant stimuli. C. Grand averaged ERP response (waveform) to deviant stimuli. D. Deviant mean amplitude. Mean amplitudes (±standard error, SE) of
 J. Jalewa et al. / Hearing Research 399 (2021) 107992
2011), with increased responses to the deviant compared to the
standard, at a range of latencies, potentially representing unique
neuronal populations recruited in the response.
The purpose of the first study was to test the hypothesis that the
‘amount of mismatch’ between the standard and deviant tones
modulate the MMN amplitude in rodents, similar to the findings in
humans. We found that the MMR amplitude was largest for the
high deviance difference, in all the components, as compared to the
low or mid deviance difference, which is in agreement with the
hypothesis. Moreover, our findings are in accordance with the
previous studies in rodents. Astikainen et al. observed MMRs in
urethane anesthetized rats in response to a frequency deviance
difference of 200Hz (5%) (Standard: 4000Hz, Deviant: 3800Hz or
4200Hz) and 500Hz (12.5%) (Standard: 4000Hz, Deviant: 3500Hz
or 4500Hz) (Astikainen et al., 2011). Another study from the same
group found responses to ascending and descending deviant tones
across different deviance magnitudes in anesthetized rats. Larger
MMRs were observed for the higher deviance difference (Deviant:
5800Hz, Standard: 4000Hz) when compared to the low difference
(Deviant: 5300Hz, Standard: 4000Hz) (Ruusuvirta et al., 2015).
Earlier, Shiramatsu et al. had observed similar effects on MMR
amplitude (Shiramatsu et al., 2013). Moreover, an effect of the
frequency deviance difference have also been demonstrated in
awake mice, suggesting that MMR is related to the magnitude of
the deviant and standard difference (Umbricht et al., 2005).
The second experiment examining probability effects found that
MMR amplitude was largest for low probability conditions when
compared to mid and high probability, supporting the hypothesis
that the rarer (‘surprising’) the deviant is, the larger the response.
Our results support the findings from previous studies (Jung et al.,
2013; Sivarao et al., 2014). Interestingly, we found that there were
Site  Probability interaction effects on mean amplitudes. A sig-
nificant Probability effect was found on the N54 mean amplitudes
for the auditory cortex site only, while an effect on the P32 mean
amplitudes was found in the frontal cortex. Although we cannot
precisely determine the location of the generators based on these
site differences, due to ambiguity attributable to volume conduc-
tion, these findings suggest that different brain regions are
responsible for the generation of P32 and N54.
Our results from the third experiment, offers preliminary sup-
port towards jitter effects on N54 component in rat. The MMR
amplitude was largest in ‘no jitter’ condition as compared to ‘low’
and ‘high jitter’ conditions. These results are in line with the human
findings that have shown a decrease in MMN amplitude when an
environmental variance (jitter) is added to the sound sequence
(Todd et al., 2018): when sounds are presented with variable SOA,
there is more uncertainty in the timing of the sequence. Although
the characteristics of the deviant and the standard remain the same
and the deviant is just as improbable as it is in a stable sequence,
the uncertainty in the regular timing of the sequence leads to more
overall uncertainty in modelling the auditory environment,
reducing the confidence in the predictive model, and thus reducing
the prediction error response. However, we note the effect of jitter
was quite small and only significant when the analysis was
confined to the most MMN-like components of the rat ERP. This
may be because the frequency separation between high and low
frequency sounds was the lowest of the three deviance differences
used in experiment 1, which was found to produce the smallest
MMR. Perhaps a more robust MMR might have resulted if high
deviance difference was used, resulting in a more substantial effect
N18, P32, N54 and N86 components in response to the deviant stimulus. E & F. ERP responses to Standard stimuli. E. Grand averaged ERP response (waveform) to standard stimuli.
F. Standard mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components in response to the standard stimulus. (For interpretation of the references
to colour in this figure legend, the reader is referred to the Web version of this article.)
13
of jitter. Overall, the pattern of findings in all the manipulations
suggest that the rat brain extracts the auditory information from
the environment and processes information in a similar fashion to
humans. Importantly, our results support the notion that the rat
brain is capable of generating MMRs similar to MMN and that the
results conform to what might be expected if a predictive coding
process occurs in rats.
