Molecular Psychiatry (2011) 16, 129–144 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp PERSPECTIVE Hierarchical temporal processing deficit model of reality distortion and psychoses RR Krishnan1, M Fivaz2, MS Kraus3 and RSE Keefe3 1Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; 2Program in Neuroscience and Neurobehavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore and 3Medical Psychology, Duke University Medical Center, Durham, NC, USA We posit in this article that hierarchical temporal processing deficit is the underlying basis of reality distortion and psychoses. Schizophrenia is a prototypical reality distortion disorder in which the patient manifests with auditory hallucinations, delusions, disorganized speech and thinking, cognitive impairment, avolition and social and occupational dysfunction. Reality distortion can be present in many other disorders including bipolar disorder, major depression and even dementia. Conceptually, schizophrenia is a heterogeneous entity likely to be because of numerous causes similar to dementia. Although no single symptom or set of symptoms is pathognomonic, a cardinal feature in all patients with schizophrenia is chronic distortion of reality. The model that we have proposed accounts for the varied manifestations of reality distortion including hallucinations and delusions. In this paper we consider the implications of this model for the underlying biology of psychoses and also for the neurobiology of schizophrenia and suggest potential targets to consider for the etiology and pathophysiology of reality distortion, especially in the context of schizophrenia. Molecular Psychiatry (2011) 16, 129–144; doi:10.1038/mp.2010.63 Keywords: hierarchical; model; schizophrenia; genes; molecular; symptom Introduction more than half of all the cases. Although no single symptom or set of symptoms is pathognomonic, a Reality distortion can be a feature of many psychiatric cardinal feature in all patients is chronic distortion of disorders such as mood disorders, delirium, dementia reality. While reality distortion can also be found in and schizophrenia. The prototypical disorder with other psychiatric states such as mania, depression, reality distortion is schizophrenia. Schizophrenia is a dementia and delirium, the ongoing presence of disorder in which the patient manifests with auditory severe reality distortion over time without an accom- hallucinations, delusions, disorganized speech and panying mood disorder is most generally associated thinking, cognitive impairment, avolition and social with the diagnosis of schizophrenia. and occupational dysfunction. Conceptually, schizo- There are many hypotheses regarding the potential phrenia is a heterogeneous and clinically diverse causes of schizophrenia, including genetic,2 viral,3 entity likely to be because of numerous causes similar neurotransmitters such as dopamine4 or interactions to dementia. The diagnosis of schizophrenia is made between neurotransmitters5 or brain structural on the basis of a varied set of characteristic signs and anomalies.6 Most of these hypotheses do not account symptoms. Oulis et al.1 investigated the lifetime for how or why these presumed causes lead to the fulfillment of five sub-criteria of the primary diag- manifestations of reality distortion in schizophrenia. nostic criterion in inpatients with a definite diagnosis They are also unidimensional and limited. We of Diagnostic and Statistical Manual of Mental recently posited that schizophrenia is the result of Disorders, fourth edition schizophrenic disorder. impairment of hierarchical temporal processing by Among the five diagnostic features captured by the brain.7 The model that we have proposed criterion A, only delusions were found to be almost accounts, in particular, for reality distortion. The universal, whereas of the remaining four, only hierarchical temporal deficit is a fundamental trait hallucinations and negative symptoms occurred in that may be a better target for the study of etiology and pathophysiology than any one of the clinical syn- Correspondence: Dr RR Krishnan, Department of Psychiatry and dromes with which reality distortion is associated. In Behavioral Sciences, Duke University Medical Center, Box 3950, this paper, we extend our discussion to consider the 4584 South Hospital, White Zone no. 45, Durham, NC 27710, implications of this model for the underlying biology USA. E-mail: [email protected] of reality distortion and psychoses and by extension Received 29 June 2009; revised 14 March 2010; accepted 8 April for the neurobiology of schizophrenia and suggest 2010 potential targets to consider for the etiology of this Hierarchical processing and schizophrenia RR Krishnan et al 130 illness. A key to begin to make sense of psychoses and 4. Each hierarchy level remembers frequently ob- reality distortion is to understand perception and served temporal sequences of input patterns and memory prediction. generates labels (assigns meaning) or constructs for these sequences. Perception 5. Each hierarchy level is capable of storing freq- uently observed sequences of patterns and devel- The classical notion of perception is to conceptualize oping invariant representations. it as similar to recording of the world as it is. But 6. When an input sequence matches a preexisting perception is not unidirectional. Vision is not the same sequence at a given layer of the hierarchy, a construct as a movie recording. It is not a bottom-up reconstruction is propagated up the hierarchy—thus eliminating of sensory input. Information in the visual world cannot details at higher levels and enabling them to learn be mapped unambiguously back onto real-world sources. higher-order inferences. But when there is no match Similar perceptual processes exist in the other sensory between input and preexisting sequences, a more modalities. Perceptual processes therefore involve sys- complete representation propagates upward. tems of inferring by matching multisensory input to a 7. Higher levels predict future input by matching 8 construct that serves as a working model of the world. partial sequences and projecting their future Helmholtz proposed that the raw ‘sensations’ generated expectations to the lower levels. by the physiological infrastructure of the eye and the 8. Higher levels of the cortical hierarchy predict the input stages of the visual brain are interpreted by future on a longer time scale, and over a wider range information derived from experience. Helmholtz de- of sensory input. Lower levels interpret limited scribed this process as making ‘unconscious inferences’ domains. about reality. More recently, Purves proposed that 9. Connections from the higher level states predis- percepts are simply subjective sensations that link pose selected transitions in the lower-level state. stimuli to the empirical significance of their sources 10. The model of the external world that is built according to the success or failure of prior stimuli-guided consists of the sum of a person’s invariant 9 behavior. ‘The conceptual basis of this alternative constructs/memories and the preexistent evolu- approach is that the percept elicited by any particular tionary configuration. This model is updated to stimulus parameter corresponds not to a statistically accommodate new experiences within the frame- determined value of the relevant qualities in the physical work of its preexisting structure. world but rather to the relative frequency of occurrence 11. As we interpret the world, the higher cortical areas of that particular stimulus parameter in relation to all are constantly comparing current circumstances to other instances of that parameter experienced in the invariant memory stores to form predictions about 9 past’. An approach similar in principle to that used to the next moment of experience (memory prediction) rationalize the percepts elicited by visual stimuli can be or more likely as posited by Purves9 about the used to explain why we hear the tones the way we do. In likelihood of the successful behavior or response. either case the key element is recognition and learning; These predictions set the stage for perception by the percepts are generated by the interaction of bottom-up priming levels likely to be activated by the bottom-up sensory input and top-down expectation of the meaning sensory signals. The overall model posits that the of the input. Hawkins suggested that this is best nature of the output from a given area of cortex explained as a hierarchical process and suggests that depends on coincidence with the patterns of the 10 this is the general operating principle of the brain. bottom-up input it is receiving at any given time. When a person is in a new situation and is Framework experiencing stimuli that do not clearly fit any top- down hypotheses derived from previous experience, The framework for understanding processing that we a given area of cortex relays the details of the patterns have outlined is an integration of what Hawkins has it receives to higher cortical areas; that is, the signals proposed with an additional axiom that humans are born are passed on to the next highest layer and this with a certain set of neural structures and functions pattern extends till a match is achieved. In this way, that help us navigate the world. These structures as a situation becomes more familiar, the representa- and functions form the basic