Neurophysiological Biomarkers Informing the Clinical Neuroscience of Schizophrenia: Mismatch Negativity and Prepulse Inhibition of Startle

Abstract

With the growing recognition of the heterogeneity of major brain disorders, and particularly the schizophrenias (SZ), biomarkers are being sought that parse patient groups in ways that can be used to predict treatment response, prognosis, and pathophysiology. A primary focus to date has been to identify biomarkers that predict damage or dysfunction within brain systems in SZ patients, that could then serve as targets for interventions designed to “undo” the causative pathology. After almost 50 years as the predominant strategy for developing SZ therapeutics, evidence supporting the value of this “find what’s broke and fix it” approach is lacking. Here, we suggest an alternative strategy of using biomarkers to identify evidence of spared neural and cognitive function in SZ patients, and matching these residual neural assets with therapies toward which they can be applied. We describe ways to extract and interpret evidence of “spared function,” using neurocognitive, and neurophysiological measures, and, suggest that further evidence of available neuroplasticity might be gleaned from studies in which the response to drug challenges and “practice effects” are measured. Finally, we discuss examples in which “better” (more normal) performance in specific neurophysiological measures predict a positive response to a neurocognitive task or therapeutic intervention. We believe that our field stands to gain tremendous therapeutic leverage by focusing less on what is “wrong” with our patients, and instead, focusing more on what is “right”.

Developing Schizophrenia

“…Fillman, Sinclair, Fung, Webster, & Shannon Weickert, 2014) both diagnoses can be subsumed within the broad category of psychosis, other diagnostic reconfigurations are also appearing: for example, a meta-analysis by the Cross Disorder Group of the Psychiatric Genetics Consortium (2013) claimed to identify putative genetic influences operating equally with respect to diagnoses of schizophrenia, bipolar disorder, major depression, autism and ADHD. An alternate strategy involves leaving diagnosis largely unquestioned but adopting different bioscientific research strategies: Light & Swerdlow (2014) propose using biomarkers to identify unimpaired neural and cognitive function amongst people given a schizophrenia diagnosis; using drug challenges and practice effects to identify areas of continuing neuroplasticity; and monitoring therapeutic progress in these areas using neurophysiological measures such as prepulse inhibition of startle.…”

Electroencephalographic Biomarkers of Psychosis: Present and Future

“…Although the relative novelty, complexity, and computational demands of independent component analysis have limited its rate of adoption in EEG studies of clinical populations (4,5), we have recently demonstrated that auditory deviance response measures, applied to cortical source activities derived from independent component analysis decomposition, can offer more detailed characterization of SZ group and individual deficits than single-channel measures, accounting for substantial portions of variance in multiple measures of clinical, cognitive, and psychosocial functioning. Source-resolved EEG measures also show promise for use in psychiatric diagnosis (5-7) and in genomic analysis (8,9).…”

“…A strategy for "translating" findings from psychiatric neuroscience to inform treatments in real-world settings involves rational use of evidence about individual subjects obtained from biomarkers to select appropriate treatments (6,8). Given the abundance of evidence of auditory system dysfunction in chronic psychotic illness (e.g., auditory hallucinations, impaired auditory attention and working memory, verbal learning and memory), interventions based on tuning the fidelity and accuracy of auditory information processing may dramatically improve cognition in SZ (10).…”

“…To this end, we recently found that the auditory mismatch negativity and later peak features of responses to unattended auditory oddball stimuli predict response to initial exposure to auditory training and are sensitive and early indices of sensory "engagement." We can envision a future in which EEG information in conjunction with other demographic, clinical, and genetic predictors may be used both to improve the identification of individuals at clinical risk for developing psychosis and to inform assignment of interventions that are most likely to provide therapeutic benefits (6,8,11).…”

“…Although it appears that electrophysiologic data, noninvasively recorded from the scalp, has tremendous promise for yielding "actionable" biomarkers of individual psychiatric status (8), much work is required to ensure their effective application in clinical settings. Given the low base rate of psychosis in the general population and the current movement toward implementing screening procedures in schools and clinics, obstacles to potential employment of EEG biomarkers (e.g., false-positive findings) are certain to arise.…”