Estimating changing contexts in schizophrenia

Abstract

SEE STEPHAN ET AL DOI101093/AWW120 FOR A SCIENTIFIC COMMENTARY ON THIS WORK: Real world information is often abstract, dynamic and imprecise. Deciding if changes represent random fluctuations, or alterations in underlying contexts involve challenging probability estimations. Dysfunction may contribute to erroneous beliefs, such as delusions. Here we examined brain function during inferences about context change from noisy information. We examined cortical-subcortical circuitry engaging anterior and dorsolateral prefrontal cortex, and midbrain. We hypothesized that schizophrenia-related deficits in prefrontal function might overestimate context change probabilities, and that this more chaotic worldview may subsequently gain familiarity and be over-reinforced, with implications for delusions. We then examined these opposing information processing biases against less expected versus familiar information patterns in relation to genetic risk for schizophrenia in unaffected siblings. In one experiment, 17 patients with schizophrenia and 24 normal control subjects were presented in 3 T magnetic resonance imaging with numerical information varying noisily about a context integer, which occasionally shifted up or down. Subjects were to indicate when the inferred numerical context had changed. We fitted Bayesian models to estimate probabilities associated with change inferences. Dynamic causal models examined cortical-subcortical circuitry interactions at context change inference, and at subsequent reduced uncertainty. In a second experiment, genetic risk for schizophrenia associated with similar cortical-subcortical findings were explored in an independent sample of 36 normal control subjects and 35 unaffected siblings during processing of intuitive number sequences along the number line, or during the inverse, less familiar, sequence. In the first experiment, reduced Bayesian models fitting subject behaviour suggest that patients with schizophrenia overestimated context change probabilities. Here, patients engaged anterior prefrontal cortex relatively less than healthy controls, in part driven by reduced effective connectivity from dorsolateral prefrontal cortex to anterior prefrontal cortex. In processing subsequent information indicating reduced uncertainty of their predictions, patients engaged relatively increased mid-brain activation, driven in part by increased dorsolateral prefrontal cortex to midbrain connectivity. These dissociable reduced and exaggerated prefrontal and subcortical circuit functions were accentuated in patients with delusions. In the second experiment, analogous dissociable reduced anterior prefrontal cortex and exaggerated midbrain engagement occurred in unaffected siblings when processing less expected versus more familiar number sequences. In conclusion, patients overestimated ambiguous context change probabilities with relatively reduced anterior frontal engagement. Subsequent reduced uncertainty about contextual state appeared over-reinforced, potentially contributing to confirmation bias and a cascade of aberrant belief processing about a more chaotic world relevant to delusions. These opposing cortical-subcortical effects relate in part to genetic risk for schizophrenia, with analogous imbalances in neural processing of less expected versus familiar information patterns.

Keywords: anterior prefrontal cortex; context; delusions; effective connectivity; schizophrenia.

See Stephan et al. (doi:10.1093/aww120) for a scientific commentary on this work. The uniquely human anterior prefrontal cortex weighs uncertain contextual beliefs, but its role in delusions is unclear. Kaplan et al. reveal how opposing changes in prefrontal and subcortical function in response to deviations from expectations versus more familiar information patterns may have relevance to delusions and genetic risk for schizophrenia.

Figure 1

Dynamic numerical inference task in Experiment 1. Subjects were presented with numbers varying stochastically (SD = 0.5) about an underlying integer (green) that was shown once at the beginning of each set. At a probabilistically defined point (hazard rate = 0.1), this underlying integer shifted up or down by one unit. Based on the deviation of the presented information from their belief about the underlying integer (prediction error), subjects indicated when they inferred a context change (C) has occurred. Subsequent reduction in prediction error (designated ‘feedback’, F) would further reduce uncertainty about this change. M = small prediction errors (<0.5) that support maintaining the belief of a relatively stable context; B = larger prediction errors (>0.5).

