Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition

Abstract

Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N = 27 schizophrenia patients and N = 28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.

Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

“…Each of these deficits contributed to reductions in signal integrity. Consistent with the inverted-U input-output relationship (figure 2), increases in resting activation would be predicted to reduce the task related signal by recruiting inhibition (66), consistent with findings with ketamine effects in healthy humans and studies of schizophrenia patients (31, 104, 105, 142, 143). Further, the hyperactivity of networks may recruit homeostatic adaptations that downregulate synaptic functional connectivity (figure 1), further impairing the capacity of networks to generate signals.…”

“…Schizophrenia appears to be associated with an “inverted-U” working memory load-dependent pattern of prefrontal activation; with increased magnitude and spatial extent of activation under conditions of low demand and activation deficits with higher working memory load (8, 103–105). Schizophrenia patients also show reduced working memory span (buffer size) and precision (104, 106, 107), but perhaps not universally (108). The reduction in working memory precision is, in itself, one form of distortion in the mnemonic representation of information.…”

“…The reduction in working memory precision is, in itself, one form of distortion in the mnemonic representation of information. Further, the reduction in mnemonic precision would be predicted to render memories more vulnerable to distortion or contamination (104), i.e., the generation of false memories, distorted beliefs, or delusions (109–111). As a result, pharmacotherapies that reduce glutamate release, such as mGluR2 agonists, might improve working memory function (95, 112) and treat psychosis (80).…”

Parvalbumin-containing GABA cells and schizophrenia: experimental model based on targeted gene delivery through adeno-associated viruses

“…Our approach of back-translation from the human SZ, in which the cellular basis of working memory failures appears to involve a lack of persistent firing of principle neurones in prefrontal regions (Fuster, 1997; Jones and Wilson, 2005; Benchenane et al ., 2010), also accounts for the observation that SZ pathology is found as a lowering in cellular markers for PV-GABAergic cells (see Introduction section for details). A particular role is played by the GABAergic circuitry, which applies inhibition to the otherwise persistent activity of principal cells, such that an optimal excitation/inhibition balance is achieved and selective cortical brain rhythms are established (Starc et al ., 2017). The rhythmic inhibition by PV-GABA cells entrains PFC with highly synchronous gamma oscillations and these may provide a physiological marker for the working memory process (Powell et al ., 2012).…”

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

“…Meta-analyses report mainly negative findings for delay-dependent accuracy impairments in schizophrenia and ketamine studies 6,23 (but see ref. 24 ). We calculated the circular standard deviation of bias-corrected…”