Neurological soft signs and gray matter changes: A longitudinal analysis in first-episode schizophrenia

Abstract

Neurological soft signs (NSS) – i.e. discrete deficits of sensory and motor function – are frequently found in schizophrenia and vary with psychopathological symptoms in the course of the disorder. Hence, persistence of NSS herald chronicity in first episode schizophrenia. To investigate the cerebral correlates of persisting NSS over time, 20 patients with first-episode schizophrenia underwent T1 magnetic resonance imaging (MRI) after remission of the acute symptoms and after 1 year of follow-up. NSS were rated on the Heidelberg Scale. Twenty age- and gender-matched control subjects were scanned once. Longitudinal gray matter (GM) changes were measured by using tensor based morphometry (TBM). At follow-up, patients demonstrated significantly decreased NSS scores. For further analysis, the patient sample was dichotomized into patients with decreasing NSS scores and patients with persistently increased scores, respectively. While patients with decreasing NSS exhibited only localized changes within the left frontal lobe, cerebellum, and cingulate gyrus, patients with persistently increased scores showed pronounced GM reductions of the sub-lobar claustrum, cingulate gyrus, cerebellum, frontal lobe, and middle frontal gyrus. Results were confirmed after correction for multiple comparisons. These findings support the hypothesis that persisting NSS refer to progressive cerebral changes in first-episode schizophrenia. Since NSS can be assessed in any clinical environment, this association facilitates the prospect that NSS can help to establish prognosis in first-episode patients with schizophrenia.

Introduction

Neurological soft signs (NSS) refer to subtle neurological abnormalities in motor coordination, sensory integration, and sequencing of complex motor acts (Heinrichs and Buchanan, 1988) and are frequently found in patients with schizophrenia. NSS are associated with psychopathological symptoms and thus decrease with remission of the acute illness. In turn, persisting NSS herald chronicity in schizophrenia (Schröder et al., 1992a, Schröder et al., 1999, Bachmann et al., 2005). These effects also apply to first-episode schizophrenia and support the notion that NSS may serve as an endophenotype (Schröder et al., 1992b, Schröder et al., 1999, Whitty et al., 2003, Bachmann et al., 2005, Chan and Gottesman, 2008). Endophenotypes are markers of a complex disease. They may consist of physiological, neuropsychological or other quantifiable traits which are intermediate between genes and overt symptomatology. As endophenotypes are less complex than phenotypes, they may pave the way towards the respective genes (Gottesman and Gould, 2003, Gottesman and Hanson, 2005).

Studies with magnetic resonance imaging (MRI) identified that pre- and postcentral gyrus, inferior frontal gyrus, premotor area, cerebellum, caudate, and thalamus are related to NSS (Schröder et al., 1992b, Dazzan et al., 2004, Thomann et al., 2009b, Heuser et al., 2011). A decreased fMRI BOLD effect in the sensorimotor cortices – which comprise the pre- and postcentral gyri – and supplementary motor area was related to motor NSS, in particular to finger-to-thumb opposition and pronation–supination (Schröder et al., 1995, Schröder et al., 1999, Kodama et al., 2001). The vast majority of the structural MRI studies used voxel-based morphometry to localize cerebral changes associated with NSS (for a review see Heuser et al., 2011). These associations, however, need to be confirmed by longitudinal studies, which will reduce the confounding effect of intraindividual morphological variability by using each subject as his or her own control.

Previous longitudinal studies described independent changes of NSS and gray matter (GM) during the course of schizophrenia (Madsen et al., 1999, Bachmann et al., 2005, Kim et al., 2005, Whitford et al., 2006, Mané et al., 2009). However, the potential associations between NSS and GM changes over time have not yet been investigated simultaneously. The results of cross-sectional studies cited above lead to the hypothesis that regional cerebral changes are related to NSS abnormalities in patients with schizophrenia.

To test this hypothesis, we used a subsample of an earlier study on NSS (Bachmann et al., 2005) which was analyzed with tensor based morphometry (TBM) according to Kipps et al. (2005), a recently available method to test for longitudinal changes in cerebral morphometry. Morphometric data and NSS as assessed after remission of acute symptoms and 1 year of follow-up were thus studied in 20 patients with first-episode schizophrenia.