Working Memory Deficits in Schizophrenia Spectrum
Disorders
Working memory (WM) deficits are a canonical deficit in people with
schizophrenia (for reviews, (Forbes et al., 2009; Lett et al., 2014;
Reichenberg, 2010), those with high schizotypy (Siddi et al., 2017), and
those at high-risk of psychosis (Millman et al., 2022). WM impairments
are broad and include verbal (reviewed in (Seabury & Cannon, 2020),
visuospatial, and executive functioning aspects of WM (Barch & Ceaser,
2012; Forbes et al., 2009). It is worth noting that poor WM performance
in people with schizophrenia is associated with a variety of neural
differences including reduced gray matter volume (Du et al., 2022;
Kochunov et al., 2022), abnormal (hypo- and hyper-) connectivity
patterns (Ding et al., 2019; Du et al., 2022; Fryer et al., 2015;
Hashimoto et al., 2010; Schutte et al., 2021; Seabury & Cannon, 2020;
Unschuld et al., 2014), hypoactive clusters (Seabury & Cannon, 2020),
and abnormal oscillations (Reilly et al., 2018). At a lower level, one
account of the WM deficit in schizophrenia suggests that PFCinhibition is disrupted, leading to impaired WM (Meiron et al.,
2022). PFC inhibition is thought to be driven by abnormal interneuron
function, which in turn reduces gamma oscillation amplitude (Reilly et
al., 2018); see also (Toader et al., 2020). A challenge in specifying
underlying neural mechanisms of the WM deficit is that there is
variability across samples with different patterns emerging in
distinguishable subgroups (Rodriguez et al., 2019). Advances in
neuroimaging provide important future paths for identifying biomarkers
of working memory that reflect schizophrenia symptoms, and for producing
therapies to mitigate symptoms. In the paragraphs below, we specify the
findings specific to auditory and visual WM as a parallel to the
sections on auditory and visual SM above.
Auditory Working Memory
Auditory WM is impaired across SSD. Deficits are known in schizophrenia,
their first-degree relatives (Seidman et al., 2012; Seidman,
Pousada-Casal, et al., 2016), and in the high-risk population (Higuchi
et al., 2013; Rutschmann et al., 1980), as is verbal WM (Seabury &
Cannon, 2020). Importantly, this deficit is apparent even in
early-course schizophrenia (Gonzalez-Blanch et al., 2006) and is
associated with abnormal neural responses (Leicht et al., 2015;
Papageorgiou et al., 2001). Importantly, auditory WM performance
predicts the presence of auditory hallucinations (Gisselgard et al.,
2014; Jenkins et al., 2018). Therefore, similar to auditory SM, WM
deficits may be related to symptoms rather than onset of
psychosis.
Potential WM biomarkers are associated with altered neural function and
patterns of neural connectivity. The neural correlates of WM deficits
include the PFC (for a review, see (Hashimoto et al., 2010), and
relevant sensory cortices (e.g., (Javitt & Sweet, 2015; Menon et al.,
2001; Stevens et al., 1998). However, when investigating the neural
correlates associated with abnormal WM functioning in schizophrenia,
there is inconsistency. Several studies reported PFChyperactivity , whereas others reported the opposite (for a review
see (Leitman et al., 2005). Other brain areas implicated in WM retrieval
include parietal regions (for a review, see (Funahashi, 2017; Hamilton
et al., 2018; Olson & Berryhill, 2009). Parietal function is also
abnormal in schizophrenia particularly in those who hallucinate
(Hashimoto et al., 2010; Wible et al., 2009) and hypoactive temporal
lobe activity (Wible et al., 2009) correlates with schizophrenia symptom
severity (Menon et al., 2001). More recent analyses investigating
altered connectivity extend these regions-of-interest findings by
identifying network dysfunction. For example, increased dorsolateral and
medial PFC connectivity in those with schizophrenia and their
nonclinical first-degree relatives, compared to controls (Unschuld et
al., 2014), and within left superior frontal gyrus (Ding et al., 2019).
Several distinct patterns of hyper- and hypo- connectivity are
associated with deficits in verbal WM in people with schizophrenia –
including altered salience network (SN), default mode network (DMN), and
frontoparietal network (FPN) interactions (Rodriguez et al., 2019).
