The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity

Abstract

Schizophrenia is a severe psychiatric disorder affecting 21 million people worldwide. People with schizophrenia suffer from symptoms including psychosis and delusions, apathy, anhedonia, and cognitive deficits. Strikingly, schizophrenia is characterised by a learning paradox involving difficulties learning from rewarding events, whilst simultaneously ‘overlearning’ about irrelevant or neutral information. While dysfunction in dopaminergic signalling has long been linked to the pathophysiology of schizophrenia, a cohesive framework that accounts for this learning paradox remains elusive. Recently, there has been an explosion of new research investigating how dopamine contributes to reinforcement learning, which illustrates that midbrain dopamine contributes in complex ways to reinforcement learning, not previously envisioned. This new data brings new possibilities for how dopamine signalling contributes to the symptomatology of schizophrenia. Building on recent work, we present a new neural framework for how we might envision specific dopamine circuits contributing to this learning paradox in schizophrenia in the context of models of reinforcement learning. Further, we discuss avenues of preclinical research with the use of cutting-edge neuroscience techniques where aspects of this model may be tested. Ultimately, it is hoped that this review will spur to action more research utilising specific reinforcement learning paradigms in preclinical models of schizophrenia, to reconcile seemingly disparate symptomatology and develop more efficient therapeutics.

Latent inhibition, aberrant salience, and schizotypy traits in cannabis users

“…This adds to a growing body of evidence supporting the potential for variation in LI performance to represent a surrogate marker to detect the core psychological disturbance that increases the risk for conversion to a full-blown psychotic disorder (Granger et al, 2020). It has been suggested that mesolimbic dopaminergic hyperfunction drives maladaptive associative learning across the early trajectory of the illness ( Kätzel et al, 2020 ; Millard et al, 2021 ), with the limited efficacy of antipsychotics, which act via D2 receptor blockade, relating to insufficient targeting to reverse aberrant salience processing and the psychological impact of years of maladaptive associate learning processes ( Kätzel et al, 2020 ). This hypothesis and supporting data highlight the potential for early intervention that would be tailored to modification of the mechanisms of salience allocation.…”

Smoking as a Common Modulator of Sensory Gating and Reward Learning in Individuals with Psychotic Disorders

“…Evidence that both aspects of PRT performance correlated with the P50 ratio and were modulated by smoking in similar ways supports the notion that rather than being pathophysiologically distinct processes, these processes likely overlap to some extent in terms of their underlying mechanisms. Predictive coding theories [ 1 ] and recent integrative models of psychosis emanating from these theories [ 2 , 3 ] provide us with a possible explanation for this link. Predictive coding theory suggests that reward learning and sensory gating are both critically reliant on more general aspects of prediction and prediction error, with recent neurobiological frameworks positioning phasic striatal dopamine firing as the key aberration-driving deficits in prediction error signaling in psychosis [ 2 , 3 ].…”

“…Predictive coding theories [ 1 ] and recent integrative models of psychosis emanating from these theories [ 2 , 3 ] provide us with a possible explanation for this link. Predictive coding theory suggests that reward learning and sensory gating are both critically reliant on more general aspects of prediction and prediction error, with recent neurobiological frameworks positioning phasic striatal dopamine firing as the key aberration-driving deficits in prediction error signaling in psychosis [ 2 , 3 ]. This has important implications for how we understand the disparate symptoms of psychosis, like anhedonia and auditory hallucinations.…”

“…Through this lens, motivational and perceptual disturbances may be conceptualized as arising from faulty prediction and/or prediction error signals. Accordingly, rather than being pathophysiologically distinct, motivational and perceptual disturbances may be governed by a common learning mechanism (for a review, see [ 2 ]), perhaps arising from aberrant phasic striatal dopamine signaling [ 3 ]. However, to date, empirical studies examining associations between motivational and perceptual disturbances in the same individuals are lacking.…”

“…For example, neuroimaging meta-analyses show that compared to controls, individuals with psychotic disorders exhibit abnormal striatal reward prediction error signals and reduced ventral striatal activation during anticipation of reward [ 7 ]. Although the mechanisms underpinning these disturbances are still unclear, findings of abnormally increased striatal dopamine synthesis, storage, and release in individuals with psychosis, relative to healthy controls [ 8 ], have led to the hypothesis that elevated levels of striatal dopamine may disrupt the phasic dopamine burst firing that supports prediction errors signals [ 3 , 9 ].…”