Failures in Learning-Dependent Predictive Perception as the Key Cognitive Vulnerability to Psychosis in Schizophrenia

Cognitive deficits present in almost all patients with schizophrenia, and account for considerable functional disability, but as typically measured in schizophrenia are unrelated to hallucinations and delusions. The absence of this relationship may be caused in part by the lack of an organizing principle of psychosis-related cognitive impairment. Most studies of cognition in schizophrenia involve standard neuropsychological tests that were devised for measuring brain injury in patients with no previous relevant illness. Human perception, thought and action—the basic elements of maintaining reality—are based upon a hierarchical process that conjoins memory and external stimuli, which we refer to as learning-dependent predictive perception. We propose that impairments in this elemental process lead to psychosis in patients with schizophrenia.

The hierarchical model posits that the nature of the output from a given area of cortex depends on temporal coincidence with the patterns of the bottom-up input it receives. If an individual experiences stimuli that do not clearly fit any top-down hypotheses derived from previous experience, a given area of cortex relays the details of the patterns it receives to higher cortical areas; the signals are passed on to the next highest layer and this pattern extends until a match is achieved. As a situation becomes more familiar, the representations of a given level of analysis are shifted to lower cortical areas, freeing higher areas for the detection of high-level patterns. The correct identification of objects, sensations, and processes in the environment is thus based upon probabilistic prediction determined by the accumulation of memories of how the perceptual world is organized and how it operates (Hawkins and Blakeslee, 2004; Purves et al, 2001).

We hypothesize that in schizophrenia, the formation and storage of invariant representations at higher hierarchical levels is insufficient. The higher levels do not provide enough input to lower levels for solving the nature of stimuli, and the lower levels do not provide adequate perceptual details to enable a sufficient establishment of perceptual context (Kraus et al, 2009). Thus, simple information must be sent repeatedly to higher levels for more effortful interpretation. Reduction in the correct identification of percepts in the context of real-world information-processing demands, affords the opportunity for arbitrary internally generated interpretations of reality to intrude upon perception and thought, leading to an accumulation of inaccurate but internally meaningful perceptions that may build upon one another into incorrect beliefs. This failed process may be at the core of the development of hallucinations and delusions. Context-based perceptions of real objects and real events are reduced in favor of an interpretation of reality that is individually determined and disconnected from the experiences and beliefs shared by others. This, we hypothesize, is the mechanism behind the development of delusions and hallucinations in patients with schizophrenia.

Recent work supports this concept (Javitt, 2009). Patients with schizophrenia have great difficulty in perceiving visual objects among noise and are unable to identify incongruous events in a virtual reality context. Although few studies have addressed whether these cognitive impairments precede the onset of psychosis, there have been some confirming data. Individuals who are soon to develop psychosis experience the perception of more elaborate sequences of verbal stimuli in auditory noise conditions (Hoffman et al, 2007). Cognitive paradigms that measure an individual's ability to distinguish percepts from noise based upon context have particular promise for identifying impairments in learning-dependent predictive perception (Koethe et al, 2009).

Richard Keefe, PhD reports that he currently or in the past 12 months has received investigator-initiated research funding support from the National Institute of Mental Health, Allon, GlaxoSmithKline, Novartis, Department of Veteran's Affairs, and the Singapore National Medical Research Council. He currently or in the past 12 months has received honoraria, served as a consultant, or advisory board member for Abbott, BiolineRx, BrainCells, BMS, Cypress Bioscience, Dainippon Sumitomo Pharma, Eli Lilly, EnVivo, Lundbeck, Merck, Pfizer, Roche, Shire, Solvay, and Takeda. Dr Keefe receives royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the MATRICS Battery (BACS Symbol Coding). He is also a shareholder in NeuroCog Trials.

Michael Kraus has no disclosures to report.

Ranga Krishnan, MD reports that he has holdings in Orexigen and indirect holdings in Cenerx. He has consulted for Amgen, BMS, CeNeRx, Corcept, Eisai, GSK, J&J, Lundbeck, Merck, Organon, Pfizer, Spracor, and Wyeth in the past 12 months.