Review
Neurological soft signs as candidate endophenotypes for schizophrenia: A shooting star or a Northern star?

https://doi.org/10.1016/j.neubiorev.2008.01.005Get rights and content

Abstract

The crucial role of neurological indicators in schizophrenia has been recognized as among the “target features” that encompass the idea that genetic and non-genetic processes lead to neurointegrative defects later manifested in neurocognitive systems. In addition, aberrant neurological indicators have also been suggested as potential endophenotypes in schizophrenia. In the current paper, we review evidence for the utility of quantifiable neurological soft signs as potential endophenotypes for schizophrenia spectrum disorders. We start by defining endophenotypes and justifying their utility. We highlight the key criteria that must be met for an endophenotype to be useful and assess the extent to which the manifestations of neurological soft signs meet these criteria. Finally, we recommend areas in which additional research should be done to further elucidate the potential use of neurological soft signs for schizophrenia research.

Introduction

Incontrovertible evidence for epidemiological genetic influences on schizophrenia has been accumulated since the 1960's (Rosenthal and Kety, 1968, McGuffin et al., 2004). However, the identification of specific genes with large effect sizes that contribute to a susceptibility to schizophrenia has not been successful using conventional molecular genetic approaches. As schizophrenia has failed to show monogenic forms and has no specific molecular or cellular markers, research at this time implicates several chromosomal regions (e.g., 1q, 8p, 22q, 2, 3, 5q, 6p, 11q, 13q, and 20p; Owen et al., 2003) that, in turn, embed several genes that have been associated with the illness, including DISC 1 (Chubb et al., 2007, Hennah et al., 2007), catechol-O-methyl transferase (Egan et al., 2001a, Shifman et al., 2002), dysbindin (Schwab et al., 2003, Turunen et al., 2007), G72 (Chumakov et al., 2002), neuregulin 1 (Stefansson et al., 2002), and RGS4 (regulator of G protein-signaling-4) (Chowdari et al., 2002, Talkowski et al., 2006). Psychiatric diagnoses are likely to have heterogeneous etiologies in that not all people with the same diagnosis carry the same assembly of susceptibility genes (Faraone et al., 1999, Sing et al., 2003, Pan et al., 2006).

On the other hand, the completion of human genome sequencing is the driving force to understand the genetic contribution to schizophrenia spectrum disorders by identifying variants associated with the disorders (Mitchell, 2002). For example, SchizophreniaGene (www.szgene.org) has been developed by Lars Bertram and colleagues at Harvard Medical School and Massachusetts General Hospital to systematically collect and synthesize the genetics data published in peer-reviewed journals. Unfortunately, despite the complete human genome data, we are still unable to specify precisely the phenotypes (the readily observed symptomatic manifestations of the genotypes such as hallucination and delusions in schizophrenia) in those individuals whose genomes we investigate. Therefore, researchers have been adopting a new direction that identifies neurobiological and neurobehavioural characteristics associated with schizophrenia, so-called “endophenotypes” (Gottesman and Gould, 2003, Gottesman and Shields, 1972) that may be more closely connected to the expressions of un-named genes (Bray et al., 2008).

A substantial number of studies, especially of at-risk offspring, have suggested that neurocognitive dysfunctions are among the most promising of the candidate endophenotypes. This view is most clearly understood within the neurodevelopmental framework (Erlenmeyer-Kimling et al., 2000, Cornblatt and Malhotra, 2001). Others (Chen and Faraone, 2000, Lenzenweger, 2006, Prescott and Gottesman, 1993) suggest that genetic vulnerability to schizophrenia may often manifest itself in schizophrenia-like personality disorders, e.g., schizotypal, rather than a full syndrome of schizophrenia. Thus, the proposed endophenotypic markers should also present in many persons with schizotypal personality disorder and their close relatives if it is in the schizophrenia spectrum.