Together, there is a network-level deficit in schizophrenia that impacts
auditory WM.
Some evidence suggests auditory WM deficits are associated with other
auditory-related symptoms such as auditory hallucinations (Geng et al.,
2020; Gisselgard et al., 2014; Jenkins et al., 2018), and auditory
processing deficits (Moschopoulos et al., 2021). For example, deficits
in MMN to pitch deviants were related to deficits in prosody processing
(non-verbal communication of emotion) in individuals with schizophrenia
(Leitman et al., 2005) and P50 suppression in the auditory ERP
correlated with WM performance (Hamilton et al., 2018). Network
connectivity also identifies altered DMN activity associated with
auditory hallucinations (Geng et al., 2020). Finally, there is an
intriguing observation that the visual word form area engages during
auditory perception and WM in people with schizophrenia (Herman et al.,
2020), suggests that broadly altered structure and function underlies
auditory WM function.
Worse WM performance is implicated in schizotypy (Park & McTigue, 1997;
Siddi et al., 2017), particularly in those who displayed more positive
and negative symptoms (Schmidt-Hansen & Honey, 2009), and was
associated with worse communication abilities (Kerns & Becker, 2008).
It has also been suggested that poorer working memory performance may be
a biomarker for increased risk of developing psychosis due to the large
effect sizes shown in schizotypy (Siddi et al., 2017). However, there is
debate as to the robustness of the WM deficit (Lenzenweger & Gold,
2000) and whether the effect is due to impaired attentional ability,
with some evidence indicating dissociable deficits (Marsh et al., 2017).
In summary, abnormalities in auditory WM in schizophrenia are seen in
diminished form in individuals with high schizotypy. This supports the
idea that traits associated with schizophrenia are on a spectrum.
Notably, compared to the auditory SM research, there is remarkably
little research conducted on biomarkers of auditory WM deficits across
the SSD.
Visual Working Memory in Schizophrenia Spectrum
Disorders
A broad literature investigates visual WM deficits in people with
schizophrenia and related disorders. Deficits in object, spatial and
verbal WM are well-documented in review articles (e.g., (Barch, 2005;
Haenschel & Linden, 2011; Piskulic et al., 2007). Briefly, across
measures of accuracy, reaction time, and confidence, individuals with
schizophrenia broadly perform less accurately, more slowly, and less
confidently than neurotypicals. Impaired WM extends to the at-risk and
schizotypy populations. In the at-risk population, two recent
meta-analyses point to WM performance as reflecting symptom severity.
Overall cognition, attention, processing speed, and WM were found to be
significantly worse in those who were high-risk compared to healthy
controls using the MATRICS Consensus Cognitive Battery (MCCB; (Zheng et
al., 2018). Including both visual and auditory measures of working
memory and symptoms using the Schedules for Clinical Assessment in
Neuropsychiatry was able to distinguish between individuals diagnosed
with schizophrenia, their unaffected first-degree relatives, and
non-clinical individuals (Kent et al., 2004). Importantly, neural
accounts for the visual WM impairment note the contributing factor of
abnormal SM and atypical prefrontal function (e.g., (Haenschel &
Linden, 2011).
A few biomarkers are associated with visual WM in SSD. There is a lower
amplitude P100 (P1) responses over electrode site Oz in individuals with
schizophrenia (Haenschel et al., 2009), and in those with high
schizotypy (Koychev et al., 2010) to a visual delayed discrimination
task, highlighting the contribution of early sensory processing on later
cognition. Others report that schizophrenia participants have abnormal
theta power during n-back performance, and reduced P100 in response to
TMS pulses (Hoy et al., 2021). Importantly, atypical gamma oscillations
can be observed in first-episode psychosis (Missonnier et al., 2020).
Additional effects likely arise from gamma-band oscillatory activity
during WM tasks that fails to increase with increased WM load in those
with schizophrenia (Basar-Eroglu et al., 2007; Cho et al., 2006). A
second biomarker of encoding-related WM deficit is the N2pc, which is
also reduced in those with schizophrenia (Mayer et al., 2020). Broadly
atypical frontal lobe activations in at risk youth (van Gool et al.,
2022) and connectivity patterns are known across schizophrenia spectrum
disorders (Briend et al., 2020; Schmidt et al., 2014), and at risk
samples (Schutte et al., 2021).