Figure 2

Behavioural performance in Experiment 1. (A) Patients with schizophrenia (SZ) responded with higher learning rates (P < 0.01) than controls. (B) Patients also perceived the average number of trials before a context change to be shorter (P < 0.02). (C) Mean Bayesian estimates of context change probabilities at C in patients and normal control subjects (NC) across trial events (320 trials on horizontal axis). Relative to normal control subjects, there was overestimation of modelled posterior probabilities of change in patients with schizophrenia (P < 0.001). Error bars are ± 1 standard error.

Figure 3

Task-related activation in Experiment 1. (A) When processing information perceived to infer a change in its underlying contextual structure (C), regions in the anterior PFC, dorsolateral PFC, parietal cortex, striatum and were engaged (n = 17 patients with schizophrenia and n = 24 normal control subjects, P < 0.05 FWE corrected). (B) Anterior PFC, DLFPC, parietal and striatal regions were engaged when processing subsequent information supporting the change decision (F) (P < 0.05 FWE corrected). (C) Dorsolateral PFC and parietal regions were engaged but relatively less robustly when processing information perceived to be consistent with maintenance of a stable context (M, P < 0.05 FWE corrected).

Figure 4

Activation at anterior PFC (APFC), dorsolateral PFC (DLPFC), and midbrain (MB) regions of interest across C and F task phases. Schizophrenia patients (SZ) had reduced anterior PFC engagement at C, but increased midbrain engagement at F (*t > 3, P < 0.05 small volume corrected). Error bars are ± 1 standard error. NC = normal control subjects.

Figure 5

Dynamic causal models. Bayesian model selection favouring an effective connectivity model (#4), where anterior PFC communicates with dorsolateral PFC; and dorsolateral PFC with parietal cortex and midbrain regions of interest. Task information inputs were at dorsolateral PFC and parietal cortex.

Figure 6

Prefrontal network effective connectivity in Experiment 1. (A) Processing information perceived to infer a change in its underlying contextual structure (C), patients with schizophrenia (SZ) had deficits in task-modulated cortical effective connectivity at parietal cortex (PAR), dorsolateral PFC (DLPFC) and anterior PFC (APFC) (P < 0.05, blue arrows). Orange arrows denote task information input (C) into the system. Black arrows denote significant task-modulated effective connectivity (n = 24 healthy control subjects and n = 17 patients with schizophrenia, P < 0.05). (B) Task-modulated connectivity during C in normal control subjects and patients with schizophrenia from (1) dorsolateral PFC to anterior PFC; (2) dorsolateral PFC to parietal cortex; (3) parietal cortex to dorsolateral PFC; (4) dorsolateral PFC to midbrain; and (5) parietal cortex to midbrain. *P < 0.05, **P < 0.005. (C) Reduced task-modulated connectivity during C in patients with schizophrenia with significant delusions (n = 7 versus 10, P < 0.05). (D) When processing feedback favouring the change decision (F), patients had increased task-modulated dorsolateral PFC–midbrain and parietal cortex–midbrain effective connectivity (P < 0.05, red arrows). (E) Task-modulated connectivity during F in normal control subjects and patients with schizophrenia from (1) dorsolateral PFC to anterior PFC; (2) anterior PFC to dorsolateral PFC; (3) dorsolateral PFC to parietal cortex; (4) dorsolateral PFC to midbrain; and (5) parietal cortex to midbrain. (F) Relatively increased task-modulated dorsolateral PFC to midbrain connectivity during F in patients with schizophrenia with significant delusions (n = 7 versus 10, P < 0.05). NC = normal control subjects.

Figure 7

Controls and unaffected siblings' activations in regions-of-interest during Experiment 2. Encoding in working memory of two numbers in the familiar number-line sequence (A) versus the opposing less expected sequence (B) in healthy control subjects (NC; n = 37) and unaffected siblings (SIB, n = 36). Regions of interest were extracted from robustly activated regions (P < 0.05 FWE corrected) centred at the same anterior PFC (1: −46 44 12) and midbrain (2: −4 −18 −8) regions differentially engaged in Experiment 1. Analogous to the findings in Experiment 1, unaffected siblings engaged relatively increased midbrain activation (P < 0.05) while processing numbers in the expected number line sequence (A), but engaged relatively reduced anterior PFC processing in the less pre-potent number sequence (B).