Variables influencing conditioning-evoked hallucinations: overview and future applications

Abstract

Hallucinations occur in the absence of sensory stimulation and result in vivid perceptual experiences of nonexistent events that manifest across a range of sensory modalities. Approaches from the field of experimental and cognitive psychology have leveraged the idea that associative learning experiences can evoke conditioning-induced hallucinations in both animals and humans. In this review, we describe classical and contemporary findings and highlight the variables eliciting these experiences. We also provide an overview of the neurobiological mechanisms, along with the associative and computational factors that may explain hallucinations that are generated by representation-mediated conditioning phenomena. Through the integration of animal and human research, significant advances into the psychobiology of hallucinations are possible, which may ultimately translate to more effective clinical applications.

The role of midbrain dopamine cells projecting to the insular cortex in mediated performance: Implications for animal models of reality testing.

“…These limitations aside, our data extend the findings of previous studies, which have leveraged mediated learning procedures as a tool for examining reality testing in animal models of schizophrenia (see Fry et al, 2022, for an extensive discussion). We know that animals that receive neonatal ventral hippocampal lesions (McDannald et al, 2011), chronic administration of N-methyl-D-aspartate receptor antagonists (Koh et al, 2018; Wu et al, 2020), phospholipase C ß1 knockdown (Kim & Koh, 2016), or transgenic expression of DISC-1 (Fry et al, 2020) have been shown to display enhanced susceptibility to impaired reality testing.…”

“…Further, we show that inactivation of this circuit is sufficient to yield impaired reality testing in wild-type mice, adding yet more evidence to point toward insular dysfunction as an area of interest for researchers looking to explore novel drug targets for treatment in schizophrenia. These studies add to a small but growing body of literature attempting to investigate the neurobiology of positive symptomology in animal models (Fry et al, 2022) as well as further our understanding of the neurobiological impacts following perturbations of the DISC-1 genetic locus. Future work with a continued focus on revealing circuit-specific pathways to impaired reality testing in animal models will be invaluable as we strive toward the ultimate goal of improving treatment modalities for humans with schizophrenia.…”

“…Alternatively, despite being tested with unflavored water in mediated performance testing, the animal displays a pattern of responding consistent with the detection of sweet-tasting stimuli. More recently, evidence has accrued to suggest that these associative learning paradigms have utility for modeling psychotic-like symptoms in animals (Busquets-Garcia et al, 2017; Fry et al, 2022; Kim & Koh, 2016; Koh et al, 2018; McDannald & Schoenbaum, 2009; McDannald et al, 2011). This includes recent work from our laboratory using transgenic mice expressing the dominant-negative form of the gene Disrupted-in-Schizophrenia–1 (DISC-1; Fry et al, 2020).…”

Devaluing memories of reward: A case for dopamine

“…Alternatively, given our approach intersects appetition and aversion, it is possible that we are engaging a heterogeneous population of dopamine cells that include those that respond to high intensity sensory stimuli and are aversive when stimulated 59 . In addition to uncovering novel mechanisms of dopamine action in learning, our studies are relevant to neuropsychiatric endophenotypes of reality testing 60 , and could be leveraged as a tool to attenuate ingestive behavior 61 and substance abuse 62 through dampening, via mesencephalic DA manipulations, the memories associated with reward.…”

Prediction, perception, and psychosis: Application of associative learning theories to schizophrenia research.

“…Interestingly, the expression of conditioned hallucinations and mediated conditioning, at least when involving a palatable food as an absent event, is also transient in that the effect is better obtained with a limited rather than an extended amount of training (e.g., Holland, 1998, 2005, Holland et al, 2008. Importantly, the enhanced processing of absent food in the animal models of schizophrenia is often observed in the form of its maintenance in the animal models and its reduction in control animals during extended training (e.g., Busquets-Garcia et al, 2017;Fry et al, 2020Fry et al, , 2022Kim & Koh, 2016; see also Kim & Koh, 2021, for a corresponding pattern of changes in neural activations).…”