Several candidate endophenotypic markers have been proposed such as sustained attention (Cannon et al., 2000, Cannon et al., 2001, Chen and Faraone, 2000, Cornblatt and Malhotra, 2001, Egan et al., 2000), visual working memory (Cannon et al., 2000, Park et al., 1995), verbal memory (Goldberg et al., 1995, Chen et al., 2000a, Chen et al., 2000b), and inhibitory control (Cadenhead et al., 2002). Comparison of the commonality and differences of endophenotypes has also been suggested among schizophrenia, depression, and ADHD (e.g., Flint and Munafo, 2007). Most recently, a multi-centre initiative, the Consortium on the Genetics of Schizophrenia (COGS), has been launched to examine the commonly identified cognitive and imaging endophenotypes of schizophrenia (Braff et al., 2007, Greenwood et al., 2007, Gur et al., 2007a, Gur et al., 2007b). However, it is still yet not fully known whether various domains of cognitive functioning reflect the presence of one underlying global cognitive deficit, or whether they independently represent a discrete cognitive risk factor that is transmitted in families of patients with schizophrenia (cf. Glahn et al., 2007, Palo et al., 2007, Straub et al., 2007).

Here, we review evidence for the utility of quantifiable neurological soft signs as potential endophenotypes for schizophrenia spectrum disorders. We define endophenotypes and justify their utility by reviewing evidence from molecular genetic studies that schizophrenia is a complex phenotype. We summarize the literature concerning the clinical significance and meaning of neurological soft signs in schizophrenia. We then highlight the key criteria that must be met for an endophenotype to be useful and assess the extent to which the manifestations of neurological soft signs meet these criteria. Finally, we recommend areas in which additional research should be conducted to further elucidate the potential use of neurological soft signs and related minor physical anomalies for schizophrenia research.

Section snippets

What is an endophenotype?

The term “endophenotype” was first described for psychopathology as an internal phenotype, i.e., not obvious to the unaided eyes, that fills the gap between symptoms and the putative genes that actualize the elusive disease processes of schizophrenia and other psychiatric disorders (Gottesman and Shields, 1972, 1973). The endophenotypes may be any neurobiological measures or indicators (Meehl, 1990) related to the underlying molecular genetics of the illness, including biochemical,

Why is endophenotype useful for schizophrenia?

There are several potential advantages to the endophenotype approach (Braff et al., 2007, Greenwood et al., 2007) to study the etiology of schizophrenia: (1) physiological and more elementary neural-based endophenotypes may more directly reflect the activities of synaptic and other neuronal mechanisms than does the more complex illness itself, and therefore they are more likely to reflect genes with larger effect sizes; (2) both the patients and their unaffected relatives may show a fairly

Neurological signs as the target features and indicators of schizophrenia

Neurological signs have previously been classified as “hard” vs. “soft” signs. The former refers to impairments of basic motor and sensory behaviour such as signs for the pyramidal system (Woods et al., 1991) and extrapyramidal system (Roger, 1992, Schroder et al., 1991, Simpson and Angus, 1970). The latter conventionally refers to non-localizing neurological abnormalities that cannot be related to impairment of a specific brain region or are not believed to be part of a well-defined

Categorization of neurological soft signs

A major issue concerning research on neurological soft signs in schizophrenia is the classification of soft signs and the instruments used for the evaluation. There are several rating scales developed for the measurement of neurological soft signs, including the Woods Scale (Smith et al., 1999a, Smith et al., 1999b), Rossi Scale (Rossi et al., 1990), Heidelberg Scale (Schroder et al., 1992b), Cambridge Neurological Inventory (Chen et al., 1995), and the Neurological Evaluation Scale (Buchanan

The criteria for endophenotypes

Researchers have proposed from three to five criteria, for useful endophenotypes with regard to schizophrenia and other psychiatric disorders (Gottesman and Shields, 1972, 1973; Tsuang et al., 1993, Cornblatt and Malhotra, 2001, Gottesman and Gould, 2003, Gould and Gottesman, 2006). Although there is no universally agreed-upon definition or evaluation of a promising endophenotype, all share and highlight several key elements in the inclusion criteria (Glahn et al., 2007). These are summarized

Structural imaging studies on neurological signs in schizophrenia

Only a few studies of chronic schizophrenic patients have investigated the anatomical substrates of neurological soft signs. The presence of neurological soft signs has been associated with an enlargement of cerebral ventricles (Weinberger and Wyatt, 1982), and with smaller brain areas (DeMyer et al., 1988), whereas no correlation has been found between neurological soft signs and the calculated ratio between the width of the ventricles and the brain (Kolakowska et al., 1985).

