Disturbed theta and gamma coupling as a potential mechanism for visuospatial working memory dysfunction in people with schizophrenia

Abstract

Working memory (WM) deficits have been repeatedly observed in people with schizophrenia (PSZ) and their unaffected biological relatives (REL). Given the apparent association with genetic liability for schizophrenia, WM deficits have been proposed as a potential endophenotype for the disorder. Abnormal neural responses during WM performance have likewise been observed in PSZ and REL and may reflect the expression of genetic liability for schizophrenia in brain function. Relatively recent investigations have examined the role of neural oscillatory activity during visuospatial WM function in healthy people, as well as dysfunction in psychopathology. This research was in part motivated by a neural model of WM proposed by Lisman and Idiart (Science 267:1512(Science 267: -1515(Science 267: , 1995 that delineated a mechanism for representing multiple stimuli within WM through systematic interactions between neural oscillations in the theta-and gamma-frequency ranges. Aberrant oscillatory activity in theta and gamma frequency ranges has since been proposed as a potential underlying factor in WM dysfunction in PSZ and REL. The experimental evidence derived from studies of healthy people that pertains to the theta-gamma model of WM is reviewed herein. Although scarce, direct examinations of theta-gamma interactions in PSZ and REL are likewise reviewed in addition to reports of separate deficits in theta and gamma frequencies observed in PSZ during WM. The implications of theta and gamma oscillatory deficits reported in PSZ are discussed in the context of the Lisman and Idiart (Science 267:1512(Science 267: -1515(Science 267: , 1995 model, as well as how these deficits may result in aberrant theta-gamma interactions that give rise to visuospatial WM dysfunction. Given evidence supporting the Lisman and Idiart (Science 267:1512(Science 267: -1515(Science 267: , 1995 model of theta-gamma interactions in WM and the lack of direct exploration of the model in schizophrenia, there is an imperative to carry out formal testing of theta-gamma interactions in PSZ and REL during WM.

Abnormal cortical neural synchrony during working memory in schizophrenia

“…During encoding of visual objects into WM the increase in theta oscillations (i.e., ERS from 3–7 Hz in 60–240 ms period after model stimulus onset) was observed in most prefrontal-posterior cortical regions, indicating that encoding not only required visual cortical processes but also prefrontal cortical activity. It has been hypothesized that theta oscillations enable encoding of multiple items into WM (Sauseng et al, 2010) and that these processes are impaired in schizophrenia (for a review see Lynn and Sponheim 2016). The theta synchrony patterns were somewhat different between the visual and prefrontal cortical regions.…”

“…Results of the present study have implications for neurobiological models of schizophrenia that describe how abnormal oscillations in neuronal populations lead to disruptions in cognitive functions such as WM. Recent experimental evidence points to how processes central to WM may be mediated through temporal interactions between cortical rhythms of low (theta and delta) and high (gamma) frequencies across a variety of cortical regions and involve the relative timing of oscillations (Carracedo et al, 2013; Roopun, 2008), and that such processes may underlie impairment in WM in schizophrenia (Lynn and Sponheim, 2016). Inhibitory interneurons may have crucial roles in modulating the temporal dynamics of neuronal rhythms, and abnormal cellular and molecular markers in PSZ suggest malfunction of cortical inhibitory interneurons in the disease (see Pittman-Polletta et al, 2015 for review).…”

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

“…Both gamma and theta oscillations are observed independently in the cortex and hippocampus but they are also coupled to each other [9] . Aberrant theta-gamma coupling can affect cognitive function in schizophrenia, such as visuospatial working memory [33] . In addition, ketamine, a pharmacological agent often to create animal models of schizophrenia, has been shown to alter gamma-theta oscillatory coupling in the hippocampus [34] .…”

Working Memory and Cross-Frequency Coupling of Neuronal Oscillations

“…The phase-amplitude coupling (PAC) is a widely observed model of CFC in which the high-frequency amplitudes are modulated by the low-frequency phases (Canolty and Knight, 2010 ; Siems and Siegel, 2020 ). Abnormal CFCs have been reported by several studies conducted in patients with Parkinson's disease, Alzheimer's disease (AD), schizophrenia, mental disorders, and anxiety (Allen et al, 2011 ; De Hemptinne et al, 2013 ; Alegre, 2016 ; Lynn and Sponheim, 2016 ; Wang et al, 2017 ). The neural modulations/entrainments are classically divided into three approaches: sensory, non-invasive electrical/magnetic, and invasive electrical entrainment (Thut and Miniussi, 2009 ; Calderone et al, 2014 ; Herrmann et al, 2016 ; Hanslmayr et al, 2019 ).…”