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Neurophysiological biomarkers for drug development in schizophrenia

Key Points

  • 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.

Abstract

Schizophrenia represents a pervasive deficit in brain function, leading to hallucinations and delusions, social withdrawal and a decline in cognitive performance. As the underlying genetic and neuronal abnormalities in schizophrenia are largely unknown, it is challenging to measure the severity of its symptoms objectively, or to design and evaluate psychotherapeutic interventions. Recent advances in neurophysiological techniques provide new opportunities to measure abnormal brain functions in patients with schizophrenia and to compare these with drug-induced alterations. Moreover, many of these neurophysiological processes are phylogenetically conserved and can be modelled in preclinical studies, offering unique opportunities for use as translational biomarkers in schizophrenia drug discovery.

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Figure 1: This figure reflects the multiple brain regions implicated in schizophrenia, and source of likely generators for specific biomarkers used in the study of schizophrenia.
Figure 2: Schematic diagram of mismatch negativity (MMN) generators in schizophrenia.
Figure 3: Visual P1 deficit in schizophrenia using local autoregressive average (LAURA) model.
Figure 4: Time/frequency domain electroencephalography measures from a control subject and a patient with chronic schizophrenia.
Figure 5: Cortical response variability is increased in patients with schizophrenia.
Figure 6: Components of the smooth pursuit eye movements: the underlying neural circuit.

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Acknowledgements

This work was supported in part by K02 MH01439 and R01 MH49,334 (D.C.J.), R03 MH76,760 and a NARSAD Young Investigator Award (K.M.S.), and RO1 MH-49826 and RO1 MH-67,014 (G.K.T.). The authors wish to thank E. Saccente for her technical assistance.

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Correspondence to Mihály Hajós.

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DATABASES

OMIM

Schizophrenia

FURTHER INFORMATION

National Institute of Mental Health — Schizophrenia

Glossary

Local field potential

The summed postsynaptic potentials recorded from neurons neighbouring a microelectrode.

Prepulse inhibition

(PPI). Prepulse inhibition is a measure of sensory gating in which a weak prestimulus (prepulse) reduces the startle response elicited by a subsequent intense auditory stimulus.

P50

An early auditory potential reflecting initial sensory activation. P50 gating refers to the decreased P50 amplitude to the second stimulus in a paired click compared to the first.

Prodromal symptoms

Symptoms that arise before the onset of fully diagnosed schizophrenia.

Perceptual feature binding

The process(es) by which elemental sensory information is combined into the representation of a perception, for example, a visual object.

Magnocellular system

In the primate visual system, the magnocellular system is specialized for rapid conduction of low resolution visual representations and motion information.

Parvocellular system

In the primate visual system, the parvocellular system is for slow conduction of high resolution visual representations and colour.

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Javitt, D., Spencer, K., Thaker, G. et al. Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov 7, 68–83 (2008). https://doi.org/10.1038/nrd2463

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