What Does This Mean for Biomarkers of Schizophrenia-Spectrum
Disorders?
In surveying the SSD literature, a patchy pattern emerges: biomarkers
associated with auditory SM (particularly the MMN) andvisual WM in individuals with schizophrenia have been examined in
detail and appear to be related to symptom severity. In contrast, the
complement, visual SM and auditory WM, receive less attention. Progress
is also hampered because there is little work conducted in SSD apart
from those with a schizophrenia diagnosis. Diagnosed individuals often
have comorbid diagnoses and require medications which can obscure the
relationship between symptoms and biomarkers. To gain a foothold in the
untapped areas (see Table 1), we argue that filling in the missing cells
(visual SM, auditory WM) across SSD will accelerate the pace of data
collection and expedite our ability to distinguish between competing
theoretical perspectives. A final deficiency is that apart from the
auditory MMN, there is little consistency in methodology, making studies
difficult to generalize across. The standardization of auditory MMN
procedures may be one of the reasons why the auditory MMN is one of the
more compelling biomarkers of schizophrenia.
Our goal is to make clear that countering these oversights may improve
the identification and characterization of useful biomarkers to better
assess and mitigate SSD. For many researchers, including ourselves,
gaining access to substantial clinical populations is improbable.
Testing special populations, especially those with psychosis, impose
ethical and practical difficulties with regards to care and consent. In
contrast, evaluating subclinical populations provides a useful option in
investigating SSD. It is also a conservative approach because those with
high schizotypy are expected to show smaller, more modest effects than
those with psychiatric diagnoses. As noted, perceptually, the auditory
MMN is the best studied biomarker associated with schizophrenia and
abnormalities persist across SSD, including in the subclinical
population. In visual WM, the range of analyses is more varied without
commitment to a particular biomarker of SSD. The absence of clear
biomarkers associated with the complementary areas of visual SM and
auditory WM make for a puzzling circumstance. Assuming a
similar pattern of sensory and working memory abnormalities in
schizotypy to those found in diagnosed schizophrenia, focusing on
schizotypy can help identify causal mechanisms that are linked to
symptom severity. In short, we encourage ERP research in auditory and
visual SM, and auditory and visual WM, preferably in the same clinical
individuals as much as possible, and across SSD and subclinical
populations.
How Could Biomarkers of Symptom Severity Improve Clinical
Outcomes?
One goal of documenting behavioral deficits and associated biomarkers of
symptom severity in schizotypy is to improve clinical outcomes,potentially by identifying appropriate treatments related
to the underlying mechanisms . Biomarkers could also document a
patient’s progress, such as improvements of deterioration over time, and
potentially identify the mechanism of improvement. For example, there is
growing evidence that sensory training methods can improve cognition in
schizophrenia. Auditory training methods that require learning to
discriminate between different frequency modulated sweeps improve
auditory processing speed (Biagianti et al., 2016) and executive
functioning (Dale et al., 2016). Extending this observation,
multisensory (visual and audio) training on three simultaneity judgment
tasks reduced the temporal binding window in a neurotypical group, with
effects lasting seven days. The multisensory versions had bigger effects
than the unisensory versions. Training duration had little effect on
improvements in the temporal binding window (Zerr et al., 2019). A
review of sensory-targeted cognitive training methods found consistent
improvements in multiple areas of cognition (Donde, Mondino, et al.,
2019), including WM (Hubacher et al., 2013; Lawlor-Savage & Goghari,
2014). If the early auditory signal is improved, this would benefit
later auditory processing. However, benefits were short-lived and
time-intensive. One theorized mechanism of sensory training is that it
induces neural plasticity, providing a window to normalize sensory and
cognitive functioning. Indeed, Donde et al. (2019) reviewed biomarkers
of schizophrenia that normalized after sensory training. They
highlighted that training imposes no known side effects and it
may provide a more holistic approach to reducing schizophrenia
symptomatology. Others note that ignoring sensory issues creates an
informational “bottleneck” that hampers patients’ ability to improve
cognitive functioning (Genevsky et al., 2010). Training in processing
speed showed greater improvements across cognitive abilities compared to
narrow effects after WM training (Cassetta et al., 2019). Improving
low-level sensory processing benefits upstream processing, but more work
is essential to determine which approach best alleviates symptoms.