For the

Genetic modeling studies

An endophenotype-based approach has the potential to assist in the genetic dissection of psychiatric diseases. Meyer-Lindenberg and Weinberger (2006) illustrate that there are at least two fungible equivalents for endophenotypes as tools for schizophrenia. In the gene discovery approach, the deficiencies in the electrophysiological response to auditory stimulation were used to identify an association of schizophrenia with the α 7 nicotinic cholinergic receptor (Freedman et al., 1997).

Conclusions

In this paper, we argue that the clinical manifestations of elicited or measured neurological soft signs can be considered to be among the candidate neurological and cognitive endophenotypes for schizophrenia. We provide substantial evidence to support the claims that neurological soft signs, motor coordination in particular, meet many of the criteria discussed above to evaluate the suitability of the presence of neurological soft signs as endophenotypes for schizophrenia. However, there are

Acknowledgements

The authors would like to thank R. Walter Heinrichs for his constructive comments on the previous versions of this paper and Todd Gould for his help in finalizing the figure illustrating neurological soft signs as another candidate endophenotype for schizophrenia. The preparation of the paper was supported partially by the Research Initiation Fund of the 100-scholar Plan (O7CX031003), a grant from Institute of Psychology, Chinese Academy of Sciences (KSCX2-YW-R-131) and a grant from the

References (172)

  • L. Flyckt et al.

    Neurological signs and psychomotor performance in patients with schizophrenia, their relatives and healthy controls

    Psychiatry Research

    (1999)
  • T.E. Goldberg et al.

    Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder

    Schizophrenia Research

    (1995)
  • G. Goldstein et al.

    The effects of antipsychotic medication on factor and cluster structure of neurological examination abnormalities in schizophrenia

    Schizophrenia Research

    (2005)
  • D. Gourion et al.

    Neurological and morphological anomalies and the genetic liability to schizophrenia: a composite phenotype

    Schizophrenia Research

    (2004)
  • W. Gunther et al.

    Brain dysfunction during motor activation and corpus callosum alterations in schizophrenia measured by cerebral blood flow and magnetic resonance imaging

    Biological Psychiatry

    (1991)
  • G. Hasler et al.

    Toward constructing an endophenotype strategy for bipolar disorders

    Biological Psychiatry

    (2006)
  • B. Ismail et al.

    Neurological abnormalities in schizophrenia: clinical, etiological and demographic correlates

    Schizophrenia Research

    (1998)
  • B. Ismail et al.

    Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates

    Journal of Psychiatric Research

    (2000)
  • B.D. Kelly et al.

    Neurological soft signs and dermatoglyphic anomalies in twins with schizophrenia

    European Psychiatry

    (2004)
  • C. Arango et al.

    Prediction of neuropsychological performance by neurological signs in schizophrenia

    American Journal of Psychiatry

    (1999)
  • C. Arango et al.

    Neurological signs and the heterogeneity of schizophrenia

    American Journal of Psychiatry

    (2000)
  • S. Bachmann et al.

    Neurological soft signs in first-episode schizophrenia: a follow-up study

    American Journal of Psychiatry

    (2005)
  • S. Bender et al.

    Which perspectives can endophenotypes and biological markers offer in the early recognition of schizophrenia?

    Journal of Neural Transmission

    (2007)
  • R.M. Bilder et al.

    Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration

    Schizophrenia Bulletin

    (1992)
  • D. Bolton et al.

    Neurological signs in obsessive compulsive disorder: standardized assessment and comparison with schizophrenia

    Behavioural Neurology

    (1998)
  • D. Bolton et al.

