Gray-matter abnormalities in deficit schizophrenia

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Abstract

Deficit schizophrenia (D-SZ) has been proposed as a putative disease subtype defined by prominent, primary negative symptoms that endure as trait-like features during periods of clinical stability. In this study, we acquired magnetic resonance images of the whole brain using a 1.5 T scanner in 19 outpatients with D-SZ, 31 with non-deficit schizophrenia (ND-SZ), and 90 healthy adults. Voxel-based morphometry was used to investigate differences in regional gray-matter volume (GMV) between outpatients with D-SZ and ND-SZ, and between the combined patient subgroups and healthy adults. Compared to healthy adults outpatients with schizophrenia showed GMV reductions, especially in left frontal and temporal cortices and in the left insula. The D-SZ subgroup showed reduced GMV in the insula bilaterally and in the left superior frontal, middle temporal and occipital gyri. Regions in which GMV reductions best distinguished D-SZ from ND-SZ patients included the superior frontal gyrus (Brodmann area 8) and superior temporal gyrus (Brodmann areas 22, 38) bilaterally, the left supplementary motor area (Brodmann area 6), left anterior cingulate, left cuneus and right putamen. These results suggest that patients with deficit schizophrenia have brain abnormalities that differ from those of patients with non-deficit schizophrenia. Further, the neuroanatomic differences between these two putative subtypes of schizophrenia involve brain regions that appear to be associated with the negative symptoms that define the deficit syndrome of schizophrenia.

Introduction

Schizophrenia is a clinically heterogeneous disease. The deficit syndrome (D-SZ) has been proposed as a putative subtype defined by prominent, primary negative symptoms that endure as trait-like features during periods of clinical stability (Carpenter et al., 1988). Efforts to validate the deficit syndrome have found that patients with D-SZ differ from patients with non-deficit schizophrenia (ND-SZ) in several respects. These include gross brain structure (Kirkpatrick et al., 2000), although the specific findings vary across studies. Using a traditional region-of-interest analysis, Buchanan et al. (1993) found that D-SZ patients had greater prefrontal white matter volume than ND-SZ patients, but the groups did not differ in prefrontal gray-matter volume. Turetsky et al. (1995) also found no relationship between frontal lobe volume and primary negative symptoms, but they did find association with decreased volume in the temporal lobes. Quarantelli et al. (2002) found that D-SZ patients had fewer structural brain abnormalities than ND-SZ patients when compared to healthy controls (HC). They found that the ND-SZ group had larger right-hemisphere ventricles than the D-SZ group. No group differences were found in the frontal lobe. Other researchers found structural abnormalities to be more prevalent in D-SZ when compared to HC, particularly in left frontal, temporal and limbic structures and related white matter tracts (Sigmundsson et al., 2001) using another automated morphometric method.

In a previous study, we found that patients with D-SZ and ND-SZ did not differ in most respects on cognitive testing after controlling for demographic background (Cascella et al., 2008). This suggests that cognitive deficits, as currently assessed, may not contribute to the definition of D-SZ as a categorical entity separate from ND-SZ. Other factors might better distinguish these subtypes, including differences in brain structure.

In an effort to further investigate qualitative vs. quantitative differences in brain structure between D-SZ and ND-SZ, the present study investigated regional gray-matter volume (GMV) in healthy controls, patients with D-SZ, and patients with ND-SZ. We conducted four comparisons. First, we compared healthy adults with a combined group of patients with schizophrenia to verify that our sample show the same patterns of neuroanatomic abnormalities found by other investigators. Next, we compared our healthy controls to the D-SZ and ND-SZ subgroups separately. Finally, we compared the D-SZ and ND-SZ groups directly. We hypothesized that, compared to healthy adults, patients with D-SZ would show greater regional reductions in GMV than patients with ND-SZ. We further hypothesized that the D-SZ group would show reduced regional GMV relative to patients with ND-SZ.

Section snippets

Participants

Fifty adults with schizophrenia, diagnosed according to criteria of the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV) (American Psychiatric Association and American Psychiatric Association Task Force on DSM-IV, 1994) participated in the study. Of these, 19 were recruited for a study of apathy in schizophrenia and traumatic brain injury and constitute the D-SZ group (the Apathy study), 31 out of a total of 38 were recruited for a study of structural neuroimaging

Demographic and clinical characteristics

Table 1 shows the demographic and clinical characteristics of the study samples. Patients with D-SZ were significantly younger than ND-SZ patients and HCs. They also completed fewer years of schooling than HCs (11.8 vs. 13.9 years) but not fewer years of schooling than the ND-SZ patients (12.2). The male/female ratio did not differ between the two patient subgroups, but there were fewer female patients than female HCs. The D-SZ and ND-SZ patients did not differ in number of previous psychiatric

Discussion

Our study shows that when a categorical distinction is made between deficit and non-deficit patients with schizophrenia, the gray-matter abnormalities of deficit patients appear to be concentrated in areas previously associated with negative symptoms of schizophrenia. Results of this critical comparison were unidirectional: GMV reductions were observed only in the ND-SZ > D-SZ analysis. Patients with ND-SZ showed no areas of significantly GMV reduction relative to patients with D-SZ.

There were

Role of funding source

Funding for this study was provided by a NARSAD Young Investigator Award, NIH grants MH60504, MH43775 and MH071473 and by the Stanley Medical Research Institute. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

NG Cascella, Vani Rao and DJ Schretlen designed the study and wrote the protocol. S Fieldstone analyzed the imaging and demographic data. A Sawa and G Pearlson contributed to the analyses and interpretation of the data. NG Cascella wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

Dr. Schretlen receives royalties for the Brief Test of Attention. All the other authors have no conflict of interest to report.

Acknowledgement

We thank Miss Yukiko Lema who assisted with the preparation and proof-reading of the manuscript.

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