Elsevier

Biological Psychiatry

Volume 46, Issue 7, 1 October 1999, Pages 908-920
Biological Psychiatry

Schizophrenia Research Series: Phenomenology and Pathophysiology
Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms

https://doi.org/10.1016/S0006-3223(99)00152-3Get rights and content

Abstract

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical–thalamic–cerebellar–cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Introduction

Research on schizophrenia pursues an elusive and difficult target. There are several reasons for this. First, there is no objective marker for the disorder that is analogous to plaques and tangles in Alzheimer’s disease. Therefore, we lack both obvious neural clues as to its mechanism and a confirmatory indicator that we are studying the correct phenotype (or individual case). Second, the phenotype that we study is almost universally said to be “heterogeneous.” Clinically, this means that symptoms vary from patient to patient, sometimes with no overlap, providing us with a significant challenge as we attempt to explain why we refer to both an affect-laden paraphrenic and an emotionally impoverished hebephrenic as suffering from “schizophrenia.” Third, efforts to define biologically meaningful “subtypes” have been unsuccessful. The search for the neural mechanisms of symptoms that apparently reflect disorders in variable domains of mental functions (hallucinations/auditory perception, “thought disorder”/language, etc.) is fragmented, tending to focus on one aspect of the disorder while ignoring others (e.g., accounting for hallucinations by invoking the temporal lobe but failing to explain why delusions or various negative symptoms are also present).

Because of the potential power of new technologies—whether they are molecular or systems level—to ultimately solve the riddle of schizophrenia and provide information about etiology, pathophysiology, or improved treatments, the definition of the phenotype and the characteristic symptoms are crucial research questions. At the end of the second millenium, we can actually imagine that some time during the next century we will understand the complex genetics and the equally complex gene–environment interactions leading to the complex biologic processes that ultimately produce the disease we call “schizophrenia.” Paradoxically, however, we are in less agreement about what we should actually call schizophrenia than we are about the best methods to study it. The definition of the phenotype to be studied with our powerful and promising new technologies remains one of the most pressing questions in schizophrenia research.

Our research on the definition of schizophrenia has been grappling with classic questions in psychopathology for many years: What are the characteristic symptoms? What are the boundaries of the disorder? What are its subtypes? What is the characteristic longitudinal course? What is the link between the clinical presentation and its underlying neural mechanisms? Should one begin by studying the clinical presentation (the phenomenotype) or some specific group of biologic markers (the biotype)? How can such a complicated clinical picture be explained parsimoniously? Andreasen 1979a, Andreasen 1979b, Andreasen 1979c, Andreasen 1982, Andreasen 1983, Andreasen 1984, Andreasen 1985a, Andreasen 1985b, Andreasen 1986, Andreasen 1987, Andreasen et al 1994b, Andreasen et al 1990a, Andreasen et al 1991, Andreasen et al 1995c, Andreasen et al 1997b, Andreasen et al 1995a, Andreasen et al 1995b, Andreasen et al 1997a.

The first and last of these questions address different facets of the clinical heterogeneity of this illness. Its diversity of symptoms, which suggests a diversity of disease processes, is perhaps its most intellectually challenging feature. Patients grouped together in our minds as “suffering from schizophrenia” may range from having prominent delusions and intensely angry affect to extremes of apathy, disinterest, and disorganization. There are three types of competing explanatory models for the apparent heterogeneity: the categorical subtypes model, the dimensional model, and the unitary model Andreasen and Carpenter 1993, Andreasen et al 1997b, Armstrong et al 1995, Andreasen and Flaum 1994, Crespo Faccaro and O’Leary 1999.

When faced with diversity of clinical presentation, most investigators instinctively search for discrete subtypes. Early categorical approaches, such as the classical Bleulerian/Kraepelinian subtypes, are still widely accepted and are frequently used in daily practice, although they have little objective validation using standard indicators such as familial aggregation, response to treatment, or neurobiologic measures. Crows Type I/Type II schema, or our own division into positive/mixed/negative subtypes, are examples of a more recent approach that attempted to unite clinical (e.g., course, symptom patterns) and neurobiologic (e.g., VBR) information in a single model Andreasen 1982, Andreasen 1985b, Andreasen et al 1994b, Andreasen et al 1990a, Crow 1980a, Crow 1985, DeGreef et al 1991. This strategy was highly generative for research in schizophrenia during the 1980s, but ultimately its explanatory powers were challenged by the need to divide patients into mutually exclusive groups, when in fact most had both positive and negative symptoms cross-sectionally and also showed a tendency to change or evolve when assessed longitudinally (Marneros et al 1991).

A more recent strategy for researching the psychopathology of schizophrenia is the development of dimensional approaches. While categorical approaches tend to follow the medical model and to classify patients into groups, dimensional approaches rely more on the measurement techniques developed in psychology and biometrics. Dimensional approaches divide symptoms into groups and identify properties that can co-occur within individual patients. Investigators have applied this model intensively during the recent decade, using correlational and factor analytic techniques to examine the interrelationships between positive and negative symptoms. The majority of these studies suggest that three dimensions account for the interrelationships among the symptoms of schizophrenia Andreasen and Grove 1986, Andreasen et al 1994b, Andreasen et al 1995b, Arndt et al 1991, Arndt et al 1996, Bilder et al 1985, Brown and White 1992, Gur et al 1991, Kulhara et al 1986, Lenzenweger et al 1989, Liddle 1987, Miller et al 1993, Minas et al 1992, Moscarelli et al 1987, Peralta et al 1992, Schuldberg et al 1990. The positive symptoms subdivide into two dimensions, a psychosis dimension and a disorganization dimension, while negative symptoms make up the third dimension.

