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Review
, 36 (1), 294-315

Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

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Review

Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

Philip R Corlett et al. Neuropsychopharmacology.

Abstract

Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects' previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

Figures

Figure 1
Figure 1
Baseline neural responses predict the psychotogenic effects of ketamine. (a) The N-Back working memory task, the circuitry it engages, and the relationship between thalamic responses during working memory performance under placebo and ketamine-induced negative symptoms. (b) CPT, the circuitry it engages and the relationship between inferior frontal gyrus responses to the task under placebo and ketamine-induced negative symptoms. (c) Sentence Completion Task, the circuitry it engages, and the relationship between task-induced responses in middle temporal gyrus acquired under placebo and ketamine-induced thought disorder. (d) The Auditory Verbal Monitoring Task, the circuitry it engages, and the relationship between task-induced responses in inferior frontal gyrus captured under placebo and auditory illusory responses engendered by ketamine. (e) The Associative Causal Learning Task, the circuitry it engages, and the relationship between prediction error responses in right frontal cortex and perceptual aberrations induced by ketamine.
Figure 2
Figure 2
A model of the reciprocal relationships between inference and learning, priors and prediction error, synaptic plasticity and neural dynamics. Inference is encapsulated in the bistable percepts of the Necker Cube, that is, when faced with ambiguous inputs, the brain entertains multiple hypotheses and makes an inference as to the best candidate. The powerful effect of learning on perception is captured by the hollow mask illusion, wherein, as a result of our overwhelming experience with faces as convex, we perceive a hollow, concave, inverted mask as convex. All predictions, or hypotheses that we entertain, have a likelihood distribution, which we compare with the inputs, computing: a prediction error; a degree of uncertainty associated with that prediction error. We speculate that fast neurotrasnmitters (GABA and glutamate) may code the prediction error and slower neuromodulators (eg, dopamine and acetylcholine, depending on the task and underlying circuitry) may compute the uncertainty.
Figure 3
Figure 3
The putative effects of acute and chronic ketamine treatment within the Bayesian model. We predict that, with repeated ketamine exposure, aberrant learning (due to deranged synaptic plasticity) and subsequent inappropriate inferences (based on perturbed neural dynamics) lead to maladaptive and inaccurate representations of the world; delusional beliefs.
Figure 4
Figure 4
Potential synaptic processes in health, acute, and chronic ketamine exposure. (a) ‘Health'—In the absence of psychotomimetic drugs, information processing at a glutamatergic synapse involves glutamate release from a presynaptic cell (regulated by NMDA receptors and mglurs), which is incident upon a postsynaptic cell. The number and functionality of postsynaptic receptors on that cell, as well as the tone of slower, nuromodulatory inputs, for example, dopamine and acetylcholine, set the ‘prior' (how much stimulation to expect) and the uncertainty (the level of confidence ascribed to that particular input), respectively. Glial cells regulate the reuptake of synaptic glutamate and its cycling back into the presynaptic cell, also under the control of NMDA and mglur receptors, as well as slower neuromodulators (like noradrenaline). (b) Acute ketamine—It blocks NMDA receptors, thus impairing the specification of prior expectancies. It has transient effects on slower neuromodulators, such as acetylcholine, thus affecting inference processes and vitiating perception and cognition. Crucially for the model at hand, ketamine administration increases presynaptic glutamate release (via effects on glial glutamate reuptake and noradrenergic signaling), and as such, AMPA receptors are excessively and inappropriately stimulated. Thus, prediction errors are registered inappropriately inducing delusion-like ideation as aberrant or inappropriate inference; an attempt to make sense of uncertain experiences. (c) Chronic ketamine—With chronic exposure, there is a compensatory increase in the number and function of NMDA receptors. However, glial glutamate reuptake remains impaired and there is a sensitization of slower dopaminergic inputs (eg, to medium spiny neurons in the striatum). As such, the delusion-like ideas characteristic of the acute phase become crystallized as new learning, that is, a new prior.

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