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.