A limitation of the current work is that no controls for deviant
probability, such as the many standards or cascade control, have
been employed, so the MMRs measured in the current study may
be due to either or both adaptation and prediction error. We have
previously used a many standards control in the same strain of rats,
using the same methodology as the current study, and have found
evidence of adaptation-independent prediction error (Harms et al.,
2014, 2018). However, because such a sequence was not run in the
current experiments, we do not know the relative contributions of
adaptation and prediction error to the observed MMR effects of
deviance difference, deviant probability or jitter. Moreover, recently
both adaptation, known as repetition suppression and the
adaptation-independent response known as prediction error, have
been brought together under the umbrella concept of predictive
coding (Parras et al., 2017; Garrido et al., 2009; Carbajal and
Malmierca, 2018). Therefore, despite not knowing whether it is
repetition suppression or prediction error response that is manip-
ulated with changing deviant probability, sequence jitter etc., these
effects still contribute to the overall process of predictive coding.
Future studies should employ the use of the many standards con-
trol or cascade control sequences to determine the relative con-
tributions of adaptation-dependent and -independent processes.
Smaller MMN amplitude in individuals with schizophrenia is a
potential index of abnormal auditory sensory memory processing
(Catts et al., 1995), a feature of schizophrenia psychopathology
(Javitt et al., 1993), demonstrated in multiple studies (Javitt et al.,
1995, 1996; Salisbury et al., 2002). Javitt and colleagues’ research
findings show that MMN amplitude is reduced in schizophrenia
across a wide range of stimulus conditions including manipulations
of stimulus deviance, probability and interstimulus/interdeviant
interval (Javitt et al., 1998; Javitt, 2000). Shelley et al. found that
schizophrenia-related MMN amplitude reductions become more
extreme as the deviant probability is reduced in schizophrenia
patients (Shelley et al., 1999). Similarly, Todd et al. found significant
main effects of probability (low: 6% and high: 20%) on MMN
amplitude in healthy individuals. Interestingly, they found a sig-
nificant reduction in MMN amplitude in schizophrenia patients in
response to low probability condition but not the high probability
condition (Todd et al., 2006). Moreover, Umbricht and colleagues
found that temporal uncertainty, which usually reduces MMN in
healthy controls, had no significant effect on the MMN amplitude in
schizophrenia patients (Umbricht et al., 2005; Todd et al., 2018). In
addition, as covered above, there is an overall trend for individuals
with schizophrenia to not only have overall reduced MMN, but to
also generate MMNs that are not responsive to manipulations that
modulate MMN in healthy controls (Todd et al., 2012). While not a
diagnostic biomarker, such effects have been hypothesised to be
associated with attentional impairments in the disorder, for
example, if every prediction-violating stimulus, no matter how
extreme, elicits the same low error response, the system has lost a
mechanism for weighing salience and directing appropriate
attentional resources (Todd et al., 2012). Research findings suggest
that the brain in schizophrenia fails to represent different
14 J. Jalewa et al. / Hearing Research 399 (2021) 107992

Fig. 4. Effect of Jitter manipulation on event related potentials obtained from auditory and frontal cortex of the control male and female rats. A & B. MMR (Deviant e
Standard). A. MMR waveform. Difference wave obtained by subtracting the responses to standard stimulus from the responses to the deviant stimulus for high (red), low (grey), no
(blue) jitter. B. MMR mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components of rat mismatch responses (MMRs). N54 component has a
significantly larger MMR amplitude in response to the no jitter (in blue) as compared to the high jitter (in red) or low jitter (in grey). C & D. ERP responses to Deviant stimuli.
C. Grand averaged ERP response (waveform) to deviant stimuli. D. Deviant mean amplitude. Mean amplitudes (±standard error, SE) of N18, P32, N54 and N86 components in response to
the deviant stimulus. E & F. ERP responses to Standard stimuli. E. Grand averaged ERP response (waveform) to standard stimuli. F. Standard mean amplitude. Mean amplitudes
(±standard error, SE) of N18, P32, N54 and N86 components in response to the standard stimulus. (For interpretation of the references to colour in this figure legend, the reader is
referred to the Web version of this article.)
