Neurophysiological models for new treatment development in schizophrenia: early sensory approaches

Abstract

Schizophrenia is a major mental disorder associated with core neurocognitive impairments. The ability to recreate these deficits in animal models is limited, hampering ongoing translational drug development efforts. This paper reviews the use of electroencephalography (EEG)-based neurophysiological measures, such as event-related potentials (ERPs) or event-related spectral perturbations (ERSPs), as novel translational biomarkers for both etiological and treatment development research in neuropsychiatry. In schizophrenia, cognitive impairments manifest as deficits not only in high-level processes, such as working memory or executive processing, but also as deficits in neurophysiological responses to simple auditory and visual stimuli. Moreover, neurophysiological responses can be assessed even in untrained animals and are therefore particularly amenable to translational, cross-species investigation. To date, several sensory-level ERP measures, including auditory mismatch negativity and N1, and visual P1 and steady-state responses, have been validated in both human clinical investigations and animal models. Deficits have been tied to impaired neurotransmission at N-methyl-d-aspartate-type glutamate receptors (NMDARs). Time-frequency analysis of ERSP permits further extension of these findings from physiological to circuit/cellular levels of analysis.

Keywords: N-methyl-d-aspartate receptor; auditory; event-related potentials; glutamate; mismatch negativity; visual.

Figure 1

Schematic illustration of the utility of event-related potentials (ERP) and event-related spectral perturbations (ERSP) for translational investigation in neuropsychiatric disorders, relative to levels of analysis proposed for the NIMH Research Domain Criteria (RDoC) initiative.

Figure 2

Summary of MMN findings in humans and monkeys, showing convergence of findings and underlying generators. (A) Head map of mismatch negativity (MMN) for indicated types of deviants (DEV) in schizophrenia. (B) Correlation between years of education completed and MMN amplitude. (C–D) Example of current source density (CSD) response profiles to tones presented either as repetitive standards (STD) or as DEV in an auditory oddball paradigm. (E) Subtraction waveforms for stimuli presented as DEV versus stimuli presented as standards showing MMN-related activity in superficial cortical layers (F) Supragranular response to DEV and standard stimuli, relative to lamina IV response.

Figure 3

Summary of evidence linking impaired MMN generation to NMDAR dysfunction in both animal and human challenge studies. (A) Effects of intracortical phencyclidine (PCP) administration on MMN-related activity in superficial layers of auditory cortex. (B) Effects of ketamine on MMN generation in healthy controls. Shaded areas represent pre- minus post-ketamine difference. (C) Schematic model of MMN generation.

Figure 4

Utility of auditory N1 as a translational measure. Auditory N1 generation as a function of interstimulus interval in (A) schizophrenia patients versus healthy control subjects; (B) Cebus monkeys pre- and post-PCP administration. (C) Relationship between surface (Surf) and intracranial current source density (CSD) responses for the monkey P25 and N40 responses as a function of interstimulus interval from supragranular and infragraular cortical layers.

Figure 5

Summary of evidence linking auditory P1/N1 response to NMDAR function. (A) Intracranial current source density profiles showing intracranial correlates of the surface P1 and N1 potentials. (B) Effect of PCP administration on ISI-dependent processing within indicated cortical layers.

Figure 6

Summary of visual ERP findings in Sz relative to underlying neuropharmacological models. Scalp amplitude of visual ERP responses to (A) high– and (B) low–spatial frequency stimuli in schizophrenia patients and healthy controls. Arrows show deficits in C1/P1 generation to low spatial frequency stimuli. (C) Response function in retinal ganglion cells showing nonlinear versus linear response curves for magnocellular (M) versus parvocellular (P) cells, respectively. (D) Nonlinear gain curves from the cat lateral geniculate nucleus, showing effects of the NMDAR antagonist 2-amino-5-phosphonovaleric acid (APV) on response curves. For corresponding response curves in schizophrenia, see Ref. .