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.

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.

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.

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.