 J. Jalewa et al. / Hearing Research 399 (2021) 107992
magnitudes of change and one interpretation is that the dynamic
range with which the brain can represent the environment is
reduced, suggesting that it is the lower ceiling (earlier asymptote),
responsible for reducing the dynamic range in schizophrenia in-
dividuals (Todd et al., 2012). While MMN reductions are not a
diagnostic biomarker of schizophrenia (Lavoie et al., 2019), they are
a biomarker of disease progression (Lavoie et al., 2018, 2019).
Overall, there exists a diminished modulation of MMN by factors
like the deviance difference/probability/jitter in schizophrenia and
being able to demonstrate these attributes in control rats, as
demonstrated here, is highly valuable in advancing research, as
such methodologies can be employed in future studies to validate
potential animal models of schizophrenia and to screen candidate
pharmacotherapies against them. However, to realise the full po-
tential of rodent MMRs as a pre-clinical tool, it will be important to
understand whether the factors deviance difference/probability/
jitter affect adaptation-dependent or -independent processes since
recent research has shown that it is the adaptation-independent (or
deviance detection) process that is impaired in schizophrenia
(Koshiyama et al., 2020).
With an increasing knowledge of the alterations occurring in
schizophrenia brain and evidences indicating cognitive impairment
as a prominent feature of schizophrenia, there has been a shift in
research towards the functional recovery in schizophrenia patients
(Schulz and Murray, 2016). Several reports have demonstrated that
attention is impaired in schizophrenia and these deficits have been
considered as a primary issue in the disease neuropathology
(Orellana et al., 2012; Shen et al., 2014; Salgado-Pineda et al., 2003).
Furthermore, schizophrenia patients are unable to respond
appropriately to an incoming stimulus due to lack of selection and
interpretation as well as their inability to shift and sustain attention
(Chudasama and Robbins, 2004). In order to develop new treat-
ments, the behavioural tasks need to hold cross-species validity so
that the potential for predictive validity of animal model studies
can be maximised. Therefore, another direction for future research
is to investigate the functional significance of MMRs in rats as found
in humans. Studies have found that task irrelevant auditory stim-
ulation results in behavioural distraction, demonstrated by
increased response times and decreased accuracy in task perfor-
mance. Using an auditory-visual cross modal distraction paradigm,
in which task relevant visual stimuli are preceded by task irrelevant
auditory standard or deviant tones, it has been suggested that
MMN reflects a potential mechanism capable of distracting ongoing
task performance (Berti, 2013). Previously, it has been suggested
that a genuine change detection mechanism is involved in trig-
gering attention switching (Escera et al., 2002). Moreover, distrac-
tion by a deviant sound is an important mechanism that enables
fast switches of attention to a potentially relevant stimulus and this
is considered as a basic mechanism of adaptation to environmental
changes (Berti, 2013).
In conclusion, we conducted systematic experiments to reveal
whether MMR in rats ‘maps on’ to human MMN with respect to the
response to changing stimulus parameters. It was found that rat
responses at two latencies (P32 and N54) showed the hypothesised
modulation in response to shifts in the ‘unexpectedness’ of the
deviant stimulus, how different it was from the standard, and how
often it was presented. Further, the jitter effect was found on N54
component only. Moreover, previous studies from the laboratory
have shown that between P32 and N54, N54 is the only one that
shows strong adaptation-independent deviance detection (Harms
et al., 2014) and is reduced by an NMDAR antagonist (another
attribute of human MMN) (Harms et al., 2018). These previous
findings from our group and the present results suggest that the
rodent MMR, particularly the N54 component measured in our
preparation, is highly ‘MMN-like’, and can be used in future animal
15
model studies (for instance, preclinical schizophrenia models) to
investigate the underlying mechanisms and pharmacology of
MMN. In sum, our results further support the potential of rodent
models in investigating MMN, whether it be to probe the neuro-
circuitry of the response, or to examine how disease-related per-
turbations of MMN are generated and how they can be ameliorated.
Acknowledgements
JJ is supported by a University of Newcastle Postgraduate
Research Scholarship, funded by the Australian government’s
Research Training Program. The research was funded by the
Australian National Health and Medical Research Council through a
project grant (APP1109283).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.heares.2020.107992.
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