Sensory Memory in Schizophrenia Spectrum
Disorders
Sensory memory (SM) refers to the window over which the neural response
to a sensory stimulus remains active after the stimulus is withdrawn.
The duration of the memory trace is brief (e.g., (Sperling, 1960) and
considered to be preattentive (Naatanen et al., 1982). Measures of SM
are appealing as a clinical biomarker because they are unaffected by
attentional focus - which is compromised in schizophrenia. The SM trace
is an input for predictive coding and very sensitive to changes in
sensory stimuli (Winkler, 2007; Winkler et al., 2009). It is also
extremely adaptive to the current environment (May & Tiitinen, 2010;
May & Tiitinen, 2007). Abnormal SM in those with schizophreniamay be domain general (Neuhaus et al., 2013; Saint-Amour et al.,
2007). To date the most research has been conducted in audition and
vision, although sensory memory in the somatosensory and olfactory
domains is reduced in schizophrenia (Somatosensory: (Ludwig et al.,
2016) Haigh et al., 2016; Olfactory: (Moberg et al., 2003; Wu et al.,
1993)) and can be tracked using similar methods to vision and audition
(Restuccia et al., 2009). Despite the numerous reports of oculomotor
dysfunction in schizophrenia and SSD, relatively little has been
reported in visual SM. We will now discuss each in turn.
Auditory Sensory Memory
Poor auditory SM impairs the encoding of simple parameters of sounds.
Neural measures of auditory SM are a clinically useful biomarker.
They are minimally affected by attention and can be measured before the
participant is aware of the percept, thereby isolating early sensory
processing from upstream cognitive processes.
In people with schizophrenia there are numerous examples of deficits in
auditory SM, including impaired pitch discrimination (distinguishing
between tones of different pitches; (McLachlan et al., 2013), tone-pair
matching (Rabinowicz et al., 2000), sound localization (Donde et al.,
2020; Donde, Martinez, et al., 2019), discrimination of intensity,
duration and sequences (Schnakenberg Martin et al., 2018) and auditory
scene segregation (Ramage et al., 2012; Weintraub et al., 2012).
Moreover, there is evidence that mismatch negativity amplitude is lower
in those with schizophrenia, reflective of a general auditory sensory
memory deficit (Catts et al., 1995), lower educational achievement
before the onset of schizophrenia, worse cognitive symptoms, poorer
global function, and longer duration of illness (Friedman et al., 2012).
There is some question over whether these abnormal auditory responses
are due to sensory memory or if they are due to problems encoding
the information in the first place. While it is difficult to disentangle
how poor early encoding impacts the ability to encode short-term memory
traces, there is evidence that both individuals with chronic
schizophrenia and individuals at their first-episode of psychosis show
deficits in encoding deviants in complex patterns (Haigh et al., 2016;
Haigh, Coffman, et al., 2017; Salisbury et al., 2018), suggesting that
memory impairments persist after encoding. However, other aspects of
audition are preserved, including the time-course of auditory SM (March
et al., 1999) and the ability to categorize syllables (Dale et al.,
2010; Haigh et al., 2019). Categorization can also show the expected
shifts when participants are habituated to one syllable (for example,
adapting to one syllable category makes it easier to detect a syllable
in another category) (Haigh et al., 2019) suggesting residual plasticity
in the auditory system. Finally, more closely associated with specific
symptoms of schizophrenia, auditory hallucinators reporting phenomenon
of speech and voices exhibit worse auditory SM (McCleery et al., 2018),
highlighting the link between auditory processing and symptomology.
There is evidence of similar, but smaller, SM abnormalities in
schizotypy that are similar to those reported in schizophrenia. However,
the number of studies focusing on schizotypy are relatively small and
often identify potential biomarkers in isolation. For example, sensory
cortices send a ‘corollary discharge’ indicating a self-generated
response compared to external in origin (Sperry, 1950). Auditory
corollary discharges are produced in the superior temporal gyri
(Creutzfeldt et al., 1989; Muller-Preuss & Ploog, 1981) and are
manifest by reduced auditory N1 ERP responses to self-generatedspeech compared to the N1 response to externally generated speech (Ford
& Mathalon, 2005). Individuals with schizophrenia show equivalent N1
amplitudes for self-generated and externally generated speech,
suggesting they cannot differentiate between conditions. Impaired
corollary discharge could reflect a confusion between self-generated
auditory hallucinations and externally generated speech (Ford &
Mathalon, 2005). In schizophrenia there is a reliable reduction in N1
amplitude (Salisbury, 2010; Shelley et al., 1999); reviewed in: (Rosburg
et al., 2008) that correlate with the perceptual deficit (Javitt et al.,
2000). Similarly, individuals with high schizotypy show equally large N1
responses to external and self-generated speech, whereas neurotypical
participants with low schizotypy show N1 suppression to self-generated
speech (Oestreich et al., 2016). Those high in schizotypy show reduced
precision in auditory sensory memory despite normal rates of acquisition
and decay (Bates, 2005).
