Neurophysiological biomarkers for drug development in schizophrenia

Abstract

Patients with schizophrenia show numerous aberrant neurophysiological signals that reflect abnormal brain functions. Recent advances in neurophysiological techniques provide more extensive and sophisticated measures to evaluate these anomalies, and present unique opportunities for use as translational biomarkers. Neurophysiological signals are analysed by two complementary methods: brain activations are viewed as a series of amplitude deflections that vary in time and space over the scalp, and brain activations are viewed as a sum of superimposed oscillations. Abnormal neurophysiological signals in schizophrenia include the mismatch negativity, the auditory and visual P300 event-related potentials, and sensory-evoked potentials such as the auditory N1 and the visual P1. A deficit of smooth-pursuit eye movement is also present in patients with schizophrenia. Measurement of neuronal synchrony by various electroencephalography data-analysis techniques has revealed anomalous neuronal network oscillations in response to sensory stimuli and during cognitive brain activities. Deficits have been reported in gamma band and beta band oscillations, as well as in slower frequencies. Some of these neurophysiological measures are abnormal not only in schizophrenia, but also in other psychiatric and neurological disorders, such as bipolar disorder, autism, attention-deficit/hyperactive disorder and Alzheimer's disease. These findings reflect impairments in neuronal network activities underlying brain dysfunction shared by different CNS illnesses. Several neurophysiological measures established in humans have been replicated in laboratory animals. Most importantly, these animal models can also reproduce disease-relevant pathophysiology. Various neurotransmitter systems (such as dopamine, GABA (γ-aminobutyric acid), glutamate and acetylcholine) and receptors — including DA₂, NMDA (N-methyl-D-aspartate), α7 nicotine and cannabinoid receptors — are implicated in abnormalities associated with schizophrenia. Modelling neurophysiological abnormalities of schizophrenia in preclinical studies offer additional options to evaluate the involvement of these neurotransmitter systems, and could reveal novel, potential therapeutic drug targets. Being phylogenetically conserved and easily quantifiable, electrophysiological signals offer exceptional translational biomarker opportunities.