    Neurological soft signs in obsessive compulsive disorder: standardised assessment and comparison with schizophrenia

    Behavioural Neurology

    (2000)
  • M.P. Boks et al.

    Neurological soft signs discriminating mood disorders from first episode schizophrenia

    Acta Psychiatrica Scandinavica

    (2004)
  • I. Bombin et al.

    Assessment tools for soft signs

    Psychiatric Annals

    (2003)
  • I. Bombin et al.

    Significance and meaning of neurological signs in schizophrenia: two decades later

    Schizophrenia Bulletin

    (2005)
  • D.L. Braff et al.

    Deconstructing schizophrenia: an overview of the use of endophenotypes in order understand a complex disorder

    Schizophrenia Bulletin

    (2007)
  • N.J. Bray et al.

    cis- and trans-Loci influence expression of the schizophrenia susceptibility gene DTNBP1

    Human Molecular Genetics

    (2008)
  • S. Browne et al.

    Determinants of neurological dysfunction in first episode schizophrenia

    Psychological Medicine

    (2000)
  • S.F. Candela et al.

    NSS in schizophrenia: research findings and clinical relevance

    Psychiatric Annals

    (2003)
  • K.S. Cadenhead et al.

    Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype

    American Journal of Psychiatry

    (2002)
  • T.D. Cannon et al.

    Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies

    American Journal of Medical Genetics

    (2001)
  • T.D. Cannon et al.

    The genetic epidemiology of schizophrenia in a Finnish twin cohort: a population-based modeling study

    Archives of General Psychiatry

    (1998)
  • E.W. Cantor-Graae et al.

    Are neurological abnormalities in schizophrenic patients and their siblings the result of perinatal trauma?

    Acta Psychiatrica Scandinavica

    (2000)
  • E. Cantor-Graae et al.

    Are neurological abnormalities in well discordant monozygotic co-twins of schizophrenic subjects the result of perinatal trauma?

    American Journal of Psychiatry

    (1994)
  • R.C.K. Chan et al.

    Blink rate does matter: a study of sustained attention and neurological signs in schizophrenia

    Journal of Nervous and Mental Disease

    (2004)
  • R.C.K. Chan et al.

    Executive dysfunctions and neurological manifestations in schizophrenia

    Hong Kong Journal of Psychiatry

    (2004)
  • R.C.K. Chan et al.

    Neurological abnormalities in Chinese schizophrenic patients

    Behavioural Neurology

    (2007)
  • R.C.K. Chan et al.

    A study of sensitivity of the sustained attention to response task in patients with schizophrenia

    Clinical Neuropsychologist

    (2004)
  • Chan, R.C.K., Chen, E.Y.H., Cheung, E.F.C., Chen, R.Y.L., Cheung, H.K., 2004. Prediction of neurological signs by...
  • Chan, R.C.K., Chen, E.Y.H., Wang, Y., Cheung, E.F.C., Chen, R.Y.L., Cheung, H.K. Contribution of neuropsychological...
  • Chan, R.C.K., Wang, L., Wang, Y., Manschreck, T.C. Neurological soft signs and their relationships to neurocognitive...
  • E.Y. Chen et al.

    Progressive deterioration of soft neurological signs in chronic schizophrenic patients

    Acta Psychiatrica Scandinavica

    (2000)
  • R.Y.L. Chen et al.

    Soft neurological signs in schizophrenic patients and their nonpsychotic siblings

    Journal of Nervous and Mental Diseases

    (2000)
  • E.Y.H. Chen et al.

    Neurological signs, age, and illness duration in schizophrenia

    Journal of Nervous and Mental Diseases

    (1996)
  • E.Y.H. Chen et al.

    Negative symptoms, neurological signs and neuropsychological impairments in 204 Hong Kong Chinese patients with schizophrenia

    British Journal of Psychiatry

    (1996)
  • E.Y.H. Chen et al.

    Neurological signs, age and illness duration in schizophrenia

    Journal of Nervous and Mental Diseases

    (1996)
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