In addition, reductions in well-characterized
cognitive-related ERPs in combination with sensory ERPs to simple
auditory stimuli have shown some utility. For example, reductions in the
P3 complex (Javitt et al., 1995; Pritchard et al., 1985), are evident
early in the disease course (Devrim-Ucok et al., 2016; Salisbury et al.,
2020), as are reductions in steady-state potentials (Light et al.,
2006), and in the slow-wave potentials associated with auditory scene
segmentation (Coffman et al., 2018; Coffman et al., 2017) that correlate
with hypoactive midcingulate cortex (Coffman et al., 2018). Reduced
amplitude of P50, mismatch negativity, P3, and antisaccades (making eye
movements in the opposite direction to a cue) are reported in
individuals with schizophrenia, and significant reductions in P50 and P3
in relatives, compared to controls. However, combining all four measures
in a multivariate analysis permitted the model to accurately (80%)
classify group assignment (Price et al., 2006). In short, throughout
early auditory sensory processing there are atypical ERPs in the
schizophrenia population. Further investigation in high schizotypy
individuals to expressly investigate auditory SM would be valuable to
understand the boundary conditions between intact and impaired function
in SSD.
Auditory Mismatch
Negativity
The most robust neural measure of SM is the mismatch negativity
(MMN). In neurotypical individuals, fronto-central electrodes record
larger (more negative) responses to an infrequent deviant stimulus than
to the standard stimulus at around 100-200ms after stimulus-onset
(Naatanen, 1985). The MMN is calculated by subtracting the EEG response
to the standard tone from response to the deviant tone producing a
difference waveform (Näätänen, 1985). In individuals with chronic
schizophrenia, the MMN is smaller (Cohen’s d: 0.99) (Javitt &
Sweet, 2015; Umbricht & Krljes, 2005), and magnetic activity in the
planum temporale (secondary auditory cortex) is reduced during auditory
SM tasks that generated a smaller (magnetic) MMN (Kircher et al., 2004).
Reduced MMN generalizes across stimuli (Erickson et al., 2016; Umbricht
& Krljes, 2005) and includes responses to pattern deviants based on
grouping (Haigh et al., 2016), pitch (Haigh, Matteis, et al., 2017),
rules (Haigh et al., 2019), and phonemes (Fisher et al., 2019).
In SSD the degree of MMN reduction correlates with symptom severity
(Fisher et al., 2019; Light & Braff, 2005). Greater reductions are
apparent in chronic schizophrenia compared to individuals at high-risk
(Shin et al., 2012). Local and global change detection have both been
found to be poor in schizophrenia suggesting evidence of abnormal
predictive coding that cannot be due to abnormal adaptation to simple
stimulus parameters (Kirihara et al., 2020). Together, these data
highlight a pervasive deficit in preconscious auditory SM that occurs
early in the auditory processing stream (Escera & Malmierca, 2014). MMN
is sensitive to the balance between excitatory and inhibitory
neurotransmitters in the auditory cortex (Holliday et al., 2018). There
is some debate regarding neurotransmitter systems’ roles in the auditory
MMN. Some evidence indicates a restored MMN with nicotinic agonists,
implicating acetylcholinergic modulation (Baldeweg et al., 2006) but see
(Knott et al., 2014), whereas other studies implicate acetylcholinergic
(Kantrowitz et al., 2018) or serotonergic influence (Sehatpour et al.,
2022).
In SSD more broadly, there is some evidence of reduced MMN. For example,
MMN to pitch oddballs successfully discriminates between neurotypicals
and people diagnosed with schizotypal personality disorder (Niznikiewicz
et al., 2009). Furthermore, combining MMN responses to multiple
deviants: duration, gap or silence instead of a tone, or location of
tone, lead to identification accuracy up to 80.5% when using
multivariate machine learning techniques. The combined MMN accuracy
correlated with global assessment of functioning, highlighting auditory
MMN as a biomarker of symptoms in chronic schizophrenia (Taylor et al.,
2017). MMN deficits are evident in early course schizophrenia (within
2-years of the first episode of psychosis; (Salisbury et al., 2007)).
There are inconsistent findings in those within 6-months of initial
psychosis (Erickson et al., 2016; Haigh, Coffman, et al., 2017), and in
those at-risk of developing schizophrenia (compare (Shin et al., 2012)
to (Hsieh et al., 2019)), or who are unaffected first-degree relatives
(Magno et al., 2008). Several accounts address why MMN deficits are
greater in those with advanced disease. One theory is that MMN is tied
to symptom severity (Kantrowitz et al., 2018), as MMN correlates with
negative symptoms in chronic (>5 years) patients (Catts et
al., 1995). Of relevance, the MMN correlates with negative
symptoms in first-episode patients, and with measures of social
functioning (Murphy et al., 2020). Certainly, individuals with chronic
schizophrenia have the most severe symptoms and neurological
consequences. For example, MMN correlates with reduced grey matter
volume in primary auditory cortex and both MMN deficits and the great
matter volume reductions increase with the duration of time past
first-episode (Salisbury et al., 2020; Salisbury et al., 2007). A recent
meta-analysis indicated that MMN shows progressively greater
abnormality, with first degree relatives showing the smallest deficit,
followed by individuals at high-risk of developing schizophrenia, and
finally recently diagnosed (early-stage schizophrenia), compared to
those with chronic schizophrenia (Erickson et al., 2016); Figure 3).