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.

Pupillometry provides an accessible option to track working memory processes with high temporal resolution. Several studies showed that pupil size increases with the number of items held in working memory; however, no study has explored whether pupil size also reflects the quality of working memory representations. To address this question, we used a spatial working memory task to investigate the relationship of pupil size with spatial precision of responses and indicators of reliance on generalized spatial categories. We asked 30 participants (15 female, aged 19-31) to remember the position of targets presented at various locations along a hidden radial grid. After a delay, participants indicated the remembered location with a high-precision joystick providing a parametric measure of trial-to-trial accuracy. We recorded participants' pupil dilations continuously during task performance. Results showed a significant relation between pupil dilation during preparation/early encoding and the precision of responses, possibly reflecting the attentional resources devoted to memory encoding. In contrast, pupil dilation at late maintenance and response predicted larger shifts of responses toward prototypical locations, possibly reflecting larger reliance on categorical representation. On an intraindividual level, smaller pupil dilations during encoding predicted larger dilations during late maintenance and response. On an interindividual level, participants relying more on categorical representation also produced larger precision errors. The results confirm the link between pupil size and the quality of spatial working memory representation. They suggest compensatory strategies of spatial working memory performance-loss of precise spatial representation likely increases reliance on generalized spatial categories.

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Sustained neural activity during the delay phase of spatial working memory tasks is compelling evidence for the neural correlate of active storage and maintenance of spatial information, however, it does not provide insight into specific mechanisms of spatial coding. This activity may reflect a range of processes, such as maintenance of a stimulus position or a prepared motor response plan. The aim of our study was to examine neural evidence for the use of different coding strategies, depending on the characteristics and demands of a spatial working memory task. Thirty-one (20 women, 23 ± 5 years) and 44 (23 women, 21 ± 2 years) participants performed a spatial working memory task while we measured their brain activity using fMRI in two separate experiments. Participants were asked to remember the position of a briefly presented target stimulus and, after a delay period, to use a joystick to indicate either the position of the remembered target or an indicated non-matching location. The task was designed so that the predictability of the response could be manipulated independently of task difficulty and memory retrieval process. We were particularly interested in contrasting conditions in which participants (i) could use prospective coding of the motor response or (ii) had to rely on retrospective sensory information. Prospective motor coding was associated with activity in somatomotor, premotor, and motor cortices and increased integration of brain activity with and within the somatomotor network. In contrast, retrospective sensory coding was associated with increased activity in parietal regions and increased functional connectivity with and within secondary visual and dorsal attentional networks. The observed differences in activation levels, dynamics of differences over trial duration, and integration of information within and between brain networks provide compelling evidence for the use of complementary spatial working memory strategies optimized to meet task demands.