Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia

Abstract

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Keywords: CP: Neuroscience; belief updating; lesion; mediodorsal thalamus; monkeys; orbitofrontal cortex; paranoia; probabilistic reversal learning task.

Figure 1.. A translational mapping of belief updating in monkeys and human participants

(A) A monkey and a human participant playing a three-choice PRL task, selecting from a set of three options and learning which is the best option, through trial and error, in an environment where the underlying reinforcement schedule changes periodically (i.e., reversals). (B) A model used to investigate how beliefs about changes in the environment influence decision-making. The graphical notation is adopted from a prior study; parameters of interest for this study are shaded in blue. (C) Integrating data between monkeys with targeted brain lesions and human participants with self-reported paranoia through computational models to identify links between neural circuits and psychopathology. MDmc, magnocellular mediodorsal thalamus; OFC, orbitofrontal cortex; wsr, win-switch rate; lsr, lose-stay rate; m₃, volatility belief; ω₂, value learning.

Figure 2.. Behavior of lesioned monkeys

(A) Illustrations of the anatomical brain lesion locations in monkeys, where the excitotoxic MDmc and OFC lesion locations are illustrated on standard coronal sections from a monkey brain atlas (Laboratory of Neuropsychology, National Institute of Mental Health). Prior studies show the actual lesion locations of the MDmc and OFC in individual monkeys.^, (B) Differences in win-switch behavior (left) and lose-stay behavior (right) for the lesion groups between pre-reversal and post-reversal phases. Top right: PRL behaviors over time (moving average across 20 lagged trials) of win-switch (left) and lose-stay (right) choices across lesion groups, with a reversal occurring after 150 trials. Each data point overlaid indicates an individual monkey’s data. Asterisks indicate significant effects of lesion group within each reversal phase (***p < 0.001, *p < 0.05; GLMM). Other symbols indicate significant effects of reversal phase within each lesion group (a, p < 0.001; +, p < 0.10).

Figure 3.. MDmc and OFC lesions differentially impact beliefs about volatility and value in monkeys

(A) Differences in volatility beliefs (m₃ parameter from the HGF model; higher values indicate greater volatility beliefs) for the lesion groups between the pre-reversal and post-reversal phases. (B) Differences in reward value learning (ω₂ parameter; higher values indicate more rapid learning about value) for the lesion groups between pre-reversal and post-reversal phases. Each data point overlaid indicates an individual monkey’s data. Asterisks indicate significant lesion group differences (***p < 0.001, **p < 0.01, *p < 0.05; GLMM). Other symbols indicate significant reversal phase differences in each lesion group (a, p < 0.001; c, p < 0.05; GLMM).

Figure 4.. Impact of the PRL task design on win-switch and lose-stay behavior and on beliefs about volatility and value in humans

(A) Win-switch and lose-stay behaviors in non-paranoid and paranoid human participants during a single-reversal (after 30 trials) three-choice PRL task. (B) Win-switch and lose-stay behaviors in non-paranoid and paranoid human participants during a multi-reversal (with a mid-way contingency shift after 80 trials) three-choice PRL task. Insets illustrate the effect of performance-based reversal (i.e., experience reversal upon 9 of 10 consecutive selections of the highest reinforcement probability deck) on trial-by-trial behavior in the multi-reversal task to show the similarity in the characteristic of task behavior in the single-reversal task versions. (C and D) Differences in beliefs about volatility (m₃ parameter from the HGF) and reward value learning (ω₂ parameter) in non-paranoid and paranoid human participants during a single-reversal three-choice PRL task (C) and during a multi-reversal three-choice PRL task (D). Asterisks indicate significant paranoia group differences (***p < 0.001, **p < 0.01; GLMM). Other symbols indicate significant reversal phase differences in each lesion group (a, p < 0.001; c, p < 0.05; GLMM).