Factor analytic studies only demonstrate a statistical relationship, however. Further work is needed to validate the dimensions and to demonstrate that they in fact have clinical or biologic meaning. Some work from our group and others has suggested that the three dimensions may have different functional neural substrates as seen with PET, different structural brain correlates as evaluated with MRI, and different and independent longitudinal courses (Andreasen et al 1995c, Andreasen et al 1997c, Andreasen et al 1996b, Arndt et al 1995, Flaum et al 1995, Gur and Pearlson 1993, Gur et al 1994, Gur et al 1991, Liddle 1996, Miller et al 1993; O’Leary et al, unpublished data). These efforts have, however, also demonstrated some of the weaknesses of the dimensional approach. The temptation to turn dimensions back into categories and to “localize” them seems nearly irresistible. Ultimately, we must explain how a process could occur that would produce temporal (i.e., psychotic) and frontal (i.e., negative) lesions in some patients and different patterns in others, and how these lesions could somehow exacerbate and remit over time. The dimensional approach has difficulty explaining how these cross-sectional and longitudinal patterns could occur.

A unitary model offers a newer alternative. This approach, which looks back to the historical position of Bleuler (1950), stresses that there is a single unifying theme to the concept of schizophrenia that permits us to identify clinically diverse patients as possessing the same phenotype. This unitary model, following Bleuler, suggests that the symptoms of schizophrenia are not primary but rather, are secondary to a more fundamental problem in a basic cognitive process. Bleuler, working within the context of the association psychology of his time, suggested that the fundamental cognitive problem in schizophrenia was “loosening of associations.” A more modern unitary model would posit neural misconnections created by aberrant brain development that leads in turn to a fundamental cognitive deficit in a process that shapes all aspects of cognition, emotion, and behavior Andreasen 1997b, Andreasen et al 1992. A heuristic unitary model would, therefore, attempt to identify a cognitive abnormality that could explain the clinical diversity of schizophrenia and would be shared by all patients diagnosed as suffering from schizophrenia. The heuristic unitary model we are currently exploring is that schizophrenia is a single illness with a single phenotype. The phenotype is not defined on the basis of symptoms, as is currently done in most studies and as is taught by the DSM approach. Instead, the phenotype is defined by a fundamental cognitive abnormality that in turn causes the diversity of symptoms with which patients present.

The “neo-Bleulerian” unitary model views schizophrenia as a neurodevelopmental and cognitive disorder. It posits cumulative negative gene–environment interactions as the etiology and resultant abnormalities in brain development (defined as continuing into early adulthood) as the pathophysiology. This model is clearly similar to the “multiple hit” model that shapes most current cancer research. The development of schizophrenia occurs as a consequence of multiple etiological factors (e.g., genetic regulation of brain development, environmental influences such as toxins) that lead to a shared pathophysiology and neurobiology in all people who have schizophrenia: problems in brain development from the time of conception to early adult life, which lead to disruptions in anatomic and functional connectivity. These neural “misconnections” in turn are expressed as abnormalities in basic and secondary cognitive processes and ultimately, as symptoms such as hallucinations, delusions, alogia, or avolition.

Section snippets

What do we mean by “neurodevelopmental”?

Neurodevelopmental mechanisms of schizophrenia are often discussed, but the term is rarely defined. The distinction between development and degeneration is challenging because the brain appears to be in a continual process of change from the moment of conception to the moment of death. At what point does this dynamic process change from one of growth and maturation to one of deterioration and decline? How does one distinguish a neurodevelopmental disorder from a neurodegenerative disorder?

What is the fundamental cognitive deficit?

As recently reviewed (Andreasen 1997a), several other investigators suggest that schizophrenia may be best defined in terms of cognitive abnormalities, although the unitary nature of their models has been implicit rather than explicit [e.g., Braff (1993) and abnormalities in information processing, Goldman-Rakic (1988) and representationally guided behavior, or Frith et al (1995) and the inability to think in metarepresentations]. Clearly, the return to Bleuler and a search for a fundamental

What are the neural mechanisms of synchrony and cognitive dysmetria?

In the motor system, synchrony of movement occurs as a consequence of very rapid on-line processing and feedback between the sensory-motor cortex and the cerebellum, mediated through the thalamus. This feedback loop permits constant checking and updating of input and output at the nanosecond level, and facilitates the rapid and smooth execution of complex motor acts such as hitting a baseball or catching a pass in football. Because this feedback loop encompasses multiple nodes that extend

What is the evidence for CCTCC dysfunction in schizophrenia?

Evidence for CCTCC dysfunction in schizophrenia was recently reviewed in an overview article (Andreasen et al 1998). Investigators have been interested in the prefrontal cortex in schizophrenia for many years, and consequently, there is substantial data supporting the (now) relatively crude concept of “hypofrontality,” using both structural and functional imaging techniques (e.g., Andreasen et al 1986, Andreasen et al 1994a, Andreasen et al 1994c, Andreasen et al 1997c, Andreasen et al 1997d,

How does cognitive dysmetria explain the symptoms of schizophrenia?

Although schizophrenia is not usually considered to be a “motor disease,” many indicators of motor dysfunction are present, suggesting that the basic abnormality in the disorder could be a brain system that mediates both motor and cognitive functions. Kraepelin described a variety of motor abnormalities in his classic textbook (Kraepelin et al 1919). Slowed reaction time is one of the oldest and most robust tests showing differences between schizophrenic patients and normal control subjects

Acknowledgements

This research was supported in part by NIMH Grants MH31593, MH40856, and MHCRC43271; a Research Scientist Award, MH00625; and an Established Investigator Award from NARSAD.

This work was presented at the conference, “Schizophrenia: From Molecule to Public Policy,” held in Santa Fe, New Mexico in October 1998. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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