Cross-Species Neurophysiological Biomarkers of Attentional Dysfunction in Schizophrenia: Bridging the Translational Gap

There has been a fundamental failure to translate preclinically-supported compounds into novel psychiatric treatments. That failure has been driven by a lack of suitable animal models of disease with concomitant biomarkers of neural-circuit function across species (Young and Geyer, 2015). Electroencephalographic (EEG) biomarkers of behavioral performance are direct assays of neural system functioning with compelling opportunity for cross-species translation (Featherstone et al, 2015). The recently developed 5-choice continuous performance test (5C-CPT) provides an example for integrating behavioral outcomes and neurophysiological biomarkers. Designed to quantify cognitive control (attention) and response inhibition in rodents and humans, the 5C-CPT has demonstrable cross-species validity including; (a) 36 h sleep deprivation-induced deficits; (b) amphetamine-induced improvement; (c) parietal requirement for performance from human fMRI and rodent lesion studies; and (d) vigilance decrement observations across time (Cope and Young, 2017). Importantly, this task is also clinically sensitive as patients with schizophrenia exhibit deficient performance (Young et al, 2017).

Until recently, it was unclear whether attentional deficits in schizophrenia patients corresponded to altered EEG biomarkers. Early evidence suggested attentional deficits in patients with abnormal EEG markers, with the latter also seen in unaffected relatives. This effect was limited however, and focused around sensory event related potentials (ERPs; P1 and N1), perhaps as a result of using the degraded stimulus CPT that places demands on perceptual processing. In contrast to other widely used human continuous performance tasks, the 5C-CPT places less of a burden on perception or other cognitive domains. In schizophrenia patients performing the 5C-CPT, we identified decreased amplitude of N2 and frontal non-target P3 ERPs compared with healthy subjects (Young et al, 2017). We have also observed that poorly performing healthy subjects exhibited: (1) reduced frontal non-target P3 amplitudes; (2) had higher response disinhibition; (3) this deficit was reversible using the frontally specific dopamine degradation blocker tolcapone; which (4) reduced the response disinhibition of these subjects (Bhakta et al, Accepted). Hence, the reduced frontal non-target P3 of healthy humans and their response inhibition was remediated with a frontal-specific treatment. Human and animal EEG studies have identified activation decrements in similar regions within the attentional network, concurrent with regions identified via fMRI studies. Studies are currently ongoing to determine whether mice similarly exhibit frontal non-target P3 EEG measures during 5C-CPT performance.

Future studies utilizing the 5C-CPT and other novel cross-species behavioral assays (eg, (Bismark et al, 2017)) aim to bridge the translational gap that limits the development of CNS therapeutics. These new tests also enable cross-species assessment of the contribution of genetic disease models to the attentional and neurophysiological abnormalities observed in neuropsychiatric patients. With greater predictive validity, drugs targeting such cognitive dysfunction are likely to prove more efficacious in psychiatric conditions. Thus, the attentional/EEG work in the 5C-CPT is an example of the ability to bridge the translational pharmacotherapeutic development divide.

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Acknowledgements

We thank Drs Bhakta, Bismark, Brigman, Cavanagh, and Swerdlow as well as Mr Sharp for the continued support in this project.

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Young, J., Light, G. Cross-Species Neurophysiological Biomarkers of Attentional Dysfunction in Schizophrenia: Bridging the Translational Gap. Neuropsychopharmacol. 43, 230–231 (2018). https://doi.org/10.1038/npp.2017.218

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